VIP-RELATED PEPTIDES FOR THE TREATMENT OF SKIN DISORDERS

Abstract: The present invention relates to pharmaceutical compositions for the treatment of skin disorders comprising as active ingredient VIP-related peptides. It has been shown by the present invention that the compositions disclosed and claimed induce cell apoptosis and therefore may be used particularly for the treatment of skin disorders associated with hyperproliferation of skin cells. The present invention also provides a method for the treatment of hyperproliferative skin disorders and/or for inducing cell apoptosis, the method involving administration to the skin area to be treated a therapeutically effective amount of the VIP-related peptide.

Description: VIP-RELATED PEPTIDES FOR THE TREATMENT OF SKIN DISORDERS FIELD AND BACKGROUND OF THE INVENTION The present invention relates to compounds, pharmaceutical compositions and methods for treating skin disorders and for inducing cell apoptosis. More particularly, the present invention relates the treatment of skin conditions associated with hyperproliferation of skin cells, which involves topical administration of lipophilized, vasoactive intestinal peptide (VIP), VIP- derived peptides and conjugates thereof (all referred to herein in the specification as "VIP-related peptides"), optionally with other substances traditionally used in the art for the treatment of such skin disorders. Additionally, a method for the induction of apoptosis in cells is disclosed, by subj ecting the cells to the VIP-related peptides . Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP), are members of a family of regulatory peptides that includes secretin and glucagon [1]. VIP, a basic 28-amino acid peptide, has been established as a modulator of growth, survival and differentiation in many cell systems, including the brain, the gastro-intestinal tract, lung and immune cells, of both primary origin and cancerous one [1]. Two possible therapeutical uses of modified, shortened and/or lipophilically derivatized VIP of agonistic nature have been reported in the art by the present applicants. IL Patent No. 87055 (corresponding to EP Patent No. 0354992 and U.S. Patent No. 5,147,855) and IL Patent No. 99924 (corresponding to EP Patent No. 0540969 and U.S. Patent No. 5,998,368) teach the treatment of male impotence by transdermal administration [13] of modified, shortened and/or lipophilically derivatized VIP, whereas EP Patent No. 0620008 and U.S. Patent No. 5,972,883 teach the treatment of neurodegenerative diseases by preferably intranasal administration of modified, shortened and/or lipophilically derivatized VIP. Natural VIP is a hydrophilic amidated peptide characterized by a very short half life in the serum and having the following sequence: His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met- Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (SEQ ID NO: 1) In order to enhance the biological availability and increase the stability of VIP, Gozes et al. have resorted to two chemical modifications, reported in the above listed patents, all of them incorporated herein by reference as if fully disclosed herein. The first is lipophilization, namely, the addition of a fatty acid moiety, designed to augment VTP's ability to penetrate biological membranes without loss of activity. Thus, Stearoyl-VIP (SEQ ID NO: 2), a molecule combining VIP with stearic acid moiety at its N-terminal was designed (see EP Patent No. 0354992). The second modification includes the replacement of native amino acids with unnatural amino acids, namely, a substitution of methionine (at position 17) by norleucine, aimed at stabilizing the molecule against oxidation, as well as at increasing its lipophiliciry. Thus, Stearoyl-Nle^-VIP, referred to herein as SNV (SEQ ID NO: 3), was designed ([2], EP 0540969). Indeed, this super analog exhibited a 100- fold potency as was compared to natural VIP in promoting neuronal survival [14, 15], through a cGMP-associated mechanism [16]. Gozes et al. have further developed a VIP antagonist that has proven useful for altering the function of the vasoactive intestinal peptide. To this end, see, for example, U.S. Patent No. 5,217,953 issued to Goze.? et al. This VIP antagonist was designed to retain the binding properties of natural VIP for its receptor, but to lack the amino acid sequence necessary for biological activity. It is believed that biological activity requires, among other factors, a phenylalanme residue at position 6. Amino acids 1-6 of natural VIP were, therefore, replaced by an amino acid segment derived from neurotensin, in order to alter the biological activity of natural VIP and to change the membrane permeability of the peptide. As such, the VIP antagonist developed by Gozes et al. is a hybrid molecule containing an amino acid sequence necessary for VTP receptor binding (i.e., amino acids 7-28 of VIP), and an N-terminal amino acid sequence corresponding to a portion of neurotensin (neurotensin amino acids 6-11). Studies have shown that this VIP hybrid antagonist, neurotensin 6 . π VIP 7 . 28 , which is referred to herein also as VHA (SEQ ID NO: 4), effectively antagonizes VTP-associated activities [18,19]. More particularly, it has been found that VHA inhibits the growth of VIP receptor bearing tumor cells such as, for example, lung tumor cells (i.e., NSCLC cells). To this end see U.S. Pat. No. 5,217,953 and references [20-22]. U.S. Pat. No. 5,565,424 issued to Goz&y et al. discloses another family of lipophilized polypeptides, which are antagonists of VIP. The VIP antagonists disclosed therein are 10-1000 times more efficacious, i.e., more potent in inhibiting VTP-associated activity, than previous VIP antagonists [14, 18]. These superactive VIP antagonists were shown to inhibit cancer growth of lung [23] and glioblastoma cells. An example of such a superactive VIP antagonist is the conjugate referred to herein as SNH, Stearoyl-neurotensin 6. j j VIP 7 . 28 (SEQ ID NO: 5). While seeking a therapeutic application, it is in many cases desirable to design smaller molecules, able to mimic the parent peptide activity, because (i) such molecules more readily penetrate through biological membranes and other biological barriers; and (ii) are characterized by lesser potential enzymatic degradation sites, resulting in enhanced bioavailability. In PCT application WO 97/40070 by Gozes et al. novel conjugates including a lipophilic moiety and a peptide sequence of 3-12 amino acids derived from VIP are disclosed. Sequences located at the VIP C-terminus, and specifically, the conjugate based on VIP's amino acids 20-23, Stearoyl-KKYL-NH2 (SEQ ID NO: 6), was identified as the core active site of VIP, responsible for the neuroprotective effects reported for VTP/SNV [27]. In addition to the above mentioned activities, VIP effects have also been documented for skin cells [3], and VIP has been directly implicated in keratinocyte proliferation [6,7,8], the major cell type in the epidermis [4]. The epidermis is a continually renewing tissue, where homeostasis is maintained by factors that influence the interrelated processes of keratinocytic life cycle, with apoptosis which serves as a mechanism for cell number control. Premature, excessive or deficient apoptosis have all been linked to homeostatic dysregulation characteristic of various skin disorders [12], such as disorders of the hyperproliferative type, including, but not limited to, basal cell carcinomas, disorders of keratinization, e.g., keratosis, various dermatoses, dandruff and psoriasis. Psoriasis, for example, is a chronic skin condition of the epidermis, diagnosed by itchy, scaling, erythematous lesions. The disease is a major cause of disability and disfigurement for between 1 to 3% of the World's population. Psoriasis conditions can range from mild to severe. In the United States, between 150,000 and 250,000 new cases of psoriasis are diagnosed each year, with about 40,000 of these cases classified as severe. This disease is characterized by a hyperproliferation of the basal cells (a several fold increase in the number of basal cells of the epidermis), thus reducing the turnover time of the epidermis from the normal 27 days to 3-4 days. This shortened interval prevents normal cell maturation and keratinization, reflected in an array of abnormal morphologic and biochemical changes. Numerous cytologic, histologic, histochemical, and biochemical alterations are known to be the result, rather than the cause, of the disease process. A number of diverse pharmacologic and other therapies have been tried for psoriasis, with varying degrees of success. These include topical use of corticosteroids (e.g., triamcinolone and hydrocortisone creams); keratolytic/destractive agents, such as anthralin or salicylic acid; lubricants, such as hydrogenated vegetable oils and white petroleum; oral retinoids, vitamin D analogs and tar based therapies. For certain patients with generalized psoriasis, it has been useful to use a variety of systemic chemotherapeutic agents, especially the antimetabolite methotrexate and the immunosuppressant cyclosporine. Photochemotherapy was introduced in 1974, the so-called PUVA treatment. This treatment consists of administering psoralen prior to partial or whole body irradiation with a special light system that emits predominately long wavelength ultraviolet light (UV-A). However, current psoriasis treatments, as well as other treatments known for hyperproliferative skin disorders, such as skin cancer, suffer from one or more deficiencies, including potential toxic side effects and achieving only temporary relief. Furthermore, because of the distressing and disfiguring nature of hyperproliferative skin disorders, there is a considerable interest in developing novel therapeutic approaches for treating these disorders. The present invention fulfills these and other needs. SUMMARY OF THE INVENTION Thus, in accordance with the teachings of the present invention there are provided compounds, pharmaceutical compositions and methods for treating skin disorders and for inducing cell apoptosis. Vasoactive intestinal peptide (VIP) is a recognized growth factor affecting many cell types. A series of lipophilic VIP analogues containing an N-terminal covalently attached stearoyl moiety was previously described. The current invention teaches of VIP derived conjugates, and specifically, Stearoyl- Nle 17 VIP (SNV), and Stearoyl-Nle 17 -neurotensin 6 .nVIP 7 . 28 (SNH), acting at μM concentrations, as cytotoxic agents for human keratinocytes. The core C- terminal active VTP-derived peptide, Stearoyl-Lys-Lys-Tyr-Leu-NH2 (St- K YL-NH2, SEQ ID NO:6), is further described as being responsible for the observed cytotoxicity. Cytotoxicity coincided with marked reduction in intracellular cGMP and was abolished by co-treatment with the endonuclease inhibitor, aurintricarboxylic acid (ATA), indicating apoptotic mechanisms. According to one aspect of the present invention there is provided a method for treating a hyperproliferative skin disorder of a patient, the method 5 comprising the step of administering to a skin area of the patient a therapeutically effective amount of a VIP-related peptide. According to further features in preferred embodiments of the invention described below, the method further comprising the step of administering a therapeutically effective amount of a substance traditionally used for treatment l o of the hyperproliferative skin disorder. According to another aspect of the present invention there is provided a method of inducing cell apoptosis, the method comprising the step of subjecting cells to a VIP-related peptide. According to yet another aspect of the present invention there is 15 provided a pharmaceutical composition for treating a hyperproliferative skin disorder comprising, as active ingredients, therapeutically effective amounts of a VIP-related peptide and a substance traditionally used for treatment of the hyperproliferative skin disorder. According to further features in preferred embodiments of the invention ό described below, the VIP-related peptide includes an amino acid sequence identified by SEQ ID NO:7. According to still further features in the described preferred embodiments the VIP-related peptide includes at least one non-natural amino acid. 5 According to still further features in the described preferred embodiments the at least one non-natural amino acid is selected from the group consisting of a D amino acid, norleucine, norvaline, α-aminobutyric acid, di- amino butyric acid, di-aminopropionic acid, -HN(CH2)nCOOH, wherein n is 3-5, -NH(CH 2 (R))n-COOH, wherein R is an alkyl, H 2 N(CH 2 ) m COOH,0 wherein m is 2-4, H 2 N-C(NH)-NH(CH2)kCOOH, wherein k is 2-3, hydroxy lysine, N-methyl lysine, ornitine, p-amino phenylalanine, TIC, naphthylelanine, a ring-methylated derivative of phenylalanine, a halogenated derivative of phenylalanine or o-methyl-ryrosine. According to still further features in the described preferred embodiments the VIP-related peptide includes at least one peptide-bond modification. According to still further features in the described preferred embodiments the at least one peptide-bond modification is selected from the group consisting of -N(CH3)-CO-, -C(R)H-C-0-0-C(R)-N-, -CO-CH 2 -, -NH- N(R)-CO-, wherein R is any alkyl, -CH 2 -NH-, -CH(OH)-CH2-, -CS-NH-, - CH=CH-, -NH-CO- and peptide derivatives -N(R')-CH2~CO-, wherein R' is a natural side chain. According to still further features in the described preferred embodiments the VIP-related peptide includes a cyclic peptide moiety. According to still further features in the described preferred embodiments the VIP-related peptide includes a lipophilic moiety. According to still further features in the described preferred embodiments the lipophilic moiety is selected from the group consisting of a saturated alkyl a branched alkyl, a non-saturated alkyl, a non-branched alkyl, a saturated acyl, a branched acyl, a non-saturated acyl and a non-branched acyl. According to still further features in the described preferred embodiments th invention provides a pharmaceutical composition for the treatment of hyperproliferative skin disorders comprising a pharmaceutically acceptable carrier and as active ingredient a VIP-related peptide selected from the group consisting of: (i) vasoactive intestinal peptide (VIP) (ii) a VIP antagonist (iii) a peptide analog of (i) or (ii) in which one or more amino acids has been replaced, added or deleted without substantially altering the biological properties of the parent peptide; (iv) a physiologically active fragment of (i), (ii) or (iii); (v) a physiologically active fragment of (i) coupled to a fragment of pituitary adenylate cyclase activating peptide (PACAP) and a peptide analog thereof in which one or more amino acids has been replaced, added or deleted; (vi) a conjugate of (i) to (v) coupled at the amino and/or the carboxy terminal to a C 1 -C 4 hydrocarbyl, C 1 -C 4 carboxylic acyl or to a lipophilic moiety; and (vii) a functional derivative of any of (i) to (vi). In one embodiment, the composition comprises VIP, of the sequence; His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn In another embodiment, the composition comprises a VIP antagonist, of the sequence: Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn In a further embodiment, the composition comprises an analog of VIP in which one or more amino acids has been replaced, of the sequence: His-Ser-Asp-Ala-X^Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-X 2 -Ala-X 3 -Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn wherein X 1 , X 2 and X 3 are the same or different and each is the residue of a natural or non-natural amino acid, provided that when both X 1 and X 3 are valine, X 2 is not methionine. In still another embodiment, the composition comprises an analog of a VIP antagonist in which one or more amino acids has been replaced, of the sequence: Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-Y^Ala-Y^Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn wherein Y 1 and Y 2 are the same or different and each is the residue of a natural or non-natural amino acid, provided that Y 2 is not methionine. The groups X 1 , X 2 and X 3 , and Y l and Y 2 , may be the same or different and each may be a natural amino acid selected from the group consisting of leucine, isoleucine, valine, tryptophan, phenylalanine and methionine, or a non- natural amino acid is selected from the group consisting of a D-amino acid, norleucine (Nle), norvaline, α-aminobutyric acid, di-amino butyric acid, di- aminopropionic acid, -HN(CH2) n COOH, wherein n is 3-5, -NH(C H 2(R))n- COON, wherein R is an alkyl, H2N(CH2)m . COOH, wherein m is 2-4, H 2 N- C(NH)-NH(CH2)kCOOH, wherein k is 2-3, hydroxy-lysine, N-methyl-lysine, ornitine, p-amino-phenylalanine, methyl-phenylalanine, halo-phenylalanine, naphthyl- alanine, TIC, o-methyl-tyrosine, octahydroindole-2-carboxylic acid, cyclohexyl- glycine and cyclopentylglycine.. In still a further embodiment, the pharmaceutical composition comprises a physiologically active fragment of VIP or of an analog thereof, having a sequence selected from the group consisting of: (i) X 4 -X 5 -X 6 -X 7 -NH-R2 (ii) X 8 -Ser-X 9 -Leu-Asn (iii) CH 2 -CO-Lys-Lys-Tyr-X 10 -MH-CH-CO-X n -NH 2 I I (CH 2 ) m Z (CH 2 ) n (iv) X 13 -NH-CH-CO-X 12 -Ser-X 9 -Leu-Asn-NH-CH-CO-NH 2 I I (CH 2 )m Z (CH 2 ) n wherein X 4 is a covalent bond, Ala, Val, Ala-Val, Val-Ala, Lys, D-Lys, Ala-Lys, Val-Lys, Ala-Val-Lys, Val-Ala-Lys or Orn; X 5 is L-Lys, D-Lys or Orn; X 6 is L-Tyr, D-Tyr, Phe, Trp or a residue of p-amino-phenylalanine; X 9 is lie or Tyr; W X 10 is a residue of a hydrophobic aliphatic amino acid; X 7 is X 10 , X 10 -Asn, X 10 -Ser, X 10 -Ile, X 10 -Tyr, X 10 -Leu, X 10 -Nle, X 10 -D- Ala, X 10 -Asn-Ser, X 10 -Asn-Ser-Ile, X 10 -Asn-Ser-Tyr, X 10 -Asn-Ser-Ile-Leu, X 10 -Asn-Ser-Tyr-Leu, X 10 -Asn-Ser-Ile-Leu-Asn or X 10 -Asn-Ser-Tyr-Leu-Asn; X 8 is a covalent bond, Asn, X 10 , X 10 -Asn, Tyr-X 10 , Tyr-X 10 -Asn, Lys- X 10 , Lys-X 10 -Asn, Lys-Tyr-X 10 , Lys-Tyr-X 10 -Asn, Lys-Lys-Tyr-X 10 , Lys-Lys-Tyr-X 10 -Asn, Val-Lys-Lys-Tyr-X 10 , Val-Ala-Lys-Lys-Tyr-X 10 -Asn or Ala-Val-Lys-Lys-Tyr-X 10 -Asn; X 11 is a covalent bond, Asn, Ser, He, Tyr, Leu, Asn-Ser, Asn-Ser-Ile, Asn-Ser-Tyr, Asn-Ser-Ile-Leu, Asn-Ser-Tyr-Leu, Asn-Ser-Ile-Leu-Asn or Asn- Ser-Tyr-Leu-Asn; X 12 is a covalent bond or Asn; X 13 is a covalent bond, X 10 , Tyr, Lys, Tyr-X 10 , Lys-X 10 , Lys-Tyr-X 10 , Lys-Lys-Tyr-X 10 , Val-Lys-Lys-Tyr-X 10 , Ala-Lys-Lys-Tyr-X 10 , or Ala-Val-Lys- Lys-Tyr-X 10 ; Z is -CONH-, -NHCO-, -S-S-, -S(CH 2 )tCO-NH- or -NH-CO(CH2)tS-; m is 1 or 2 when Z is -CONH-, -S-S- or -S(CH2)tCO-NH-, or m is 2, 3 or 4 when Z is -NH-CO- or -NH-CO(CH2)tS-; n is 1 or 2 when Z is -NH-CO-, -S-S- or -NH-CO(CH2)tS- or n is 2, 3 or 4 when Z is -CO-NH- or-S(CH 2 )tCO-NH-; and t is 1 or 2. According to this embodiment, examples of such fragments of VIP or of an analog thereof are selected from the group consisting of: Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH 2 Lys-Lys-Tyr-Leu-NH 2 Lys-Lys-Tyr-dAla-NH 2 Val-Lys-Lys-Tyr-Leu-NH 2 Ala-Val-Lys-Lys-Tyr-Leu-NH 2 Asn-Ser-Ile-Leu-Asn-NH 2 Lys-Lys-Tyr-Val-NH 2 Ser-Ile-Leu-Asn-NH Asn-Ser-Tyr-Leu-Asn-NH 2 Asn-Ser-Ile-Tyr-Asn-NH 2 Ala-Val-Lys-NH 2 Lys-Tyr-Leu-NH 2 Lys-Lys-Tyr-Nle-NH 2 Ala-Val-Lys-Lys-Tyr-NH 2 Val-Lys-Lys-Tyr-Leu~NH 2 Leu-Asn-Ser-Ile-Asn-NH 2 Tyr-Leu-Asn-Ser-Ile-Asn-NH 2 In still another embodiment, the composition comprises a peptide consisting of a physiologically active fragment of VIP coupled to a fragment of pituitary adenylate cyclase activating peptide (PACAP) or an analog thereof, said peptide being selected from the group consisting of the novel peptides VIP I 5.23PACAP 24 . 2 7 and VIPi5. 23 Nle 17 PACAP 24 . 27 of the sequences: Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu, and Lys-Gln-Nle-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu In a most preferred embodiment, th composition comprises a VIP- related peptide that is a conjugate selected from the group consisting of: 0) R1-Y1-X1-X1'-X1"-X2-NH-Y2-R2 (ii) Rl-Yl-X3-Ser-X4- eu-Asn-NH-Y2-R2 (iii) Rl-Yl-NH-CH-CO-Xl-Xl , -Xl"-X5-NH-CH-CO-X6-NH-Y2-R2 I I (CH 2)m - Z - (CH 2 ) n (iv) Rl-Yl-X8-NH-CH-CO-X7-Ser-X4-Leu-Asn-NH-CH-CO-NH-Y2-R2 I I (CH 2)m - Z - (CH 2 ) n (v) Rl-Yl-His-Ser-Asp-Ala-X9-X14-Thr-Asp-Asn-Tyr- Thr-Arg-Leu-Arg-Lys-Gln-XlO-Ala-Xll-Xl-Xr- Xl"-X5- X15-X16-X17-Leu-Asn-NH-Y2-R2 (vi) Rl -Yl -Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr~Thr- Arg-Leu-Arg-Lys-Gln-X10-Ala-Xl l-Xl-Xl'-Xl "-X5-X15-X16- X17-Leu- Asn- H-Y2-R2 (vii) Rl - Y 1 -Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-X 10-Ala-X 1 -X 1 -X 1 '- Xl"-X5-X15-X16-X17-Leu-Asn-NH-Y2-R2 (viii) Rl-Yl-X12-Gln-X10-Ala-Xl 1-Xl-Xl'-Xl"-X5-Ala-Ala-Val-Leu-X13-NH- Y2-R2 wherein, Rl is selected from the group consisting of hydrogen and a saturated or unsaturated lipophilic group having at least 4 carbon atoms; R2 is selected from the group consisting of hydrogen, a saturated or unsaturated lipophilic group having at least 4 carbon atoms, a lipophilic group substituted by X3-Ser-X4-Leu-Asn-NHR2 or a spacer consisting of 1-3 residues of a non-charged amino acid coupled to X1-XP-XF'-X2-NH-Y2-R2, with the proviso that at least one of Rl and R2 is a lipophilic group; Yl and Y2 are each independently -CH2-, -CO-, or a covalent bond; XI is a covalent bond, Ala, Val, Ala- Val, Val- Ala, Lys, D-Lys, Ala-Lys, Val-Lys, Ala-Val-Lys, Val-Ala-Lys or Orn; XI ' is Lys, D-Lys or Orn; XI" is Tyr, D-Tyr, Phe, Trp or a residue of p-amino phenylalanine; X4 is He or Tyr; X5 is a residue of a hydrophobic aliphatic amino acid; X2 is X5, X5-Asn, X5-Ser, X5-Ile, X5-Tyr, X5-Leu, X5-Nle, X5-D- Ala, X5-Asn-Ser, X5-Asn-Ser-Ile, X5-Asn-Ser-Tyr, X5-Asn-Ser-Ile-Leu, X5- Asn-Ser-Tyr-Leu, X5-Asn-Ser-Ile-Leu-Asn or X5-Asn-Ser-Tyr-Leu-Asn; X3 is a covalent bond, Asn, X5, X5-Asn, Tyr-X5, Tyr-X5-Asn, Lys-X5, Lys-X5-Asn, Lys-Tyr-X5, Lys-Tyr-X5-Asn, Lys-Lys-Tyr-X5, Lys-Lys-Tyr- X5-Asn, Val-Lys-Lys-Tyr-X5, Val-Ala-Lys-Lys-Tyr-X5-Asn or Ala-Val-Lys- Lys-Tyr-X5-Asn; X6 is a covalent bond, Asn, Ser, He, Tyr, Leu, Asn-Ser, Asn-Ser-Ile, Asn-Ser-Tyr, Asn-Ser-Ile-Leu, Asn-Ser-Tyr-Leu, Asn-Ser-Ile-Leu-Asn or Asn- Ser-Tyr-Leu-Asn; X7 is a covalent bond or Asn; X8 is a covalent bond, X5, Tyr, Lys, Tyr-X5, Lys-X5, Lys-Tyr-X5, Lys- Lys-Tyr-X5, Val-Lys-Lys-Tyr-X5, Ala-Lys-Lys-Tyr-X5, or Ala-Val-Lys-Lys- Tyr-X5; X9 is a residue of a natural or non-natural amino acid, a residue of a natural or non-natural amino acid attached to threonine or a residue of a natural or non-natural amino acid attached to phenylalanine; X10 and XI 1 are each independently a residue of a natural or non- natural amino acid; X12 is a covalent bond, Lys, D-Lys or Orn; XI 3 is a covalent bond or Asn; X14 is Phe or Thr; XI 5 is Asn or Ala; X16 is Ser or Ala; XI is He or Val; Z is -CONH-, -NHCO-, -S-S-, -S(CH 2 ) t CO-NH- or -NH-CO(CH 2 ) t S-; m is 1 or 2 when Z is -CONH-, -S-S- or -S(CH 2 )tCO-NH-, or m is 2, 3 or 4 when Z is -NH-CO- or -NH-CO(CH2) t S-; n is 1 or 2 when Z is -NH-CO-, -S-S- or -NH-CO(CH2)tS- or n is 2, 3 or 4 when Z is -CO-NH- or-S(CH 2 ) t CO-NH-; and t is 1 or 2. According to still further features in the described preferred embodiments XI, XI ' are lysine, XI" is tyrosine X2 and X5 are leucine. According to still further features in the described preferred embodiments X10 is norleucine. According to still further features in the described preferred embodiments one of Rl-Yl and R2-Y2 is hydrogen. According to still further features in the described preferred embodiments X10 and XI 1 are each independently selected from the group consisting of leucine, isoleucine, norleucine, valine, tryptophan, phenylalanine, 01 methionine, octahydroindole-2-carboxylic acid, cyclohexylglycine and cyclopentylglycine. According to still further features in the described preferred embodiments X5 is a residue of a D- or L-amino acid selected from the group consisting of alanine, leucine, isoleucine, norleucine, valine, methionine and norvaline. According to still further features in the described preferred embodiments X9 is alanine or glycine. According to still further features in the described preferred embodiments the Rl and R2 are each independently of a formula CH3(CH2)k O, where k is an integer from 2 to 16. According to still further features in the described preferred embodiments k equals 16. In one embodiment, the composition comprises a conjugate of VIP or of a VIP analog, of the sequence: R 1 - Y 3 -His-Ser-Asp-Ala-X^Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-X 2 -Ala-X 3 -Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH-Y 4 -R 2 wherein X 1 , X 2 and X 3 are the same or different and each is the residue of a natural or non-natural amino acid; R 1 and R 2 are the same or different and each is hydrogen, a saturated or unsaturated lipophilic group or a C 1 -C 4 hydrocarbyl or Cι~C 4 carboxylic acyl, with the proviso that at least one of R 1 and R 2 is a lipophilic group; and Y 1 and Y 2 may be the same or different and each is -CH 2 - or a bond in case the associated R 1 and R 2 is hydrogen and Y 1 may further be -CO-. In another embodiment, the composition comprises a conjugate of a VIP antagonist or of an analog thereof, of the sequence: R^Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-Y^Ala-Y 2 -Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-AsnNH- R 2 wherein 523 R 1 and R 2 are the same or different and each is hydrogen, a saturate or unsaturated lipophilic group or a -C 4 hydrocarbyl or C C 4 carboxylic acyl, with the proviso that at least one of R 1 and R 2 is a lipophilic group; and Y 1 and Y 2 are the same or different and each is the residue of a natural or non-natural amino acid. In a further embodiment, the composition comprises a conjugate of a peptide according to any one of claims 7 to 9, said conjugate having at the 1 amino and/or carboxy terminal radicals R and R , the same or different, each of them being hydrogen, a saturated or unsaturated lipophilic group or a C -C 4 hydrocarbyl or C 1 -C 4 carboxylic acyl, with the proviso that at least one of R 1 and R 2 is a lipophilic group. The lipophilic moiety in said conjugates is selected from the group consisting of a saturated or unsaturated hydrocarbyl or carboxylic acyl radical having at least 5 carbon atoms, and is preferably selected from caproyl (Cap), lauroyl (Lau), palmitoyl, stearoyl (St), oleyl, eicosanoyl, docosanoyl, and the corresponding hydrocarbyl radicals hexyl, dodecyl, hexadecyl, octadecyl, eicosanyl, and docosanyl, and is preferably stearoyl. Examples of conjugates used according to the invention are selected from the group consisting of: Stearoyl-VIP (St-VIP) Stearoyl- norleucine 17 -VIP (St-Nle 17 -VIP ; SNV) Caproyl- norleucine 17 -VIP (Cap-Nle 17 -VIP) Stearoyl-leucine 5 , norleucine 17 -VIP (St-Leu 5 , Nle I7 -VIP) Stearoyl-leucine 5 , leucine 17 -VTP (St-Leu 5 , Leu 17 - VIP) Stearoyl-threonine 7 -VTP (St-Thr 7 -VIP) Stearoyl- norleucine 17 -neurotensin 6 -π VTP 7 _ 28 (SNH) Stearoyl-VIP I6 . 285 St-VIP 7 . 28 and St- VIPι 6 . 28 Stearoyl-Lys-Lys-Tyr-Leu-NH 2 Stearoyl- VIPi 5 . 23 PACAP 24 . 27 and Stearoyl- VTPι 5 . 23 Nle 17 PACAP 24 . 27 : According to still further features in the described preferred embodiments the hyperproliferative skin disorder is selected from the group consisting of psoriasis, hyperproliferation caused by papilloma virus infection, dermatoses, warts, corns, calluses, dandruff and skin cancer. According to still further features in the described preferred embodiments the therapeutically effective amount of a vasoactive intestinal peptide derived conjugate is formulated into a pharmaceutical composition. According to still further features in the described preferred embodiments the pharmaceutical composition contains a pharmaceutically acceptable carrier. According to still further features in the described preferred embodiments the substance is selected from the group consisting of an immunosuppressant, an antimetabolite, a corticosteroid, vitamin D, a vitamin D analog, vitamin A, a vitamin A analog, tar, coal tar, a keratolytic agent, a keratoplastic agent, an anti-pruritic agent, an emollient, a lubricant, a disinfectant, an antiseptant, photosensitizer and UV irradiation. The present invention successfully addresses the shortcomings of the presently known configurations by providing a novel use of potent lipophilic VIP derived conjugates for the treatment of hyperproliferative skin disorders BRIEF DESCRIPTION OF THE DRAWINGS The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the W description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. In the drawings: FIG. 1 illustrates starved HaCaT cell viability, as assessed by the metabolic dye, MTS, in the presence of the indicated concentrations of stearyl peptides: SNV (SEQ ID. NO:3), SNH (SEQ ID NO:5) and St-KKYL-NH 2 (SEQ ID NO:6). FIG. 2 illustrates starved 4th passage (4°) human keratinocytes viability, as assessed by the metabolic dye, MTS, in the presence of the indicated concentrations of stearyl peptides: SNV (SEQ ID NO:3), SNH (SEQ ID NO:5) and St-KKYL-NH 2 (SEQ ID NO:6) and St-VTP(15-23)PACAP(24-27) (SEQ ID NO:21). FIG. 3 illustrates starved HT29 cell viability, as assessed by the metabolic dye, MTS, in the presence of 10 μM stearyl peptides: SNV (SEQ ID NO:3), SNH (SEQ ID NO:5) and St-KKYL-NH 2 (SEQ ID NO:6). FIGs. 4A-E are phase contrast microscopy images of HaCaT cultures under different experimental conditions. 4A: Control cultures (10% FCS supplemented MEM). 4B: HaCaT cells following a 48 h growth in 0.1% BSA supplemented MEM (starved HaCaT). 4C. Starved HaCaT cells following a 24 h treatment with 10 μM SNH. 4D. Starved HaCaT cells following a 24 h treatment with ATA (25 μM). 4E. Starved HaCaT cells following a 24 h co- treatment with 10 μM SNH and 25 μM ATA. FIG. 5 A illustrates HaCaT cell viability in the presence of 5 and 10 μM stearyl peptides, as evaluated by MTS. 0 indicates cells without treatment. FIG. 5B illustrates the restoration of HaCaT cell viability by the simultaneous incubation of starved HaCaT with 25 μM ATA and SNV (SEQ ID NO:3), SNH (SEQ ID NO:5) and St- KYL-NH (SEQ ID NO:6), as evaluated by MTS. 0 indicates treatment with ATA only (without stearyl peptides). FIG. 5C illustrates the restoration of HaCaT cell viability by the simultaneous incubation of starved HaCaT with 25 μM ATA and SNV (SEQ ID NO:3), SNH (SEQ ID NO:5) and St-KKYL-NH 2 (SEQ ID NO:6), as evaluated by LDH release to condition medium. 0 indicates treatment with ATA only (without stearyl peptides), and FIG. 6 illustrates SNV (SEQ ID NO:3) induced increases in cGMP production by HaCaT cells, as determined by enzyme immuno assay (EIA). DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is of compounds, pharmaceutical compositions and methods for treating skin disorders and for inducing cell apoptosis. More particularly, the invention discloses a new treatment of skin conditions associated with hyperproliferation of skin cells, which treatment involves topical administration of lipophilized, vasoactive intestinal peptide (VΙP)-derived conjugates, optionally with other substances traditionally used in the art for the treatment of such skin disorders. The principles and operation of the present invention may be better understood with reference to the drawings and accompanying descriptions. Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of the components set forth in the following description or exemplified in the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. Thus, according to one aspect of the present invention there is provided a method for treating a hyperproliferative skin disorder of a patient. The method according to this aspect of the present invention is effected by administering to a skin area of the patient a therapeutically effective amount of a vasoactive intestinal peptide derived conjugate. Previous studies, as described in the Background section above, have indicated the usefulness of VIP derived conjugates, modified by a lipophilic moiety, as therapeutic agents in, for example, the treatment of male impotence and neurodegenerative diseases. Derivatization rationale lies in the ability to increase biological barriers penetration and stability of the molecule, both of which result in a greater bioavailability. Specifically, modifications included direct the molecules to their potential use in a topical manner, the latter is of special importance while seeking treatment for skin disorders. The expression "VIP-related peptides", when referring to the conjugates, will be referred to herein also as "VIP derived conjugate", "VIP related conjugates" and "conjugates", which are interchangeably used herein and refer to the conjugates of the present invention, as described hereinbelow and exemplified by "stearoyl peptides" . Specifically a VIP derived conjugate includes a peptidic portion derived from VIP attached to a hydrophobic moiety. The phrases "skin disorder" or "skin disease" as used herein in the specification and in the claim section that follows, include to abnormal skin conditions, as manifested in, but not limited to, hyperproliferative skin disorders and disorders of keratinization, cornification and scaling skin conditions. The former includes, for example, various dermatoses, such as atopical dermatitis, contact dermatitis, seborrheic dermatitis, chronic eczematous dermatitis, psoriasis, hyperproliferation caused by papilloma virus infection and skin cancer, such as squamous cell carcinoma and basal cell carcinoma. Certain benign hyperproliferative of the skin result from excess keratin deposition (hyperkeratosis) of the corneous layer. Such hyperproliferative disorders include, for example, epidermolytic hyperkeratosis and follicular keratosis. One common benign hyperproliferative disorder is hypertrophic scar formation (a keloid), a sharply elevated, irregularly-shaped, progressively enlarging scar due to the formation of excessive amounts of collagen in the corium during connective tissue repair following surgical and traumatic lacerations. While such hypertrophic tissue repair is most evident at sites of 01 external wound healing, keloid-prone individuals also manifest hypertrophic scarring internally. The major consequences of external keloid scarring are mainly cosmetic, although keloids can also result in varying degrees of psychological and social trauma for the afflicted individuals. In such cases, surgical or laser intervention is indicated because there is currently no generally effective topical or systemic treatment for this condition. Other hyperkeratotic afflictions include, for example, corns (heloma), calluses (tyloma) and warts (condyloma). These are well defined, thickened lesions of the epidermis, which occur at skin sites that are normally involved in chronic mechanical stress (corns and calluses) or infected with papilloma virus (warts). Pain produced by the thickened tissue can cause these lesions to be debilitating. Traditionally, keratolytic agents, such as salicylic acid and resorcinol, have been applied topically to these lesions to solubilize intercellular bonds resulting in desquamation of the thickened, hyperkeratotic tissues. In addition, hyperkeratinizing and/or hyperproliferative skin is associated in conditions such as ichthyosis, porokeratoses, palmoplantar keratodermas, eczema, dandruff and dry skin. The term "treatment" should be understood in the context of the present invention as prevention, alleviation, amelioration, improvement, minimization or abolishment of the abnormal conditions or symptoms manifested or associated with a skin disorder. The term patienf refers to a subject in need of such treatment, such as, but not limited to, a mammal, preferably a human. The VIP derived conjugates of the present invention may be administered by any conventional method which is known in the art, such as, but not limited to, parenterally, orally, and via inhalation routes, with topical administration being the preferred mode of administration. The phrase "administering to a skin area", as herein described in the specification and in the claim section that follows, refers to administering a VIP-related peptide/conjugate of the present invention to an afflicted skin or a lesion. The term "topical administration" is used herein in its conventional sense to indicate delivery of a topical drug or pharmacologically active agent to the skin or mucosa, as in, for example, the treatment of various skin disorders. By the term "drug", or the phrases "active ingredienf and "pharmacologically active agent" is meant a chemical compound suitable for topical administration and which induces a desired therapeutic effect. By the phrase "effective amount of a drug" is meant a sufficient amount of a compound, to provide the desired local effect and performance at a reasonable benefit/risk ratio attending any medical treatment. "Therapeutically effective amount", "an amount sufficient" or "an effective amount" is that amount of a given VIP-related peptide, which antagonizes or inhibits cell proliferation, induces differentiation or result in cell death of cells, such as keratinocytes, both in vivo and in vitro, or, which provides either a subjective relief of symptom(s) in a patient or an objectively identifiable improvement, as noted by a clinician or other qualified observer. Vasoactive intestinal peptide related of the present invention include a peptide sequence, either full length or a fragment, linear or cyclic, derived from vasoactive intestinal peptide (VIP, SEQ ID NO:l) and/or VHA (SEQ ID NO:4) and modified at its C- and/or N-terminus by a hydrophobic moiety, as is further described herein. Previous, as well as current works, have identified two active stretches of amino acids, both of which are located in the C terminus of the VIP, namely, amino acids 20-23, corresponding to Lys-Lys-Tyr-Leu (SEQ ID NO:7), or interchangeably, YL (SEQ ID NO:7), and amino acids 24-28, corresponding to Asn-Ser-Ile-Leu-Asn (SEQ ID NO: 19). Thus, according to a presently preferred embodiment of the present invention, the VIP-related peptide includes the sequence KKYL (SEQ ID NO:7) as part of its peptidic portion. According to another preferred embodiments of the invention, and in order to render the treatment provided by the present invention more effective, a therapeutically effective amount of a substance traditionally used for treatment of the hyperproliferative skin disorder is coadministered along with a VIP-related peptide. The phrase "substances traditionally used for the treatment of the hyperproliferative skin disorder" refers to known therapeutic agents or treatment approaches, presently employed in the management of skin disorders. Various modalities are known in the art for the treatment of hyperproliferative skin disorders, such as psoriasis, all of which are potentially formulated with the conjugates of the present invention for treating any one or more of the skin disorders described hereinabove. While several mechanisms of action are hypothesized for the different agents, such combination therapy preferably employs combinations of non overlapping mechanisms, such as immunosuppression by corticosteroids, all as is further detailed hereinbelow. According to another aspect of the present invention there is provided a method of inducing cell apoptosis. The method is effected by subjecting cells to a vasoactive intestinal peptide related peptide. Apoptosis is an evolutionary conserved, gene-directed, active cell death that follows an orderly pattern of morphologic and biochemical changes. Common histologic observations have established that a strict sequence of events is shared by all apoptotic cells. These include loss of cell contact accompanied by cell rounding and smoothing of the cell surface, loss of cytoskeletal integrity, cell shrinkage with resultant compaction of the cytoplasm and organelles, nuclear and chromatin condensation, chromatin fragmentation, formation of apoptotic bodies and engulfment. Throughout the various tissues of the organism, apoptosis normally functions in developmental remodeling, regulation of cell numbers, and defense against damaged, virus- infected, auto-reactive and transformed cells [5, 9, 17]. Agents and events that can activate the apoptotic pathway are many and varied, and include growth factors, hormones, cytokines, UV and gamma irradiation, disruption of oxidative pathways and cell matrix interactions [10]. However, the pattern of apoptosis itself is highly conserved, indicative of a limited number of shared effector mechanisms that trigger apoptosis [24]. The pathway is conceptually divided into three mechanistically distinct phases: induction (or initiation), effector and degradation [11]. In the induction phase, the heterogeneous stimuli (mentioned above) activate receptor- and non- receptor-mediated signal transduction pathways and second messengers such as cAMP, inositol triphosphate, diacylglycerol and ceramides [17, 25]. The pathways are not reserved for apoptotic signaling, but are also used for other cellular functions, such as growth control. The outcome of signaling depends on the particular inducing stimulus (which may affect one or more signal transduction pathways), the developmental or physiologic state of the cell, and the cell's lineage. A common outcome of the different signal transduction pathways that impact on apoptosis is interference with the cell cycle. A major control of apoptotic susceptibility is determined by the cell cycle and its G l and Q2 checkpoints, which prevent aberrant DNA synthesis and mitosis [26]. These checkpoints also control cell cycle arrest necessary for commitment to normal terminal differentiation. The effector phase, common to all cell types, is regulated by distinct classes of "cell death genes", e.g., the bcl-2 genes can suppress cell death at the transition from induction to effector phases [35]. Many viral proteins are also effective inhibitors of cellular proteins controlling the inductive phase of apoptosis. Tumor promoters and oncogenes function analogously to viral proteins to inhibit apoptosis and promote proliferation. During the effector pathway enzymes of the caspase family (activated by Cytochrome C, released from the compromised mitochondria), activate other effector proteins that will be involved in the degenerative phase, possibly including additional proteases, endonucleases and transglutaminases. The action of which result in the characteristic morphologic cascade, typifying apoptosis [38]. The epidermis is a continually renewing tissue in which homeostasis ismaintained by factors that influence the interrelated processes of keratinocyte W 01 proliferation, differentiation, senescence and cell death. An important feature of homeostasis in the epidermis is regulation of total cell numbers. Studies have established that apoptosis is a controlling factor of the cell birth to cell death ratio [39]. New cells are produced in the proliferative compartment, primarily the basal cell layer, and are balanced by cell death (terminal differentiation/apoptosis). Terminal differentiation, by itself, may be an elaborated apoptotic pathway [40]. Thus, premature, excessive or deficient apoptosis have all been linked to homeostatic dysregulation characteristic, of skin disorders. For example, there is increasing evidence that apoptotic dysregulation contributes to the hyperplasia and aberrant differentiation typical of the psoriatic plaque [12]. In addition, the discovery that many oncogenes and anti-oncogenes belong to the apoptotic pathway identified cell death as an important factor in the development of neoplasia. Increase in cell division alone is apparently insufficient for continuous tumor development, and additional dysregulation of apoptosis is required (like lossof function mutations in p53, over-expression of bcl-2 and c-myc, which appear in squamous cell carcinoma, basal cell carcinoma and cutaneous lymphomas) [11]. Escape from apoptosis functions primarily at the level of tumor promotion, allowing initiated cells to clonally expand as well as to acquire additional mutations. ATA, a triphenylmethane dye, has been previously used to establish causal relationship between DNA laddering and cell death. As such, it was shown to inhibit nuclease activity, involved in the apoptotic pathway, resulting in reduced DNA fragmentation, associated with increased cell survival [36]. While not wishing to be limiting, the remarkable restoration in keratinocyte cell viability, as exemplified in the Examples section that follows, obtained by co- incubation of VIP derived conjugates of the present invention, associate the mechanism of cell death induction with pathways affected by ATA, such as the apoptotic pathway. Furthermore, as described in the examples section below, it seems that new protein synthesis is responsible only in part for the suggested apoptotic cell death in this system. Data in the literature report of many examples where inhibitors of RNA or protein synthesis fail to interfere with the apoptotic pathway. On the contrary, some of these inhibitors were reported to enhance the susceptibility of cells to apoptosis induction or even induced apoptosis by themselves, thus indicating that macromolecular synthesis is not a general requirement for apoptosis [37]. For instance, DNA degrading enzymes were found to be constitutively present in the nucleus and only require activation. Dysregulation of the apoptotic pathway has been implicated in the pathogenesis and promotion of skin diseases, such as skin cancer and psoriasis. It has been previously suggested that terminal differentiation of the keratinocyte is a specialized form of apoptosis [11]. Apoptosis was suggested as the default pathway taken in the absence of continued proliferation or normal differentiation. The time between commitment to death and execution of the apoptotic effector phase was suggested to be extended in normally differentiating keratinocytes, relative to rapid apoptosis of abnormal or unnecessary keratinocytes, to allow expression of proteins subserving the differentiated function. For normal function, the apoptotic pathway, as the foundation of keratinocyte terminal differentiation, must be completed. In psoriasis, failure to complete the apoptotic pathway may result in abnormal retention of nuclei in the stratum corneum (parakeratosis). Thus, the cytotoxic effect of the VIP-related peptides of the present invention may be a result of their induction of excessive differentiation in the keratinocytes, resulting in unavoidable death. Regardless of the mechanism underlying cell death induction, the development of potent skin permeable agents having anti- proliferative effects, as exemplified by SNV (SEQ ID NO:3), SNH (SEQ ID NO:5), Stearoyl- VIP 15 . 23 PACAP 24 . 27 (SEQ ID NO:21) and Stearoyl-KKYL- H2 (SEQ ID NO:6) is highly favorable for the management of hyperproliferative skin disorders. According to yet another aspect of the present invention there is provided a pharmaceutical composition for treating a hyperproliferative skin disorder. The pharmaceutical composition according to this aspect of the present invention, comprising, as active ingredients, therapeutically effective amounts of a VTP-related peptide and a substance traditionally used for treatment of the hyperproliferative skin disorder. The pharmaceutically active ingredients of the present invention can be administered to an organism per se, or in a pharmaceutical composition mixed with suitable carriers and or excipients. Pharmaceutical compositions suitable for use in context of the present invention include those compositions in which the active ingredients are contained in an amount effective to achieve an intended therapeutic effect. As used herein a "pharmaceutical composition" refers to a preparation of one or more of the VIP-related peptides described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components such as traditional drugs, physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Hereinafter, the phrases "physiologically suitable carrier" and "pharmaceutically acceptable carrier" are interchangeably used and refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered VIP-related peptide. Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate processes and administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference. While various routes for the administration of VIP-related peptides are possible, and were previously described, for the purpose of the present invention, the topical route is preferred, and is assisted by a topical carrier. The topical carrier is one, which is generally suited for topical drug administration and includes any such materials known in the art. The topical carrier is selected so as to provide the composition in the desired form, e.g., as a liquid or non-liquid carrier, lotion, cream, paste, gel, powder, ointment, solvent, shampoo, liquid diluent, drops and the like, and may be comprised of a material of either naturally occurring or synthetic origin. It is essential, clearly, that the selected carrier does not adversely affect the active agent or other components of the topical formulation, and which is stable with respect to all components of the topical formulation. Examples of suitable topical carriers for use herein include water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, waxes, and the like. The composition of the invention may also be administered in the. form of a shampoo, in which case conventional components of such a formulation are included as well, e.g., surfactants, conditioners, viscosity modifying agents, humectants, and the like. Preferred formulations herein are colorless, odorless ointments, lotions, creams and gels. Ointments are semisolid preparations, which are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be' used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., 1995), at pages 1399- 1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water- soluble ointment bases are prepared from polyethylene gly cols of varying molecular weight; again, reference may be made to Remington: The Science and Practice of Pharmacy for further information. Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations, in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in-water type. Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethylcellulose, or the like. Creams containing the selected VIP derived conjugates are, as known in the art, viscous liquid or semisolid emulsions, either oil-in-water or water-in- oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation, as explained in Remington, supra, is generally a nonionic, anionic, cationic or amphoteric surfactant. Gel formulations are preferred for application to the scalp. As will be appreciated by those working in the field of topical drug formulation, gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Shampoos for treating psoriasis and other skin conditions associated with hyperproliferation and/or a keratolytic disorder, such as dandruff, may be formulated with the VIP derived conjugate and standard shampoo components, i.e., cleansing agents, thickening agents, preservatives, and the like, with the cleansing agent representing the primary ingredient, typically an anionic surfactant or a mixture of an anionic and an amphoteric surfactant. Various additives, known to those skilled in the art, may be included in the topical formulations of the invention. For example, solvents may be used to solubilize certain drug substances. Other optional additives include skin permeation enhancers, opacifiers, anti-oxidants, gelling agents, thickening agents, stabilizers, and the like. As has already been mentioned hereinabove, topical preparations for the treatment of skin disorders according to the present invention may contain other pharmaceutically active agents or ingredients, those traditionally used for the treatment of such disorders. These include immunosuppressants, such as cyclosporine, antimetabolites, such as methotrexate, corticosteroids, vitamin D and vitamin D analogs, vitamin A or its analogs, such etretinate, tar, coal tar, anti pruritic and keratoplastic agents, such as cade oil, keratolytic agents, such as salicylic acid, emollients, lubricants, antiseptic and disinfectants, such as the germicide dithranol (also known as anthralin) photosensitizers, such as psoralen and methoxsalen and UV irradiation. Other agents may also be added, such as antimicrobial agents, antifungal agents, antibiotics and anti- inflammatory agents. The topical compositions of the invention may also be delivered to the skin using conventional "transdermal"-type patches, wherein the drug composition is contained within a laminated structure, that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is contained in a layer, or "reservoir", underlying an upper backing layer. The laminated structure may contain a single reservoir, or it may contain multiple reservoirs. In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. The particular polymeric adhesive selected will depend on the particular drug, vehicle, etc., i.e., the adhesive must be compatible with all components of the drug-containing composition. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form. The backing layer in these laminates, which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility. The material selected for the backing material should be selected so that it is substantially impermeable to the drug and to any other components of the drug-containing composition, thus preventing loss of any components through the upper surface of the device. The backing layer may be either occlusive or nonocclusive, depending on whether it is desired that the skin become hydrated during drug delivery. The backing is preferably made of a sheet or film of a preferably flexible elastomeric material. Examples of polymers that are suitable for the backing layer include polyethylene, polypropylene, and polyesters. During storage and prior to use, the laminated structure includes a release liner. Immediately prior to use, this layer is removed from the device to expose the basal surface thereof, either the drug reservoir or a separate contact adhesive layer, so that the system may be affixed to the skin. The release liner should be made from a drug/vehicle impermeable material. Such devices may be fabricated using conventional techniques, known in the art, for example by casting a fluid admixture of adhesive, drug and vehicle onto the backing layer, followed by lamination of the release liner. Similarly, the adhesive mixture may be cast onto the release liner, followed by lamination of the backing layer. Alternatively, the drug reservoir may be prepared in the absence of drug or excipient, and then loaded by "soaking" in a drug/vehicle mixture. As with the topical formulations of the invention, the drug composition contained within the drug reservoirs of these laminated system may contain a number of components. In some cases, the drug may be delivered "neat," i.e., in the absence of additional liquid. In most cases, however, the drug will be dissolved, dispersed or suspended in a suitable pharmaceutically acceptable vehicle, typically a solvent or gel. Other components, which may be present, include preservatives, stabilizers, surfactants, and the like. Both the topical formulations and the laminated drug delivery systems may in addition contain a skin permeation enhancer. While the conjugates of the present invention have been specifically designed so as to increase their biological membrane penetration, it may yet be desirable to enhance the inherent permeability of the skin to the drug. Thus, an adequate therapeutic levels of the drug, passing through a reasonably sized area of unbroken skin, can be assured by coadministration of a skin permeation enhancer with such drugs. Suitable enhancers are well know in the art and include, for example, dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N- dimethylacetamide (DMA), decylmethylsulfoxide (CIO MSO), C2-C6 alkanediols, and the 1 -substituted azacycloheptan-2-ones, particularly 1-n- dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Whitby Research Incorporated, Richmond, Va.), alcohols, and the like. Other examples of suitable carriers are olive oil, glycerin, lubricants, nitroglycerin and Sefsol™, and mixtures thereof. Sefsol is a trademark (Nikko Chemicals, Tokyo) for, 1-glyceryl monocaprylate, glyceryl tricaprylate and sorbitan monocaprylate. The pharmaceutical compositions herein described may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. The topical compositions and drug delivery systems of the invention can be used in the prevention or treatment of the skin conditions identified above. When used in a preventive method, susceptible skin is treated prior to any visible lesions on areas known to be susceptible to such lesions in a particular individual. Dosing is dependent on the type, the severity and manifestation of the affliction and on the responsiveness of the subject to the VIP derived lipophilic conjugates, as well as the dosage form employed the potency of the particular conjugate and the route of administration utilized. Persons of ordinary skill in the art can easily determine optimum dosages, dosing methodologies and repetition rates. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l). Thus, depending on the severity and responsiveness of the condition to be treated, dosing can be a single or repetitive administration, with course of 01 00523 treatment lasting from several days to several weeks or until cure is effected or diminution of the skin lesion is achieved. Conjugates of the present invention contain a peptide constituent. "Peptides" and "polypeptides" are chains of amino acids (typically L-amino acids) whose α-carbons are linked through peptide bonds formed by a condensation reaction between the carboxyl group of the α-carbon of one amino acid and the amino group of the α-carbon of another amino acid. The terminal amino acid at one end of the chain (i.e., the amino terminal) has a free amino group, while the terminal amino acid at the other end of the chain (i.e., the carboxy terminal) has a free carboxyl group. As such, the term "amino terminus" (abbreviated N-terminus) refers to the free α-amino group on the amino acid at the amino terminal of the peptide or to the α-amino group (imino group when participating in a peptide bond) of an amino acid at any other location within the peptide. Similarly, the term "carboxy terminus" (abbreviated C-terminus) refers to the free carboxyl group on the amino acid at the carboxy terminus of a peptide or to the carboxyl group of an amino acid at any other location within the peptide. Typically, the amino acids making up a polypeptide are numbered in order, starting at the amino terminal and increasing in the direction of the carboxy terminal of the polypeptide. Thus, when one amino acid is said to "follow" another, that amino acid is positioned closer to the carboxy terminal of the polypeptide than the "preceding" amino acid. The term "residue" as used herein refers to an amino acid or an amino acid mimetic that is incorporated into a peptide by an amide bond or an amide bond mimetic. As such, the amino acid may be a naturally occurring amino acid or, unless otherwise limited, may encompass known analogs of natural amino acids that function in a manner similar to the naturally occurring amino acids (i.e., amino acid mimetics). Thus, according to still further features in the described preferred embodiments the vasoactive intestinal peptide derived conjugate includes at least one non-natural amino acid. The at least one non- „ ^ , PCT/IL01/00523 natural amino acid is preferably selected from the group consisting of a D amino acid, norleucine, norvaline, α-aminobutyric acid, di-amino butyric acid, di-aminopropionic acid, -HN(CH2) n COOH, wherein n is 3-5, -NH(CH 2 (R))n- COOH, wherein R is an alkyl, H2N(CH2) m COOH, wherein m is 2-4, H2N- C(NH)-NH(CH2)kCOOH, wherein k is 2-3, hydroxy lysine, N-methyl lysine, ornitine, p-amino phenylalanine, TIC, naphthylelanine, a ring-methylated derivative of phenylalanine, a halogenated derivative of phenylalanine or o- methyl-tyrosine. It will be readily apparent to those of ordinary skill in the art that the peptidic moiety of the VIP derived conjugates of the present invention may be subject to various changes, such as insertions, deletions, and substitutions, either conservative or non-conservative, where such changes might provide for certain advantages in their use, i.e., to increase biological activity, bioavailability, stability and biological membrane penetration. By conservative substitutions is meant replacing an amino acid residue with another which is biologically and/or chemically similar, e.g., one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as, for example, Gly, Ala; Val, He, Leu; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe, Tyr. Residues which can be modified without loosing the biological activity of the VIP derived conjugate can be identified by single amino acid substitutions, deletions, or insertions using conventional techniques known to those of ordinary skill in the art, this especially true of the VIP derived conjugates of the present invention, being that they are relatively short in length. In addition, the contributions made by the side chains of the residues can be probed via a systematic scan with a specified amino acid (e.g., Ala). The VIP derived conjugates of the present invention are relatively short in length and are typically no more than 28 amino acids in length. As such, it is feasible to prepare such conjugates using any of a number of chemical peptide synthesis techniques well known to those of ordinary skill in the art, including both solution methods and solid phase methods, with solid phase synthesis being presently preferred In particular, solid phase synthesis in which the C-terminal amino acid of the peptide sequence is attached to an insoluble support followed by sequential addition of the remaining amino acids in the sequence is the preferred method for preparing the VIP antagonists of the present invention. Techniques for solid phase synthesis are described by Barany and Merrifield, Solid-Phase Peptide Synthesis, in The Peptides: Analysis, Synthesis, Biology (Gross and Meienhofer (eds.), Academic press, New York, vol. 2, pp. 3-284 (1980)); Merrifield, et al., J. Am. Chem. Soc. 85, 2149-2156 (1963); and Stewart, et al., Solid Phase Peptide Synthesis (2nd ed., Pierce Chem. Co., Rockford, 111. (1984)), the teachings of which are hereby incorporated by reference. Solid phase synthesis is started from the carboxy-terminal end (i.e., the C-terminus) of the peptide by coupling a protected amino acid via its carboxyl group to a suitable solid support. The solid support used is not a critical feature of the present invention provided that it is capable of binding to the carboxyl group while remaining substantially inert to the reagents utilized in the peptide synthesis procedure. For example, a starting material can be prepared by attaching an amino-protected amino acid via a benzyl ester linkage to a chloromethylated resin or a hydroxymethyl resin or via an amide bond to a benzhydrylamine (BHA) resin or p-methylbenzhydrylamine (MBHA) resin. Materials suitable for us as solid supports are well known to those of skill in the art and include, but are not limited to, the following: halomethyl resins, such as chloromethyl resin or bromomethyl resin; hydroxymethyl resins; phenol resins, such as 4-(α-[2,4-dimethoxyphenyl]-Fmoc- aminomethyl)phenoxy resin; tert-alkyloxycarbonyl-hydrazidated resins, and the like. Such resins are commercially available and their methods of preparation are known by those of ordinary skill in the art. The acid form of the peptides of the present invention may be prepared by the solid phase peptide synthesis procedure using a benzyl ester resin as a solid support. The corresponding amides may be produced by using benzhy rylamine or methylbenzhydrylamine resin as the solid support. Those skilled in the art will recognize that when the BHA or MBHA resin is used, treatment with anhydrous hydrofluoric acid to cleave the polypeptide from the solid support produces a polypeptide having a terminal amide group. The α-amino group of each amino acid used in the synthesis should be protected during the coupling reaction to prevent side reactions involving the reactive α-amino function. Certain amino acids also contain reactive side- chain functional groups (e.g., sulfhydryl, amino, carboxyl, hydroxyl, etc.), which must also be protected with appropriate protecting groups, to prevent chemical reactions from occurring at those sites during the polypeptide synthesis. Protecting groups are well known to those of skill in the art. See, for example, The Peptides: Analysis, Synthesis, Biology, Vol. 3: Protection of Functional Groups in Peptide Synthesis (Gross and Meienhofer (eds.), Academic Press, New York (1981)), the teachings of which are incorporated herein by reference. A properly selected α-amino protecting group will render the α-amino function inert during the coupling reaction, will be readily removable after coupling under conditions that will not remove side chain protecting groups, will not alter the structure of the peptide fragment, and will prevent racemization upon activation immediately prior to coupling. Similarly, side- chain protecting groups must be chosen to render the side chain functional group inert during the synthesis, must be stable under the conditions used to remove the α-amino protecting group, and must be removable after completion of the polypeptide synthesis under conditions that will not alter the structure of the polypeptide. Illustrative examples of protecting groups for an α-amino group include, but are not limited to, the following: aromatic urethane-type groups such as, for O 01/93889 example, fluorenylmethyloxycarbonyl (Fmoc), carbobenzoxy (Cbz), and substituted benzyloxycarbonyls including p-chlorobenzyloxycarbonyl, o- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 2,6- dichlorobenzyloxycarbonyl, etc.; aliphatic urethane-type groups such as, for example, butyloxycarbonyl (Boc), t-amyloxycarbonyl, isopropyloxycarbonyl, 2-(p-biρhenylyl)-isopropyloxycarbonyl, allyloxycarbonyl, etc.; and cycloalkyl urethane-type groups such as, for example, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxy-carbonyl, adamantyloxycarbonyl (Adoc), etc. In a presently preferred embodiment, fluorenylmethyloxycarbonyl (Fmoc) is the α-amino protecting group used. For the side chain amino group present in lysine (Lys), any of the protecting groups described above for the protection of the α-amino group are suitable. Moreover, other suitable protecting groups include, but are not limited to, the following: butyloxycarbonyl (Boc), p-chlorobenzyloxycarbonyl, p-brorhobenzyloxycarbonyl, o-chlorobenzyloxycarbonyl, 2,6- dichlorobenzyloxy- carbonyl, 2,4-dichlorobenzyloxycarbonyl, o- bromobenzyloxycarbonyl, p-nitro- benzyloxycarbonyl, t-butyloxycarbonyl, isopropyloxycarbonyl, t-amyloxy- carbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxy- carbonyl, adamantyloxycarbonyl, p- toluenesulfonyl, etc. Preferably, the side chain amino protecting group for Lys is tert-butyloxycarbonyl (Boc). For protection of the guanidino group of arginine (Arg), examples of suitable protecting groups include, but are not limited to, the following: nitro, tosyl (Tos), carbobenzoxy (Cbz), adamantyloxycarbonyl (Adoc), butyloxycarbonyl (Boc), 4-metnoxy-2,3,6-trimethylbenzenesulfonyl (Mtr) and 2,2,5,7,8-pentamethylchloroman-6-sulfonyl (PMC). In a presently preferred embodiment, 4-methoxy-2,3,6-trimethylbenzenesulfonyl and 2,2,5,7,8-penta- methylchloroman-6-sulfonyl are the protecting groups used for Arg. The hydroxyl group on the side chains of serine (Ser), threonine (Thr) or tyrosine (Tyr) can be protected by a C1-C4 alkyl such as, for example, methyl, O 01/93889 ethyl and t-butyl, or by a substituted benzyl such as, for example, p- methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl and 2,6- dichlorobenzyl. The preferred aliphatic hydroxyl protecting group for Ser, Thr and Tyr is t-butyl. The carboxyl group of aspartic acid (Asp) may be protected by, for example, esterifϊcation using groups such as benzyl, t-butyl, cyclohexyl, cyclopentyl, and the like. For Asp, t-butyl is the presently preferred protecting group. The basic imidazole ring in histidine (His) may be protected by, for example, t-butoxymethyl (Bom), butyloxycarbonyl (Boc) and fluorenylmethyloxycarbonyl (Fmoc). In a preferred embodiment, t- butoxymethyl (Bom) is the protecting group used. Coupling of the amino acids may be accomplished by a variety of chemistries known to those of skill in the art. Typical approaches involve either the conversion of the amino acid to a derivative that will render the carboxyl group more susceptible to reaction with the free N-terminal amino group of the polypeptide fragment, or use of a suitable coupling agent such as, for example, N,N'-dicyclohexylcarbodimide (DCC) or N,N'-diisopropylcarbodiimide (DIPCDI). Frequently, hydroxybenzotriazole (HOBt) is employed as a catalyst in these coupling reactions. Appropriate synthesis chemistries are disclosed in The Peptides: Analysis, Structure, Biology, Vol. 1: Methods of Peptide Bond Formation (Gross and Meienhofer (eds.), Academic Press, New York (1979)); and Izumiya, et al., Synthesis of Peptides (Maruzen Publishing Co., Ltd., (1975)), both of which are incorporated herein by reference. Generally, synthesis of the polypeptide is commenced by first coupling the C-terminal amino acid, which is protected at the α-amino position by a protecting group such as fluorenylmethyloxycarbonyl (Fmoc), to a solid support. Prior to coupling of Fmoc- Asn, the Fmoc residue has to be removed from the polymer. Fmoc-Asn can, for example, be coupled to the 4-(α-[2,4- dimethoxyρhenyl]-Fmoc-amino-methyl)ρhenoxy resin using N,N'- dicyclohexylcarbodimide (DCC) and hydroxybenzotriazole (HOBt) at about 25 °C, for about two hours with stirring. Following the coupling of the Fmoc- protected amino acid to the resin support, the α-amino protecting group is removed using 20% piperidine in DMF at room temperature. After removal of the α-amino protecting group, the remaining Fmoc- protected amino acids are coupled stepwise in the desired order. Appropriately protected amino acids are commercially available from a number of suppliers (e.g., Nova (Switzerland) or Bachera (California)). As an alternative to the stepwise addition of individual amino acids, appropriately protected peptide fragments consisting of more than one amino acid may also be coupled to the "growing" polypeptide. Selection of an appropriate coupling reagent, as explained above, is well known to those of skill in the art. It should be noted that since the VIP derived conjugates of the present invention are relative short in length, this latter approach (i.e., the segment condensation method) is not the most efficient method of peptide synthesis. Each protected amino acid or amino acid sequence is introduced into the solid phase reactor in excess and the coupling is carried out in a medium of dimethylformamide (DMF), methylene chloride (CH2CI2) or, mixtures thereof. If coupling is incomplete, the coupling reaction may be repeated before deprotection of the α-amino group and addition of the next amino acid. Coupling efficiency may be monitored by a number of means well known to those of skill in the art. A preferred method of monitoring coupling efficiency is by the ninhydrin reaction. Polypeptide synthesis reactions may be performed automatically using a number of commercially available peptide synthesizers (e.g., Biosearch 9500, Biosearch, San Raphael, California). The peptide can be cleaved and the protecting groups removed by stirring the insoluble carrier or solid support in anhydrous, liquid hydrogen fluoride (HF) in the presence of anisole and dimethylsulfide at about 0 °C. for about 20 to 90 minutes, preferably 60 minutes; by bubbling hydrogen bromide (HBr) continuously through a 1 mg/10 mL suspension of the resin in trifiuoroacetic acid (TFA) for 60 to 360 minutes at about room temperature, depending on the protecting groups selected; or, by incubating the solid support inside the reaction column used for the solid phase synthesis with 90% trifiuoroacetic acid, 5% water and 5% triethylsilane for about 30 to 60 minutes. Other deprotection methods well known to those of skill in the art may also be used. The conjugates of the present invention can be isolated and purified from the reaction mixture by means of peptide purification well known to those of skill in the art. For example, the polypeptides may be purified using known chromatographic procedures such as reverse phase HPLC, gel permeation, ion exchange, size exclusion, affinity, partition, or countercurrent distribution. See, the Example Section, infra, for a detailed description of the methods and protocols used to synthesize and purify the VIP antagonists of the present invention. Although the VIP derived conjugates of the present invention are preferably prepared or produced using chemical peptide synthesis techniques such as described above, it will be understood by those of ordinary skill in the art that they can also be prepared by other means including, for example, recombinant techniques. The amino acids referred to herein are described by shorthand designations as follows: Table A Amino Acid Nomenclature Name 3-letter 1 letter Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic Acid Asp D Cysteine Cys C Glutamic Acid Glu E Glutamine Gin Q Glycine Gly G Histidine His H Homoserine Hse „ Isoleucine He I Leucine Leu L Lysine Lys K Methionine Met M Methionine sulfoxide Met (0) ~ Methionine methylsulfonium Met (S--Me) ~ Norleucine Nle „ Norvaline Nva — Phenylalanine Phe F Proline Pro P Serine Ser s Threonine Thr T Tryptophan Trp w Tyrosine Tyr Y Valine Val V Following synthesis, the peptidic moiety is further derivatized by a lipophilic moiety, with, for example alkyl or acyl groups as described hereinabove, by methods commonly used in the art. Additionally and preferably, according to still further features in the described preferred embodiments, the vasoactive intestinal peptide derived conjugate includes at least one peptide-bond modification. An amide bond mimetic includes peptide backbone modifications well known to those skilled in the art. For example, peptide bonds (-CO-NH-) within the peptide may be substituted by N-methylated bonds (-N(CH3 CO-), ester bonds (-C(R)H-C-0- 0-C(R)-N-), ketomethylene bonds (-CO-CH2-), α-aza bonds (-NH-N(R)-CO-), wherein R is any alkyl, e.g., methyl, carba bonds (-CH2-NH-), hydroxyethylene bonds (-CH(OH)-CH2-), thioamide bonds (-CS-NH-), olefinic double bonds (- CH-CH-), retro amide bonds (-NH-CO-), peptide derivatives (-N(R)-CH2-CO- ), wherein R is the natural side chain on the carbon atom. These modifications can occur at any of the bonds along the peptide chain and even at several (2-3) at the same time. According to still further features in the described preferred embodiments the VIP-related includes a cyclic peptide moiety, as is further described hereinbelow. Several approaches are utilized for the synthesis of cyclic peptides. For example, cyclic peptides containing intramolecular amide bonds, i.e., -CONH- or -NHCO- may be prepared through conventional solid phase synthesis. Thus, peptide chains may be assembled on the solid support while incorporating suitable amino and carboxyl side chain protected amino acid derivatives at the positions selected for cyclization. Following completion of peptide chain assembly, the protecting groups can be selectively removed from the corresponding amino and carboxyl functions, leaving other protecting groups and the peptide-support bond intact. Cyclization can then be accomplished using known peptide coupling agents. Finally, the cyclic peptide may be cleaved from the support along with deprotection of side chain moieties using known procedures, and purification of the desired cyclic peptide can be achieved by chromatographic techniques. Cyclic peptides containing intramolecular disulfide bond, i.e., -S-S-, may be prepared through conventional solid phase synthesis while incoφorating S-protected cysteine or homocysteine residues at the positions selected for cyclization. Following completion of peptide chain assembly, two possible routes for cyclization can be performed: 1. Selective removal of S- protecting groups with a consequent on-support oxidation of free corresponding two SH-functions, to form S'-S bonds. This may be followed by conventional removal of the product from the support and appropriate chromatographic purification. 2. Removal of the peptide from the support along with complete side-chain deprotection, followed by oxidation of free SH- functions in highly dilute aqueous solution. Both routes lead to the same final desired product. Cyclic peptides containing intramolecular S-alkyl bonds, i.e., - S(CH2)tCO-NH or -NH-CO(CH2)tS-, may be prepared through conventional solid phase synthesis. Thus, an amino acid residue with suitable amino- protected side chain, and a suitable S-protected cysteine or homocysteine residue may be incorporated during peptide chain assembly at positions selected for cyclization. The blocked side-chain amino function is selectively deprotected followed by bromoacylation. The peptide can then be detached from the support, along with side-chain deprotection, under acidic conditions. Under neutral or slightly basic conditions, the corresponding free SH and bromoacylated moieties may then selectively interact at high dilution to afford the desired cyclic peptide. According to preferred embodiments of the present invention the vasoactive intestinal peptide derived conjugate includes a lipophilic moiety, such as, saturated alkyl, branched alkyl, non-saturated alkyl, non-branched alkyl, saturated acyl, branched acyl, non-saturated acyl and non-branched acyl. The term "alkyl" is used herein to refer to substituents that are monovalent aliphatic hydrocarbon radicals. The alkyl groups may be straight- chain or branched-chain, with for example, straight-chain alkyl groups of C4- C20. Examples of suitable alkyl radicals include, but are not limited to, the following: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl. The term "acyl" is used herein to refer to an organic radical derived from an organic acid by removal of the hydroxyl group. For example, the acyl radical or group "butyryl" is derived from butanoic acid by removal of the hydroxyl group. Similarly, the acyl group "stearyl" is derived from stearic acid by removal of the hydroxyl group. In accordance with the present invention, the acyl group may be saturated or unsaturated, with acyl groups having, for example, four to twenty carbon atoms. A "saturated" acyl or alkyl group is one which has no double or triple bonds, whereas an "unsaturated" acyl or alkyl group is one which has double or triple bonds. Suitable acyl groups include, but are not limited to, the following: butyryl, caproyl, octanoyl, lauryl, myristyl, palmityl, stearyl, aracidyl, linoceryl, etc. In addition to the foregoing, it will be readily apparent to those of ordinary skill in the art that a large number of other acyl groups can be derived from various organic acids by removal of the hydroxyl group. The vasoactive intestinal peptide derived conjugate of the present invention is preferably of any of the formulae listed below: (i) R1-Y1-X1-X1'-X1"-X2-NH-Y2-R2 (ii) Rl-Yl-X3-Ser-X4-Leu-Asn-NH-Y2-R2 (iii) R1-Y1-NH-CH-C0-X1-X1'-X1"-X5-NH-CH-C0-X6-NH-Y2-R2 I I (CH 2)m - Z - (CH 2 ) n (iv) Rl-Yl-X8-NH-CH-C0-X7-Ser-X4-Leu-Asn- H-CH-C0-NH-Y2-R2 I I (CH 2)m - Z - (CH 2 ) n (v) Rl-Yl-His-Ser-Asp-Ala-X9-X14-Thr-Asp-"Asn-Tyr- Thr-Arg-Leu-Arg-Lys-Gln-X10-Ala-Xl l-Xl-Xl'-Xl"-X5- X15-X16-X17-Leu-Asn-NH-Y2-R2 (vi) Rl -Y 1 -Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr-Thr- Arg-Leu-Arg-Lys-Gln-X10-Ala-Xll-Xl-X -Xl"-X5-X15-X16- X17-Leu-Asn-NH-Y2-R2 (vii) Rl-Yl-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-X10-Ala-Xl-Xl-Xl'-Xl"-X5- X15-X16-X17-Leu-Asn-NH-Y2-R2 (viii) Rl-Yl-X12-Gln-X10-Ala-Xl l-Xl-Xl'-Xr , -X5-Ala-Ala-Val-Leu-X13-NH-Y2-R 2 wherein, Rl is selected from the group consisting of hydrogen and a saturated or unsaturated lipophilic group having at least 4 carbon atoms; R2 is selected from the group consisting of hydrogen, a saturated or unsaturated lipophilic group having at least 4 carbon atoms, a lipophilic group substituted by X3-Ser-X4-Leu-Asn-NH .2 or a spacer consisting of 1-3 residues of a non-charged amino acid coupled to Xl-Xr-Xl"-X2-NH-Y2-R2, with the proviso that at least one of Rl and R2 is a lipophilic group; Yl and Y2 are each independently -CH2-, -CO-, or a covalent bond; XI is a covalent bond, Ala, Val, Ala- Val (SEQ ID NO: 8), Val-Ala (SEQ ID NO: 9), Lys, D-Lys, Ala-Lys (SEQ ID NO: 10), Val-Lys (SEQ ID NO: 11), Ala-Val-Lys (SEQ ID NO: 12), Val-Ala-Lys (SEQ ID NO: 13), or Orn; XI ' is Lys, D-Lys or Orn; XI" is Tyr, D-Tyr, Phe, Trp or a residue of p-amino phenylalanine; X4 is He or Tyr; X5 is a residue of a hydrophobic aliphatic amino acid; X2 is X5, X5-Asn, X5-Ser, X5-Ile, X5-Tyr, X5-Leu, X5-Nle, X5-D- Ala, X5-Asn-Ser, X5-Asn-Ser-Ile, X5-Asn-Ser-Tyr, X5-Asn-Ser-Ile-Leu, X5- Asn-Ser-Tyr-Leu, X5-Asn-Ser-Ile-Leu-Asn or X5-Asn-Ser-Tyr-Leu-Asn; X3 is a covalent bond, Asn, X5, X5-Asn, Tyr-X5, Tyr-X5-Asn, Lys-X5, Lys-X5-Asn, Lys-Tyr-X5, Lys-Tyr-X5-Asn, Lys-Lys-Tyr-X5, Lys-Lys-Tyr- X5-Asn, Val-Lys-Lys-Tyr-X5, Val-Ala-Lys-Lys-Tyr-X5-Asn or Ala-Val-Lys- Lys-Tyr-X5-Asn; 01 X6 is a covalent bond, Asn, Ser, He, Tyr, Leu, Asn-Ser (SEQ ID NO: 14), Asn-Ser-Ile (SEQ ID NO: 15), Asn-Ser-Tyr (SEQ ID NO: 16), Asn-Ser- Ile-Leu (SEQ ID NO: 17), Asn-Ser-Tyr-Leu (SEQ ID NO: 18), Asn-Ser-Ile- Leu-Asn (SEQ ID NO: 19), or Asn-Ser-Tyr-Leu-Asn (SEQ ID NO: 20); X7 is a covalent bond or Asn; X8 is a covalent bond, X5, Tyr, Lys, Tyr-X5, Lys-X5, Lys-Tyr-X5, Lys- Lys-Tyr-X5, Val-Lys-Lys-Tyr-X5, Ala-Lys-Lys-Tyr-X5, or Ala-Val-Lys-Lys- Tyr-X5; X9 is a residue of a natural or non-natural amino acid, a residue of a natural or non-natural amino acid attached to threonine or a residue of a natural or non-natural amino acid attached to phenylalanine; XI 0 and XI 1 are each independently a residue of a natural or non- natural amino acid; XI 2 is a covalent bond, Lys, D-Lys or Orn; X13 is a covalent bond or Asn; X14 is Phe or Thr; XI 5 is Asn or Ala; XI 6 is Ser or Ala; XI 7 is He or Val; Z is -CONH-, -NHCO-, -S-S-, -S(CH 2 ) t CO-NH- or -NH-CO(CH ) t S-; m is 1 or 2 when Z is -CONH-, -S-S- or -S(CH 2 )tCO-NH-, or m is 2, 3 or 4 when Z is -NH-CO- or -NH-CO(CH2)tS-; n is 1 or 2 when Z is -NH-CO-, -S-S- or -NH-CO(CH )tS- or n is 2, 3 or 4 when Z is -CO-NH- or-S(CH 2 ) t CO-NH-; and t is 1 or 2. Preferably, XI, XI' are lysine, XI" is tyrosine X2 and X5 are leucine, thus yielding the KKYL (SEQ ID NO: 7), identified as the core active fragment within the VTP peptide. Additionally and preferably, XI 0, the amino acid residue at position 17 of the full length VIP peptide, is norleucine. Additionally and preferably, one of Rl-Yl and R2-Y2 is hydrogen. Additionally and preferably, XI 0 and XI 1 are each independently selected from the group consisting of leucine, isoleucine, norleucine, valine, tryptophan, phenylalanine, methionine, octahydroindole-2-carboxylic acid, cyclohexylglycine and cyclopentylglycine. Additionally and preferably, X5 is a residue of a D- or L-amino acid selected from the group consisting of alanine, leucine, isoleucine, norleucine, valine, methionine and norvaline. Additionally and preferably, X9 is alanine or glycine. Additionally and preferably, the Rl and R2 are each independently of a formula CH3(CΗ " 2)kCO, where k is an integer from 2 to 16, preferably k equals 16, i.e., stearyl. Examples of the conjugates useful in the treatment of skin disorders according to the invention are conjugates including a lipophilic moiety and peptides of characterized by a core sequence Lys-Lys-Tyr-Leu (SEQ ID NO:7) which is derived from positions 20-23 of the VIP sequence, and is shared by the VIP related peptide, PACAP. Additional or alternative sequences are of peptides including the core sequence Asn-Ser-Ile-Leu-Asn (SEQ ID NO: 19), which is derived from positions 24-28 of the VIP sequence, and 24-27 of the PACAP peptide including the core sequence Ala-Ala- Val-Leu (SEQ ID NO:23). These sequences, modified peptides thereof, in which amino acid residues have been replaced, added, deleted or chemically modified or combinations of these sequences, such as, but not limited to, (i) Stearoyl- VIP (SEQ ID NO:2); (ii) Stearyl~norleucme i7 -VIP (SEQ ID NO: 3); (iii) Stearoyl- norleucine 17 - neurotensin 6 . π VIP 7 . 28 (SEQ ID NO:5) » ( iv ) Stearoyl-Lys-Lys- Tyr-Leu-NH2 (Stearoyl-KKYL-NH2, SEQ ID NO:6); (v) Stearoyl-VTP 15 _ 23 PACAP 24 . 27 (SEQ ID NO:21); and (vi) Stearoyl- VIP 15 . 23 Nle 17 PACAP 24 _ 27 (SEQ ID NO:22). Inhibition of keratinocytes growth would be highly advantageous as a means for controlling the symptoms of hypeφroliferative skin disorders, as previously described. The conjugates described herein, composed of VIP related peptides modified at their N-terminal by the fatty acid group, stearoyl, acted as potent cytotoxic agents on human keratinocytes, including the HaCaT cell line (to this end, see Examples section, below). Previously, the cytotoxic effect of several fatty acids was reported [32]. All human lines, that were examined, responded in a dose-dependent cell death to the presence of 10-50 μM stearic acid, with varying sensitivities. While no clear answer exists to explain the observed cytotoxic effect, non-specific toxicity as a result of lipid droplets or lipid inclusions in the cytoplasm of the cells (steatosis), leading to irreversible cell degeneration [33], as well as specific effects on membrane function [34] were speculated. Although no cytotoxic effect of free stearic acid was evident in HaCaT cells, a possible contribution of the fatty moiety to the observed effect should be considered. These results reinforce the speculation on the necessity for both the peptide and the stearic acid components. Further examination of VIP derived conjugates effects on neonatal keratinocytes, has revealed that the cytotoxic effect was maintained in these cells, albeit less pronounced. The effect was also evident in the human colon carcinoma, HT29 cell line. SNV (SEQ ID NO:3), SNH (SEQ ID NO:4) and St-KKYL-NH (SEQ ID NO:6) all maintained their impact, as well as similar potency ranking in the three cell types, SNH (SEQ ID NO:4) being the most efficacious one in serum starved cells. Superior activity of SNV (SEQ ID NO:3) and SNH (SEQ ID NO:4) in the keratinocyte model, may also involve a parameter of preference to specific VIP receptors on characterizing these cells, and may bear significance in targeting specific VTP- related drugs toward therapeutics, and affecting VIP receptor bearing cells. While cAMP was not implicated in the SNV (SEQ ID NO:3) induced effects [14], SNV (femtomolar-nanomolar concentrations) -mediated increases in cGMP were implicated in neuronal survival [1 ]. Here, cytotoxic SNV (SEQ ID NO:3) concentrations significantly reduced cGMP levels (by 70 %). Hence, reduced cGMP levels may, in combination with other signals, initiate apoptosis, as described hereinabove. Although the current therapies for the treatment of, for example, psoriasis, commonly share the feature of inhibiting hyperproliferation of keratinocytes, they act through different cellular mechanisms and are accompanied by a variety of side effects that are at best unpleasant and often dangerous. For instance, tar based therapies are uncomfortable and a nuisance to apply. Immunosuppressants like methotrexate can predispose to malignancy, cyclosporine can cause renal damage and hypertension, glucocorticoids can cause local and serious systemic side effects such as adrenal suppression, vitamin D analogs can cause disordered calcium metabolism, and retinoids can have a broad range of side effects and are teratogens. Because of the distressing and disfiguring nature of psoriasis and the unsatisfactory aspects of current therapies, there is considerable interest in developing additional therapeutic approaches to treating this, and other, hypeφroliferative skin disorders. Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples. EXAMPLES Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion. The following protocols and experimental details are referenced in the Examples that follow. MA TERIALS AND EXPERIMENTAL METHODS Solid Phase Peptide and Conjugates Synthesis: Peptides were prepared by solid phase synthesis using the Fmoc chemistry as described [28]. Additional detailed solid phase synthetic and purification procedures were described in U.S. Patent Nos. 5,565,424, 5,147,855 and EP Patent No. 0620008B1 issued to Gozes et al, which are incoφorated herein by reference. Small scale automated synthesis was achieved using an ABIMED AMS-422 multiple peptide synthesizer (Abimed Analyses - Technik, Langenfeld, Germany) with 25 μmols of corresponding amino acid-bound-polymer (Rinkamide, Novabiochem, Laufelfingen, Switzerland) in each reaction vessel. Side chain protecting groups were: Boc for Lys and Tφ; Trt for Asn, Cys, Gin and His; t-Butyl for Asp, Glu, Ser, Thr and Tyr. The lipophilic stearyl group was added at the termination of the peptide chain assembly to the free α-amino group [13]. The crude cleaved peptide (after treatment of the peptidyl-resin with 90% trifiuoroacetic acid/5% H2θ/5% triethlysilane, v/v/v) was precipitated by ether, collected by centrifugation, dissolved in H2O and lyophilized. Cyclic VIP derived conjugates synthesis was achieved as described in PCT application. No. WO 97/40070 by Gozes et al. which is incoφorated herein in its entirety by reference. VIP, PACAP27 [29] and VHA were purified by reversed-phase high performance liquid chrα atography (RP-HPLC) on semipreparative RP-18 Lichrospher, 10 μm 250X10 mm column (Merck, Darmstadt, Germany), eluted by a gradient established between solution A (0.1% TFA v/v in H2O) and solution B (75% acetonitrile in H2O with 0.1% TFA) in the following conditions: t=0-5 min, 80% A, 20% B. t=5-60 min, A=30%, B=70%. SNV, SNH and St-KKYL-NH2 were purified by preparative RP-8 Lichrosorb, μm 250X25 mm column, with t=0-10 min, A, B=50%, t=10-50 min, B=100%. Shorter, more hydrophobic peptides required longer B=100% run. The isolated peptides were subjected to analytical RP-HPLC to confirm their purity and to amino acid analysis to verify their composition. Mass spectrometry was employed for molecular weight determinations. Cell cultures: Neonatal keratinocytes: Primary human neonatal keratinocytes were purchased from Clonetics (NHEK Cat. No. CC-2503, CA, USA) in their cryopreserved form, and cultivated in Keratinocyte Serum Free medium (K- SFM, Gibco-BRL, Gaithersburg MD, USA) supplemented with 25 μg/ml bovine pituitary extract (BPE) and 0.1 ng ml human recombinant epidermal growth factor (EGF). This medium is based on MCDB 153 medium, enriched by various hormones (insulin 5 μg/ml, tri-iodothyronine, transferrin, hydrocortisone 0.5 μg/ml, cholera toxin, adenine). Subculturing was achieved under serum free conditions, using trypsin: EDTA solution (0.025:0.01%), and neutralizing by soybean trypsin inhibitor (0.05 mg/ml, Biological Industries, Beit Haemek, Israel). HaCaT: Human HaCaT keratinocytes were a kind gift from Prof. Fusenig [30]. Cells were routinely propagated in minimal Eagle's Essential medium, MEM supplemented with 1% Pen-Strep-Nystatin, 2 mM L-Gln and 10% fetal calf serum (FCS, Biological Industries, Beit Haemek, Israel) under humidified atmosphere with 10% CO2 at 37 °C. Subculturing was achieved by trypsinization with Versene solution (trypsin:EDTA 0.25:0.02%), and neutralizing by serum containing medium. HT29: The human colon carcinoma cell line was routinely propagated in RPMI-1640 supplemented with 1% Pen-Strep-Nystatin, 2 mM L-Gln and 10% FCS under humidified atmosphere with 10% CO2 at 37 °C. Subculturing was achieved by trypsinization with Versene solution and neutralizing by serum containing medium. Cell viability assays: 1. Colorimetric MTS assay: Neonatal keratinocytes: Cells were seeded 10,000/well in 96 well microtiter plates (Nunc, Roskilde, Denmark), in K-SFM supplemented with bovine pituitary extract (BPE) and recombinant EGF (rEGF). The following day, medium was changed to K-SFM lacking EGF and BPE (basal medium), in order to achieve a quiescent state. Following 48 h, the medium was replaced by fresh basal medium supplemented with peptides at the indicated concentrations for an additional 22-24 h. Cells were used in their third or forth passage. Cell viability was monitored by 1.5-3 h incubation with MTS reagent (CellTiter 96 AQueous cell proliferation kit, #G5430, Promega, Madison WI, USA), oxidation of which by active mitochondria results in color development, at 490 nm. HaCaT: Cells were seeded 4,000/well in 96 well microtiter plates, in 5% FCS supplemented MEM. The following day, cells were starved by changing the medium to MEM supplemented with 0.1% bovine serum albumin (BSA) for a 48 h period, after which the peptides were added, in fresh medium, at the specified concentrations and incubation proceeded for 22-24 h period. Cell viability was monitored by 1.5-3 h incubation with the MTS reagent. Alternatively, for moderate starvation or a non-starvation protocol, cells were seeded in 10% FCS supplemented MEM, and peptides were added the following day in fresh 2% or 10% FCS supplemented medium for a 72 h period, respectively. Cell viability was monitored by 1.5-3 h incubation with the MTS reagent. HT29: Cells were seeded 4,000/well into 96 well plates in 10% supplemented RPMI-1640 (Biological Industries, Beit Haemek, Israel). Medium was changed to 0.1% BSA supplemented RPM the following day, for a 48 h period. Stearyl peptides were added, in fresh 0.1% BSA medium for additional 22-24 h. Cell viability was monitored by addition of the MTS reagent during the last 3 h of incubation. 2. Lactate dehydrogenase (LDH) determination: Supernatants from HaCaT cells exposed to stearyl peptides, with or without 25 μM aurintricarboxylic acid (ATA), the endonuclease inhibitor (Sigma, St Louis, Missouri, USA), were collected, from same wells used for MTS determination, and LDH activity evaluated by LDH-cytotoxicity detection (Boehringer-Mannheim, Mannheim, Germany), according to manufacturer's instructions. The combined LDH activity from burst cells treated with 5% Triton-XlOO in 50 mM Tris-HCl, and the LDH values obtained from their respective medium (prior to Triton treatment), were used to define 100% LDH activity (per well). Values obtained from samples were normalized according to their ratio relative to this 100% value. Measurements of intracellular cGMP accumulation: HaCaT cells were seeded, 4x10^ per 35 mm dish (Corning, MA, USA), in 5% FCS supplemented MEM, as above. On the following day, cells were starved by changing the medium to MEM supplemented with 0.1% BSA for a 48 h period. On the forth day, the medium was changed to fresh MEM (without supplements). SNV was added for a stimulation period of 15 min. Control cultures received saline. Following stimulation, the cultures were washed three times with cold PBS, and the cyclic nucleotides extracted by 30 min incubation at 4 °C in 80% ethanol and mechanical removal of the cells. The resulting suspension was pelleted by centrifugation at 2000xg for 15 min at 4 °C. The supernatants were transferred to fresh tubes and dried by Eppendorf concentrator 5301 (Eppendorf, Hamburg, Germany). Cyclic GMP content in the samples was assayed by a cGMP enzymeimmunoassay (EIA) system kit (Amersham, International Pic. Little Chalfont, Buckinghamshire, UK) according to manufacturer's instructions. EXPERIMENTAL RESULTS Anti-Proliferative Effects of Stearoyl Modified VIP-related Peptides on HaCaT cells: The lipophilic VIP antagonist, SNH, was tested for its antiproliferative activity on HaCaT cells following a 24 h incubation period (Figure 1). Results indicated that at 7.5 μM, SNH produced essentially complete cell killing. In order to estimate the time dependence of cytotoxic effect manifestation, SNH was applied for a shorter exposure period. Thus, activity of SNH was already evident after a 2 h exposure, when only 32% of the cells maintained their viability, as compared to control cultures (not shown). To test whether the stearoyl moiety, at the micromolar concentrations utilized, contributed to the cell killing effect, the super VIP agonist, SNV, was further tested. As illustrated in Figure 1, high concentration SNV (10 μM) proved to be a cytotoxic agent for the HaCaT line, inflicting not only in inhibition of cell proliferation, but near total cell destruction. Based on these observations, aiming to pinpoint the exact part of the VIP peptide, accountable for the observed cytotoxic activity, several stearoyl- modified peptides, encompassing fragments derived from the entire VIP peptide, were synthesized and evaluated. Similar to VIP, all stearoyl peptides employed were in their C-terminal amidated form. Some of these peptides also served as controls, examining the possibility of non-specific, stearyl dependent, cytotoxic effect. The various peptides, with the relevant controls, are summarized in Table 1, according to their location in the VIP peptide. Data in Table 1 indicates the following: first, stearic acid by itself was not cytotoxic to HaCaT cells, nor was its mere addition to a peptide (such as represented by gonadotropin releasing hormone, GnRH). Second, the N-terminus of the VIP peptide was less relevant to effect manifestation. Sequences of the N-terminal and middle part of the VIP peptide exhibited reduced activity, while the C- terminus part of the peptide was its active site, specifically, the KKYL sequence (Figure 1, Table 1). Third, non-covalent mixtures of stearic acid with VIP, [Nle i VIP (SEQ ID NO:2) or VHA (SEQ ID NO:4) were not cytotoxic. Table 1 Effects of stearic acid and stearoyl peptides on HaCaT cell viability Cell Survival (Percent of Control) St-peptide sequence [M] 5xl0- 6 lO" 5 5xl0- 5 SNV 54±6 22±4 ND SNH 60+6 4+1 ND N-Terminus: St-VIP(l-15) - 80+4 St-VD?(1-14) 88±3 86±4 ND C-Terminus: St-VIP(15-28) - 87±3 82+4 St-VIP(l 5-23)PACAP(24-27) 78±8 22+11 ND St-VIP(21-25) [KYLNS] 89±3 86+2 ND St-Vff(20-23) [KKYL] 74±9 36±+4 ND Stearic acid inactive inactive inactive Stearic acid+VTP inactive inactive inactive Stearic acid+VIP(Nle 17 ) inactive inactive inactive Stearic acid+VHA inactive inactive inactive St-GnRH inactive 82±2 76±3 ND - not determined. St=StearoyI; Inactive indicates +10% of control values (assigned to 100%). All peptides are in their C-terminal amidated form. Cytotoxic effects on neonatal human keratinocytes and human colon carcinoma HT-29 cell line: Since marked cytotoxic effects of SNV, SNH and St-KKYL-NH2 were observed with the HaCaT cell line, human neonatal keratinocytes were examined. As presented in Figure 2, susceptibility to stearoyl-modified VTP- derived conjugates was maintained in the neonatal keratinocytes. Similar results were also obtained with the colon carcinoma cell line, HT29, cultured under similar conditions as HaCaT (Figure 3). All three peptides maintained their impact, demonstrating similar potency and efficacy in the two cell lines, HaCaT and HT29. Somewhat different efficacy was evident in the neonatal keratinocytes. In either case, SNH was the most efficacious analog. Incubation of the HaCaT line with the stearyl peptides in the presence of serum, resulted in diminution of the effect (especially for SNH), till its total abolishment (Table 2). Culturing conditions consisted on the following: Cells were seeded into 96 well plates in either 5% (I, II) or 10% (III). FCS supplemented MEM. In (I) the peptide was added after three days in culture, in (II) and (III) the peptide was added after 24 h in culture (arrows indicate medium change). The following day the peptides were added in fresh 2 or 10% (II, III) FCS supplemented medium for a period of 72 h. The 0.1% BSA supplemented MEM (I) represents the routine conditions in which experiments were conducted. Table 2 Serum content effects on stearyl peptides cytotoxicity in HaCaT cells Culture conditions PeptideflO "5 M] % Survival I dayl day2 day4 day5 5% FCS — > 0.1% BSA — > 0.1% BSA+peptide (24h) SNV 22 SNH 4 St-KKYL 36 II dayl day2 day5 10%FCS — > 2% FCS+peptide (72h) SNV 25 SNH 49 St-KKYL 29 m dayl day2 day5 10%FCS — > 10% FCS+peptide (72h) SNV 60 SNH inactive St-KKYL inactive Mode of cytotoxic effect: Microscopic evaluation revealed a change from the cobble stone appearance under serum-enriched culture conditions (Figure 4A) to cellular elongation and a higher degree of infra-cellular spacing under serum-deprived conditions (Figure 4B). The massive cellular death that has occurred following stearoyl-peptides treatment (Figure 1, Table 1) was evaluated microscopically (Figure 4C, SNH, 10 μM and similar results were obtained for SNV and St- KKYL-NH2). A characterization of the possible mechanism involved, namely, necrotic, apoptotic or a combination of the two, was performed. To that end, the endonuclease inhibitor, ATA, an apoptosis marker commonly utilized to distinguish between these two types of cell death [31] was applied, at 25 μM concentration, together with the cytotoxic peptides. ATA interferes with the final degradation phase of the apoptotic process. While ATA itself did not dramatically change cellular morphology (Figure 4D), a remarkable restoration in cell viability was observed in cultures co-treated with SNH and ATA (Figure 4E). A quantitative evaluation of the results (by the MTS assay) showed that ATA had some intrinsic cytotoxic effect (Figure 5A as compared to Figure 5B). Thus, the ATA-restored viability value in the presence of the stearyl peptides, as demonstrated by MTS in Figure 5B, was limited to the level of viability observed in wells containing ATA only. The LDH activity, an indicator of membranal integrity, exhibited the exact mirror image of the MTS measurements (Figure 5C). The dependency of the process upon new protein synthesis was further explored. To this end, the inhibitor of protein synthesis, cycloheximide (CHI, 10 μg/ml), was added to HaCaT cultures together with the peptide, on the fourth day of culturing. CHI has a cytotoxic effect by itself, similar in its magnitude to that observed by 5 μM SNH (Table 3). It is not surprising then, that co-treatment of CHI and SNH at this concentration did not result in improved survival of the cells. Although the percent of surviving cells is T IL01/00523 almost 5 times larger at the 10 μM SNH + CHI as compared to 10 μM SNH alone (P<0.005), the improvement was only marginal compared to a 100% survival. Table 3 Effects of cycloheximide co-treatment on SNH cytotoxicity in HaCaT cells Treatment % Surviving cells CONTROL 100+2.6 CHI (10 μg/ml) 69+1.4 SNH (5 μM) 66+3.2 SNH (lO μM) 1.8+0.8 SNH (5 μM) + CHI 64+2.8 SNH (10 μM) + CHI 8.8+1.8 Cyclic GMP: SNV activated cGMP formation dose-dependently, having two peaks of activity (Figure 6). However, 10 " ^ M SNV strongly decreased basal cGMP level in the cells, which may be related to its observed cytotoxicity at this concentration. Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. LIST OF REFERENCES [I] Gozes, I., Fridkin, M., Hill, JM. and Brenneman, D.E. (1999) Current Medicinal Chemistry 6, 1019-1034. [2] Gozes I, Reshef A, Salah D, Rubinraut S, Fridkin M (1994). Endocrinology 134: 2121-2125. [3] Editorial (1991) VIP and the skin. Lancet 337, 886-888. [4] Odland, G.F. (1983) In: Biochemistry and physiology of the skin (Edited by Goldsmith LA), pp. 3-63. New York. [5] Kerr FR, Wylie AH, Currie AR (1992). Br J Cancer 26: 39-257. 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[15] Gozes, I., Bardea, A., Reshef, A., Zamostiano, R., Zhukovsky, S., Rubinraut, S., Fridkin, M. and Brenneman, D.E. (1996) Proc. Natl. Acad. Sci. USA 93, 427-432. [16] Ashur-Fabian, O., Perl, O., Lilling, G., Fridkin, M. and Gozes, I. (1999) Peptides 20, 629-633. [17] McConkey D.J. and Orrenius S. (1994). Trends Cell Biol 4: 370-374. [18] Gozes, I., McCune, S.K., Jacobson, L., Warren, D., Moody, T.W., Fridkin, M. and Brennemen, D.E. (1991) J. Pharmacol. Exp. Therap. 257, 956-966. [19] Gressens, P., Hill, J.M., Gozes, I., Fridkin, M. and Brenneman, D.E. (1993) Nature 362, 155-158. [20] Moody, T.W., Zia, F., Draoui, M., Brenneman, D.E., Fridkin, , M., Davidson, A. and Gozes, I. (1993) Proc. Natl. Acad. Sci. USA 90, 4345- 4349. [21] Zia, H., Hida, T., Jakowlew, S., Birrer, M., Gozes, Y, Reubi, J.C., Fridkin, M., Gozes, I. and Moody, T.W. (1996) Cancer Res. 56, 3486- 3489. [22] Lilling, G., Wollman, Y., Goldstein, M.N., Rubinraut, S., Fridkin, M., Brenneman, D.E. and Gozes, I. (1995) J. 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[32] Fermor, B.F., Masters, J.R.W., Wood, C.B., Miller, J., Apostolov, K. and Habib, N.A. (1992) Eur. J. Cancer 28A (6,7), 1143-1147. [33] Moskowitz, M.S. (1967) In: Rothblatt GH, ed. Lipid metabolism in tissue culture cells. Philadelphia, D. Kritchevsky Wistar Inst. Press. [34] Spector, A.A. and Yorek, M.A. (1985) J. Lipid Res. 26, 1015-1035. [35] Cory S. (1995). Ann Rev Immunol 13: 513-543. [36] Stewart, B. W. (1994) J. Natl. Cane. Inst. 86, 1286-1296. [37] Martin, S.J. (1993) Trends Cell Biol. 3, 141-144. [38] Haake A.R., Roublevskaia I., Cooklis M. (1998). J Invest Dermatol [39] Budtz P.E. and Spies I. (1987). Cell Tissue Res 256: 475-486. [40] Polakowska R.R. and Haake A.R. (1994). Cell Death Differ 1: 19-31.

Claims: CLAIMS: 1. A pharmaceutical composition for the treatment of hyperproliferative skin disorders comprising a pharmaceutically acceptable carrier and as active ingredient a peptide selected from the group consisting of: (vii) vasoactive intestinal peptide (VIP) (viii) a VIP antagonist (ix) a peptide analog of (i) or (ii) in which one or more amino acids has been replaced, added or deleted without substantially altering the biological properties of the parent peptide; (x) a physiologically active fragment of (i), (ii) or (iii); (xi) a physiologically active fragment of (i) coupled to a fragment of pituitary adenylate cyclase activating peptide (PACAP) and a peptide analog thereof in which one or more amino acids has been replaced, added or deleted; (xii) a conjugate of (i) to (v) coupled at the amino and/or the carboxy terminal to a Cι-C 4 hydrocarbyl, C C 4 carboxylic acyl or to a lipophilic moiety; and (vii) a functional derivative of any of (i) to (vi). 2. The pharmaceutical composition according to claim 1, comprising VIP of the sequence: His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn 3. The pharmaceutical composition according to claim 1, comprising a VIP antagonist of the sequence: Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn 4. The pharmaceutical composition according to claim 1, wherein said analog of VIP in which one or more amino acids has been replaced has the sequence: His-Ser-Asp-Ala-X^Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-X 2 -AIa-X 3 -Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn wherein X 1 , X 2 and X 3 are the same or different and each is the residue of a natural or non-natural amino acid, provided that when both X 1 and X 3 are valine, X 2 is not methionine, 5. The pharmaceutical composition according to claim 1, wherein said analog of a VIP antagonist in which one or more amino acids has been replaced has the sequence: Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-Y -Ala-Y -Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn wherein Y and Y are the same or different and each is the residue of a natural or non-natural amino acid, provided that Y is not methionine. 6. The pharmaceutical composition according to claim 4 or 5, wherein X 1 , X 2 and X , and Y and Y , are the same or different and each is a natural amino acid selected from the group consisting of leucine, isoleucine, valine, tryptophan, phenylalanine and methionine, or a non-natural amino acid is selected from the group consisting of a D-amino acid, norleucine (Nle), norvaline, α-aminobutyric acid, di-amino butyric acid, di-aminopropionic acid, -HN(CH 2 ) n COOH, wherein n is 3-5, -NH(C H 2(R))n-COON, wherein R is an alkyl, H 2 N(CH2)mCOOH, wherein m is 2-4, H2N~C(NH)-NH(CH 2 )kCOOH, wherein k is 2-3, hydroxy-lysine, N-methyl-lysine, ornitine, p-amino- phenylalanine, methyl- phenylalanine, halo-phenylalanine, naphthylalanine, TIC, o-methyl-tyrosine, octahydroindole-2-carboxylic acid, cyclohexylglycine and cyclopentylglycine. 01 7. The pharmaceutical composition according to claim 1, wherein said physiologically active fragment of VIP or of an analog thereof has a sequence selected from the group consisting of: (i) X 4 -X 5 -X 6 -X 7 -NH-R2 (ii) X 8 -Ser-X 9 -Leu-Asn (iii) CH CO-Lys-Lys-Tyr-X^-NH-CH-CO-X 11 -NH 2 I I (CH 2)m Z (CH 2 ) n (iv) X 13 -NH-CH-CO-X 12 -Ser-X 9 -Leu-Asn-NH-CH-CO-NH 2 (CH 2 ) m (CH 2 )n wherein X 4 is a covalent bond, Ala, Val, Ala- Val, Val- Ala, Lys, D-Lys, Ala-Lys, Val-Lys, Ala-Val-Lys, Val-Ala-Lys or Orn; X 5 is L-Lys, D-Lys or Orn; X 6 is L-Tyr, D-Tyr, Phe, Trp or a residue of p-amino-phenylalanine; X 9 is He or Tyr; X 10 is a residue of a hydrophobic aliphatic amino acid; X 7 is X 10 , X 10 -Asn, X 10 -Ser, X 10 -Ile, X 10 -Tyr, X 10 -Leu, X 10 -Nle, X 10 -D- Ala, X 10 -Asn-Ser, X 10 -Asn-Ser-Ile, X 10 -Asn-Ser-Tyr, X 10 -Asn-Ser-Ile-Leu, X 10 -Asn-Ser-Tyr-Leu, X 10 -Asn-Ser-Ile-Leu-Asn or X 10 -Asn-Ser-Tyr-Leu-Asn; X 8 is a covalent bond, Asn, X 10 , X 10 -Asn, Tyr-X 10 , Tyr-X I0 -Asn, Lys- X 10 , Lys-X 10 -Asn, Lys-Tyr-X 10 , Lys-Tyr-X 1 °-Asn, Lys-Lys-Tyr-X 10 , Lys-Lys-Tyr-X 10 -Asn, Val-Lys-Lys-Tyr-X 10 , Val-Ala-Lys-Lys-Tyr-X 10 -Asn or Ala-Val-Lys-Lys-Tyr-X 10 -Asn; X 11 is a covalent bond, Asn, Ser, He, Tyr, Leu, Asn-Ser, Asn-Ser-Ile, Asn-Ser-Tyr, Asn-Ser-Ile-Leu, Asn-Ser-Tyr-Leu, Asn-Ser-Ile-Leu-Asn or Asn- Ser-Tyr-Leu-Asn; X 12 is a covalent bond or Asn; X 13 is a covalent bond, X 10 , Tyr, Lys, Tyr-X 10 , Lys-X 10 , Lys-Tyr-X 10 , Lys-Lys-Tyr-X 10 , Val-Lys-Lys-Tyr-X 10 , Ala-Lys-Lys-Tyr-X 10 , or Ala-Val-Lys- Lys-Tyr-X 10 ; Z is -CONH-, -NHCO-, -S-S-, -S(CH 2 ) t CO-NH- or -NH-CO(CH 2 ) t S-; m is 1 or 2 when Z is -CONH-, -S-S- or -S(CH2)tCO-NH-, or m is 2, 3 or 4 when Z is -NH-CO- or -NH-CO(CH2) t S-; n is 1 or 2 when Z is -NH-CO-, -S-S- or -NH-CO(CH2)tS- or n is 2, 3 or 4 when Z is -CO-NH- or-S(CH2) t CO-NH-; and t is 1 or 2. 8. The pharmaceutical composition according to claim 7, wherein said physiologically active fragment of VIP or of an analog thereof is selected from the group consisting of: Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH Lys-Lys-Tyr-Leu-NH 2 Lys-Lys-Tyr-dAla-NH 2 Val-Lys-Lys-Tyr-Leu-NH 2 Ala-Val-Lys-Lys-Tyr-Leu-NH 2 Asn-Ser-Ile-Leu-Asn-NH 2 Lys-Lys-Tyr-Val-NH 2 Ser-Ile-Leu-Asn-NH 2 Asn-Ser-Tyr-Leu-Asn-NH 2 Asn-Ser-Ile-Tyr-Asn-NH 2 Ala-Val-Lys-NH 2 Lys-Tyr-Leu-NH Lys-Lys-Tyr-Nle-NH 2 Ala-Val-Lys-Lys-Tyr-NH 2 Val-Lys-Lys-Tyr-Leu-NH 2 Leu-Asn-Ser-Ile-Asn-NH 2 Tyr-Leu-Asn-Ser-Ile-Asn-NH 2 9. The pharmaceutical composition according to 1, comprising a peptide consisting of a physiologically active fragment of VIP coupled to a fragment of pituitary adenylate cyclase activating peptide (PACAP) or an analog thereof, said peptide being selected from the group consisting of VJJPi 5 _ 3 PACAP 24 - 27 and VIP 15 _ 23 Nle 17 PACAP 24 . 27 of the sequences: Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala- Val-Leu, and Lys-Gln-Nle-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala- Val-Leu, and 10. The pharmaceutical composition according to claim 1, comprising a conjugate of VIP or of a VIP analog, of the sequence: R 1 - Y 3 -His-Ser-Asp-Ala-X^Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-X 2 -Ala-X 3 -Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH-Y 4 -R 2 wherein X 1 , X 2 and X 3 are the same or different and each is the residue of a natural or non-natural amino acid; R 1 and R 2 are the same or different and each is hydrogen, a saturated or unsaturated lipophilic group or a C } -C 4 hydrocarbyl or C 1 -C 4 carboxylic acyl, with the proviso that at least one of R 1 and R 2 is a lipophilic group; and Y 1 and Y 2 may be the same or different and each is -CH - or a bond in case the associated R 1 and R 2 is hydrogen and Y 1 may further be -CO-. 11. The pharmaceutical composition according to claim 1, comprising a conjugate of a VIP antagonist or of an analog thereof, of the sequence: R'-Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg- Lys-Gln-Y^Ala-Y 2 -Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-AsnNH- R 2 wherein R 1 and R 2 are the same or different and each is hydrogen, a saturated or unsaturated lipophilic group or a C 1 -C 4 hydrocarbyl or C 1 -C 4 carboxylic acyl, with the proviso that at least one of R 1 and R 2 is a lipophilic group; and Y 1 and Y 2 are the same or different and each is the residue of a natural or non-natural amino acid. 12. The pharmaceutical composition according to claim 1, comprising a conjugate of a peptide according to any one of claims 7 to 9, said conjugate having at the amino and/or carboxy terminal radicals R 1 and R 2 , the same or different, each of them being hydrogen, a saturated or unsaturated lipophilic group or a Cι-C 4 hydrocarbyl or C 1 -C 4 carboxylic acyl, with the proviso that at least one of R 1 and R 2 is a lipophilic group. 13. The pharmaceutical composition according to any one of claims 10 to 12, wherein said lipophilic moiety is selected from the group consisting of a saturated or unsaturated hydrocarbyl or carboxylic acyl radical having at least 5 carbon atoms. 14. The pharmaceutical composition according to claim 13, wherein said lipophilic moiety is a saturated or unsaturated carboxylic acyl having at least 5 carbon atoms selected from caproyl (Cap), lauroyl (Lau), palmitoyl, stearoyl (St), oleyl, eicosanoyl, docosanoyl, and the corresponding hydrocarbyl radicals hexyl, dodecyl, hexadecyl, octadecyl, eicosanyl, and docosanyl. 15. The pharmaceutical composition according to claim 14, wherein said conjugate is selected from the group consisting of: Stearoyl-VIP (St-VIP) Stearoyl- norleucine 17 - VIP (St-Nle 17 -VIP ; SNV) Caproyl- norleucine 17 - VIP (Cap-Nle 17 -VIP) Stearoyl-leucine 5 , norleucine 17 - VIP (St-Leu 5 , Nle 17 -VTP) Stearoyl-leucine 5 , leucine 17 - VIP (St-Leu 5 , Leu 17 -VιP) Stearoyl-threonine 7 -VIP (St-Thr 7 -VIP) Stearoyl- norleucine 17 -neurotensin 6 .π VIP 7 . 2 s (SNH) Stearoyl- VIPι 6 . 28 , St-VIP 7 . 28 and St- VIPι 6 . 28 Stearoyl-Lys-Lys-Tyr-Leu-NH 2 Stearoyl- VIPi 5 . 23 PACAP 24 . 27 and Stearoyl- VIPi5- 23 Nle 17 PACAP 2 4- 2 7 : 16. Use of a peptide as defined in any one of the claims 1 to 15 for the preparation of a pharmaceutical composition for the treatment of hyperproliferative skin disorders. 17. A method for treating a hyperproliferative skin disorder of a patient, the method comprising the step of administering to a skin area of the patient a therapeutically effective amount of a peptide as defined in any one of the claims 1 to 15. 18. The method of claim 17, wherein said hyperproliferative skin disorder is selected from the group consisting of psoriasis, hyperproliferation caused by papilloma virus infection, dermatoses, eczemas, keratodermas, porokeratoses, keratosis, hyperkeratosis, keloid, ichthyosis, dry skin, warts, corns, calluses, dandruff and skin cancer. 19. The method of claim 17, wherein said therapeutically effective amount of said peptide is formulated into a pharmaceutical composition. 20. The method of claim 19, wherein said pharmaceutical composition contains a pharmaceutically acceptable carrier. 21. The method of claim 17, further comprising the step of administering a therapeutically effective amount of a substance traditionally used for treatment of said hyperproliferative skin disorder. 22. The method of claim 21, wherein said substance is selected from the group consisting of an immunosuppressant, an antimetabolite, a corticosteroid, vitamin D, a vitamin D analog, vitamin A, a vitamin A analog, tar, coal tar, a keratolytic agent, a keratoplastic agent, an anti-pruritic agent, an emollient, a lubricant, a disinfectant, an antiseptanf, a photosensitizer and UV irradiation. 23. A pharmaceutical composition for treating a hyperproliferative skin disorder comprising, as active ingredients, therapeutically effective amounts of a peptide as defined in any one of the claims 1 to 15 and a substance traditionally used for treatment of said hyperproliferative skin disorder. 24. The pharmaceutical composition of claim 23, wherein said hyperproliferative skin disorder is selected from the group consisting of psoriasis, hyperproliferation caused by papilloma virus infection, dermatoses, eczemas, keratodermas, porokeratoses, keratosis, hyperkeratosis, keloid, ichthyosis, dry skin, warts, corns, calluses, dandruff and skin cancer. 25. The pharmaceutical composition of claim 24, wherein said substance is selected from the group consisting of an immunosuppressant, an antimetabolite, a corticosteroid, vitamin D, a vitamin D analog, vitamin A, a vitamin A analog, tar, coal tar, a keratolytic agent, a keratoplastic agent, an anti-pruritic agent, an emollient, a lubricant, a disinfectant, an antiseptant, a photosensitizer and UV irradiation. 26. A method of inducing cell apoptosis, the method comprising the step of subjecting cells to a a peptide as defined in any one of the claims 1 to 15. 27. A pharmaceutical composition as claimed in any one of claims 1-15 and 23- 25, adapted for topical application. 28. A pharmaceutical composition according to claim 27, wherein the pharmaceutical composition is in the form of a cream, gel, suspension, ointment, solution, foam or liposomal composition. 29. A peptide selected from the group consisting of VIPι 5 . 23 PACAP 24 . 27 and VIPi 5 _ 23 Nle 17 PACAP 24 . 27 , of the sequences: Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu, and Lys-Gln-Nle- Ala- Val-Lys-Lys-Tyr-Leu-Ala-Ala- Val-Leu

Inventors: BRENNEMAN E DOUGLAS, FRIDKIN MATITYAHU, GOZES ILLANA, GRANOTH RUTH, BRENNEMAN, E., DOUGLAS, FRIDKIN, MATITYAHU, GOZES, ILLANA, GRANOTH, RUTH
Applicants: BRENNEMAN E DOUGLAS, FRIDKIN MATITYAHU, GOZES ILLANA, GRANOTH RUTH, UNIV RAMOT, US HEALTH, YEDA RES & DEV, BRENNEMAN, E., DOUGLAS, FRIDKIN, MATITYAHU, GOZES, ILLANA, GRANOTH, RUTH, RAMOT UNIVERSITY AUTHORITY FOR APPLIED RESEARCH &, THE GOVERNMENT OF THE UNITED STATES OF AMERICA REPRESENTED BY THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES, YEDA RESEARCH AND DEVELOPMENT CO. LTD.
Application year: 2001
Main classification: A61K38
IPC codes: A61K38, A61P17