Compounds for medicinal use

Muramyl peptide compounds are useful in the prophylaxis of cancers and particularly in the treatment of precancerous lesions associated with cancers of the mucosa or epithelium.

FIELD OF THE INVENTION 
The present invention relates to the use of muramyl peptide compounds in 
the prophylaxis of cancers, including the treatment of pre-cancerous 
conditions. 
BACKGROUND OF THE INVENTION 
Cancer is a term which is used to describe the development of abnormal 
cells which grow in a rapid and uncontrolled manner and are often 
invasive. The invasion of vital organs frequently results in the death of 
a patient. 
Cancer is extremely widespread and, indeed, it is thought that about 30% of 
people are likely to contract cancer at some time in their lives with 
cancer being the cause of death in around 20%. Traditional treatments for 
cancer include surgery and radiotherapy but, more recently, attention has 
been turned to the development of chemotherapeutic or cytotoxic agents 
which can damage or kill cancer cells. 
In recent years, increasing attention has been drawn towards the occurrence 
of tissue changes that are indicative of an increased risk for the 
subsequent development of particular cancers at that site of change. A 
variety of these have been described, including modifications of the 
intestinal wall (intestinal polyps) which are associated with increased 
incidence of cancers of the colon and rectum, alterations of the skin 
(actinic keratoses) which are associated with carcinomas of the skin, and 
condylomata of the cervix, which are associated with cancer of the uterine 
cervix. To one skilled in the art, these conditions or tissue changes 
tending to proceed to cancer, to be associated with the development of 
cancer, or to carry a significant risk of cancer are known as precancerous 
conditions or lesions. In some cases, the cause of these precancerous 
conditions is reasonably well established, as in the case of actinic 
keratoses resulting from excessive exposure to sunlight, or infection with 
human papilloma virus in the case of condylomata of the cervix (Cancer in 
Practice by G J G Rees, S E Goodman and J A Bullimore. Pub 
Butterworth-Heinemann, Oxford, 1993). In other cases, the cause of the 
precancerous lesion has not been identified. 
The present invention relates to the use of certain muramyl peptide 
compounds (MDPs) in the prophylaxis of cancer and especially in the 
treatment of precancerous lesions. 
It has long been known that non-specific stimulation of the immune system 
can be brought about by exposure to bacteria, or components extracted from 
bacterial cells. The specific components responsible for this activity 
were identified as sugar-containing peptides of the cell wall, and further 
biochemical analysis of the peptides identified them as the peptidoglycan 
component of the cell wall. The smallest effective synthetic molecule was 
found to be an N-acetyl-muramyl-L-alanyl-D-isoglutamine (Merser et al, 
Biochem. Biophys. Res. Comm. 66 1316 (1975)) which is often referred to as 
a prototype muramyl dipeptide or prototype MDP. 
Subsequently, a wide variety of analogues of prototype muramyl dipeptide 
were synthesised, some of which have been proposed as treatments for the 
restoration of immune function or the non-specific stimulation of the 
immune system. These analogues, and prototype MDP itself are known as 
muramyl peptide compounds (MDPs). 
In the past, some work has been carried out on the use of MDPs in the 
treatment of cancer and, for example, Key et al, J. Natl. Cancer Inst., 
69(5), 1189-1198 (1982) describe the treatment of lung melanoma metastases 
with liposomes containing an MDP derivative. Later, the same group of 
workers investigated the optimal conditions and limitations for the 
eradication of melanoma metastases using a liposome encapsulated MDP 
derivative, MTP-PE (Fidler et al, Cancer Imnunol. Inmmunother., 21(3) 
169-173 (1986)). In addition it was found that orally administered 
non-liposome encapsulated MTP-PE produced tumouricidal activity in both 
lung and peritoneal macrophages and was effective in inhibiting lung and 
lymph node metastasis although it was not effective in eradicating well 
established melanoma metastases (Fidler et al, J. Immunol., 138(12), 
4509-4514 (1987)). 
Phillips et al, J. Biol. Response Modif., 6(6), 678-691 also describe work 
relating to the treatment of experimental pulmonary metastases using 
liposomes containing lipophilic MDP analogues. Again, the compounds were 
used to treat experimentally induced pulmonary B16 melanoma tumours in 
mice. However, Kleinerman et al in J. Clin. Oncology, 9(2), 259-267 (1991) 
concluded that it is unlikely that the MDP derivative L-MTP-PE can serve 
as a single modality in treating metastatic disease. 
Some MDPs have been used in clinical trials for human therapy. For example, 
Kleinerman et al (Kleinerman, E S, Cancer Immunol. Immunother, 34: 
211-220, 1992) have used a lipophilic analogue in a liposomal formulation 
in the treatment of lung metastases developed in patients with 
osteosarcoma. 
SUMMARY OF THE INVENTION 
Despite the above attempts to demonstrate the utility of MDPs in the 
treatment of cancer, and despite the fact that MDP was discovered about 20 
years ago, no single example of a significant beneficial effect of MDP in 
the treatment of a cancer in man has been recorded. 
However, the present inventors have now discovered that certain muramyl 
peptide derivatives are particularly effective in a method for the 
treatment of precancerous lesions, the method comprising administering to 
a patient suffering from a precancerous lesion an effective amount of a 
muramyl peptide compound. This method of treatment therefore constitutes a 
prophylactic approach to the treatment of cancers. 
Not only is this approach novel, it is clearly beneficial to the patient, 
as it is always preferable to prevent the occurrence of a cancer rather 
than undergo the long, dangerous, uncomfortable and frequently 
unsuccessful treatment of an existing cancer. 
Therefore, in a first aspect of the present invention, there is provided 
the use of a muramyl peptide compound in the preparation of an agent for 
the treatment of a precancerous lesion. 
The agent may be used for the treatment of any type of precancerous lesion 
although it is especially preferred for the treatment of precancerous 
lesions leading to mucosal or epithelial cancers. 
The present invention also provides the use of a muramyl peptide compound 
in the preparation of an agent for the prophylaxis of a cancer. 
Again, the agent may be used for the prophylaxis of any type of cancer 
although it is most succesfully used for the prophylaxis of epithelial and 
mucosal originating cancers. The prophylactic activity of the agent arises 
in some cases from its use in the treatment of precancerous lesions but 
there may also be cases where the agent has a prophylactic effect for 
patients at risk of cancer but having no precancerous lesions. 
Pyrogenicity is a problem which has caused difficulties for the 
exploitation of certain muramyl peptide compounds. Pyrogenicity may be 
attenuated by appropriate formulations (for example the liposomal 
formulations of U.S. Pat. No. 4,522,811 and U.S. Pat. No. 4,684,625), but 
in general it will be preferable to choose for use in the present 
invention a muramyl peptide compound of low intrinsic pyrogenicity. 
DETAILED DESCRIPTION OF THE INVENTION 
Many muramyl peptide compounds useful in the present invention fall within 
general formula I: 
##STR1## 
wherein: R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.22 acyl 
group; 
R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.22 acyl group; 
R.sup.3 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group; 
R.sup.4 represents a C.sub.1 -C.sub.21 alkyl group or a C.sub.6 or C.sub.10 
aryl group; 
R.sup.5 represents a hydrogen atom; and 
R represents the residue of an amino acid or a linear peptide built up of 
from 2 to 6 amino acid residues, at least one of the residues being 
optionally substituted with a lipophilic group. 
Preferred acyl groups for R.sup.1 and R.sup.2 are C.sub.1 -C.sub.5 acyl 
groups such as acetyl; it will be appreciated that the carbon count in the 
acyl group does not include the carbonyl moiety. Preferred alkyl groups 
for R.sup.3 are C.sub.1 -C.sub.4 alkyl groups such as methyl and ethyl. 
Preferred alkyl groups for R.sup.4 are C.sub.1 -C.sub.6 alkyl groups, 
particularly C.sub.1 -C.sub.4 alkyl groups, such as methyl or ethyl; 
phenyl is a preferred aryl group. 
R preferably represents a mono-, di- or tri-peptide. The proximal peptide 
residue (or the only peptide residue, if there is only one) is preferably 
that of an L-amino acid. Examples include: 
______________________________________ 
L-alanyl L-tryptophanyl 
L-valyl L-lysyl 
L-leucyl L-ornithyl 
L-isoleucyl L-arginyl 
L-.alpha.-aminobutyryl 
L-histidyl 
L-seryl L-glutamyl 
L-threonyl L-glutaminyl 
L-methionyl L-aspartyl 
L-cysteinyl L-asparaginyl 
L-phenylalanyl L-prolyl 
L-tyrosyl L-hydroxyprolyl 
______________________________________ 
L-alanyl is preferred, as is L-threonyl. 
The next amino acid from the proximal end of the peptide is preferably of 
the D-configuration. It is preferably acidic and may be D-glutamic or 
D-aspartic acid or a mono-, di- or mixed C.sub.1 -C.sub.22 (preferably 
C.sub.1 -C.sub.6) alkyl ester, amide or C.sub.1 -C.sub.4 alkyl amide 
thereof. (The expression "mixed" is illustrated when one carboxyl group is 
amidated and the other esterified. D-isoglutamine and D-glutamate are 
preferred. 
A third amino acid residue from the proximal end of the chain, if there is 
one, is preferably of the L-configuration, as indicated above in relation 
to the proximal amino acid residue. L-alanyl and L-lysyl are preferred. 
The amino acid residue or linear peptide is optionally substituted with at 
least one lipophilic group. The lipophilic group may be a C.sub.10 
-C.sub.22 acyl group such as stearoyl or a di-(C.sub.10 -C.sub.22 
acyl)-sn-glycero-3'-hydroxy-phospheryloxy-group wherein for example each 
of the C.sub.10 -C.sub.22 acyl groups can be a palmitoyl group. The 
lipophilic group may alternatively (or in addition, as more than one 
substitution may be present) be a C.sub.1 -C.sub.10 ester group, such as a 
C.sub.2 -C.sub.6 ester group: a butyl ester is an example. 
Examples of muramyl dipeptides within the scope of general formula I 
include: 
muroctasin, otherwise known as MDP-Lys (L18) (N.sup.2 
-(N-acetylmuramyl-L-alanyl-D-isoglutaminyl)-N.sup.6 -stearoyl-L-lysine); 
MTP-PE 
(N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanyl-2-(1',2'-dipalmitoyl-s 
n-glycero-3'-hydroxy-phosphoryloxy)ethylamide, monosodium); 
murabutide (N-acetylmuramyl-L-alanyl-D-glutamine-.alpha.-N-butyl ester); 
and 
t-MDP (N-acetylmuramyl-L-threonyl-D-isoglutamine). 
The preparation of muroctasin is disclosed in EP-A-0021367 and U.S. Pat. 
No. 4,317,771. The preparation of MTP-PE is disclosed in EP-A-0025495. The 
preparation of murabutide is described in Lefrancier et al, J. Med. Chem., 
25 87 (1982). The preparation of t-MDP can be prepared by methods known in 
the art. Patent publications which give details of the preparations of 
muramyl peptide compounds generally include BE-A-0834753, BE-A-0834754, 
BE-A-0847103, BE-A-0849214, DE-A-2710455, DE-A-2922533, DE-A-2747379, 
DE-A-2912865, FR-A-2355505, FR-A-2358159, FR-A-2375249, EP-A-0004512, 
EP-A-0002677, JP-A-54063016, JP-A-54073729, JP-A-55019236, U.S. Pat. No. 
4,082,735 and U.S. Pat. No. 4,082,736. (The preparation of prototype 
muramyl dipeptide is disclosed in DE-A-2450355 and U.S. Pat. No. 
4,235,771.) All the documents referred to in this specification are 
incorporated herein by reference. 
Not all muramyl dipeptides useful in the present invention fall within 
general formula I. Many fall within general formula II, which represents a 
very much preferred group of compounds for use in the invention: 
##STR2## 
wherein: R represents a residue of an amino acid or a linear peptide built 
of from 2 to 6 amino acid residues, at least one of the residues being 
optionally substituted with a lipophilic group; and 
n is 1 or 2. 
The compound may also be an anomer of general formula II. Preferred values 
for R are as described above in relation to general formula I. It is 
particularly preferred that the peptide R correspond to the peptide in 
prototype MDP (L-Ala-D-isoGln). Alternatively, in another preferred 
embodiment, R may represent L-Ala-D-Glu. 
The preferred value for n is 1. 
Compounds of general formula II are disclosed in U.S. Pat. No. 4,395,399 
and the preferences set out in that document are equally preferred in the 
present invention. Additionally, in this invention, the group R may be 
substituted lipophilically as described above. 
One of the most preferred compounds for use in the present invention falls 
within general formula II and is 
N-acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-L-alanyl-D-isoglutamin 
e (GMDP), the structure of which is: 
##STR3## 
This compound (Compound II in U.S. Pat. No. 4,395,399), also known as 
glycopin, has already undergone preclinical toxicity testing and 
pharmacokinetic investigations required for licensing for clinical use in 
the USSR (as it then was). The acute toxicity in mice, measured by the 
LD.sub.50 test is 7 g/kg. This figure shows the compound to be almost an 
order of magnitude less toxic than muroctasin which has an LD.sub.50 value 
in mice of 625 mg/kg and for which the therapeutic use is associated with 
unpleasant side effects such as fever. 
While the pyrogenicity of GMDP is about 50% that of MDP and has not 
prevented its clinical evaluation, it may in some circumstances be 
preferable to use an even less pyrogenic analogue. Such an analogue is 
available, and is 
N-acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-L-alanyl-D-glutamic 
acid (GMDP-A), which is Compound III in U.S. Pat. No. 4,395,399, and whose 
structure is as follows: 
##STR4## 
Other preferred compounds within the scope of general formula II include: 
N-acetyl-D-glucosaminyl-(.beta.1-4)-N acetylmuramyl-L-alanyl-L-isoglutamine 
(GMDP-LL) which has the structure: 
##STR5## 
N-acetyl-D-glucosaminyl-(.beta.1-4)-N acetylmuramyl-L-alanyl-D-glutamine 
n-butyl ester (GMDP-OBu) which has the structure: 
##STR6## 
N-acetyl-D-glucosaminyl-(.beta.1-4)-N 
acetylmuramyl-L-alanyl-D-isoglutaminyl-L-lysine (GMDP-Lys) which has the 
structure: 
##STR7## 
N.sup..alpha. 
-N-acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-L-alanyl-D-isoglutam 
inyl!-N.sup..epsilon. -stearoyl-L-lysine (GMDP-Lys(St)) which has the 
structure: 
##STR8## 
Other useful compounds include: 
N.sup..alpha. -N 
-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetyl-muramyl-L-alanyl-.gamma.-D-glu 
tamyl!-N.sup..epsilon. -stearoyl-L-lysine which has the structure: 
##STR9## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-L-alanyl-D-glutamic 
acid dibenzyl ester which has the structure: 
##STR10## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-N-methyl-L-alanyl-D-iso 
glutamine which as the structure: 
##STR11## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-(.beta.1-4)-N-acetyl-D- 
glucosaminyl-(.beta.1-4)-N-acetylmuramyl-bis-(L-alanyl-D-isoglutamine) 
which has the structure: 
##STR12## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-(.beta.1-4)-N-acetyl-D- 
glucosaminyl-(.beta.1-4)-N-acetylmuramyl-bis-(L-alanyl-D-glutamic acid) 
which has the structure: 
##STR13## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-(.beta.1-4)-N-acetyl-D- 
glucosaminyl-(.beta.1-4)-N-acetylmuramyl-bis-(L-alanyl-D-isoglutaminyl-L-ly 
sine) which has the structure: 
##STR14## 
N-acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-(.beta.1-4)-N-acetyl-D- 
glucosaminyl-(.beta.1-4)-N-acetylmuramyl-bis-L 
alanyl-D-isoglutaminyl-N.sup..epsilon. -stearoyl-L-lysine!: 
##STR15## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-L alanyl-D-isoglutamine 
1-adamantyl ester which has the structure: 
##STR16## 
L-Threonyl-N.sup..epsilon. - 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetyl-muramyl-L-alanyl-.gamma.-D-i 
soglutaminyl!-L-lysyl-L-prolyl-L-arginine which has the structure: 
##STR17## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetyl-muramyl-L-alanyl-.gamma.-D-iso 
glutaminyl-L-threonyl-L-lysyl-L-prolyl-L-arginine which has the structure: 
##STR18## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-L-alanyl-.alpha.-D-glut 
amyl-L-lysyl-L-threonyl-N.sup..epsilon. 
-stearoyl-L-lysyl-L-prolyl-L-arginine which has the structure: 
##STR19## 
N.sup..epsilon. 
-N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetyl-muramyl-L-alanyl-.gamma.-D- 
isoglutaminyl!-L-lysyl-L-histidyl-L-glycine amide which has the structure: 
##STR20## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-L-alanyl-D-isoglutaminy 
l-L-glutamyl-L-tryptophan which has the structure: 
##STR21## 
N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetylmuramyl-L-alanyl-D-isoglutaminy 
l-.epsilon.-aminohexanoyl-L-glutamyl-L-tryptophan which has the structure: 
##STR22## 
N.sup..alpha. 
-N-Acetyl-D-glucosaminyl-(.beta.1-4)-N-acetyl-muramyl-L-alanyl-D-isogluta 
minyl!-N.sup..epsilon. -stearoyl-L-lysyl-L-glutamyl-L-tryptophan which has 
the structure: 
##STR23## 
N-acetylmuramyl-L-alanyl-D-glutamine n-butyl ester which has the structure: 
##STR24## 
In the above structures, the following abbreviations are used: 
Bzl--benzyl; 
Me--methyl; 
Ahx--.epsilon.-aminohexanoyl. 
The most preferred compound is GMDP followed by GMDP-A, and murabutide. 
Glucosaminyl-muramyl dipeptides within the scope of general formula II can 
be prepared relatively cheaply and in reasonably large quantities by the 
process disclosed in U.S. Pat. No. 4,395,399. The preparation disclosed is 
based on the extraction and purification of the disaccharide component 
from the bacterium Micrococcus lysodecticus and its subsequent chemical 
linkage to a dipeptide synthesised for example by conventional peptide 
chemistry. However, the disaccharide may equally well be chemically 
synthesised using standard sugar chemistry. 
A further advantage of the preferred compounds of general formulae I and II 
mentioned above is that they are water soluble which facilitates their 
administration to patients. 
The prophylactic use of MDPs may arise from the effectiveness of the 
compounds in the treatment of pre-cancerous conditions. 
An example of such a pre-cancerous condition occurs in cervical cancer 
where cancer tends to be initiated by the formation of papillomas which 
may be associated with infection by a strain of human papilloma virus. 
Papillomas can easily be detected and are generally treated by 
cauterisation or with liquid nitrogen followed by surgical removal. 
However, if left untreated, the papillomas tend to progress to neoplasia 
and the formation of cervical cancer which is extremely difficult to 
treat. Since the mortality rate of women with cervical cancer is very 
high, it is obviously desirable to prevent neoplasia. Prophylactic 
treatment of papillomas has had some measure of success, but surgical 
treatment does not entirely prevent recurrence. There is good evidence 
that colorectal cancer, mostly adenocarcinomas arising from the surface 
epithelium, is another type of cancer that can arise from benign 
precancerous lesions, in this case intestinal polyps. 
Examples of other precancerous lesions (and, in parentheses, the potential 
subsequent malignant condition) which can be treated according to this 
invention are genital warts (cancer of the uterine cervix); anal warts 
(cancer of the anus); intestinal polyps (colorectal cancer); actinic 
keratoses (basal, squamous cell carcinomas and melanomas); erythroplasia 
of Queyrat (penile squamous carcinoma); Bowens disease (penile squamous 
carcinoma); penile warts (cancer of the penis); leucoplakia (cancer of the 
vulva); lichen planus (cancer of the oral mucosa); adenomatous gastric 
polyps (gastric cancer); papillomas of the bladder epithelium (bladder 
carcinoma); and oesophogeal papillomas (oesophageal squamous cell 
carcinoma). 
This list is, however, given by way of example only and it should be 
understood that the present invention is of use in the treatment of any 
precancerous lesion likely to give rise to a mucosal or epithelial cancer. 
In all such types of cancer, it is generally more effective to treat the 
pre-cancerous stage before neoplasia than to attempt to treat the cancer 
after neoplasia has occurred. 
It will be remarked that the examples given above are all cancers of 
epithelial or mucosal tissue. Indeed, it is believed that the 
effectiveness of MDPs in the treatment of mucosal and epithelial 
originating cancers may arise, at least in part, from their activity as 
stimulators of mucosal immunity. In particular, it has been found that 
levels of IgA are especially high in patients treated with GMDP and GMDP-A 
although it should be stressed that the effectiveness of the present 
invention is not dependent on the correctness of this theory. 
It is expected that MDPs will be especially useful in the preparation of 
agents for the treatment of papillomas of the cervix, anus or colorectal 
area, or precancerous conditions of the skin or oral mucosa. These agents 
will therefore be useful for the prophylaxis of the cancers just 
mentioned. 
In some cases the treatment of the pre-cancerous condition with MDPs will 
result in disappearance of the pre-cancerous condition but it may be that 
the treatment will simply prevent neoplasia. 
In some cases, treatment of the precancerous condition will be with the MDP 
analogue alone. However, at other times, the treatment with the MDP 
analogue will be adjunct or adjuvant therapy, being performed in addition 
to surgery, cryosurgery, laser vaporisation, chemotherapy, immunotherapy 
or radiation therapy. 
The observation that MDPs are effective in the treatment of pre-cancerous 
conditions is particularly surprising in the view of the large amount of 
work that has been carried out on the use of MDPs in cancer without this 
previously becoming apparent. 
The types of cancer to which this aspect of the invention applies in 
particular are as mentioned above. 
In certain circumstances, cancers may not be associated with detectable 
precancerous lesions as such. However, it is recognised in medicine that 
various endogenous markers exist, most of which are genetic markers, which 
indicate a predisposition of their carriers to particular types of cancer. 
MDPs may therefore be administered to the carriers of such markers and also 
to other patients known to be at high risk of contracting cancer as a 
prophylactic treatment to prevent cancer developing. Examples of patients 
with a high risk of contracting cancer include patients carrying a genetic 
marker, patients who have a family history of the disease or people who 
work in a high risk environment, for example in an area which has high 
radiation levels. 
Therefore in a further aspect of the invention there is provided the use of 
a muramyl peptide in the preparation of an agent for the prophylaxis of 
cancer in a patient carrying an endogenous marker for cancer or otherwise 
identified as being at high risk of contracting a cancerous condition. 
This type of prophylactic use could not be contemplated with conventional 
cancer therapies. Radiation therapy and chemotherapy both have side 
effects which are much too severe to be tolerated by a healthy person who 
is merely at some risk of becoming ill. 
The route of administration of the compounds will, of course, depend on the 
type of precancerous lesion or cancer being treated. However, typical 
routes of administration would be oral (suitable for any precancerous 
lesions or cancers but particularly for precancerous lesions and cancers 
of the mouth and GI tract); vaginal (for cervical cancer and associated 
precancerous lesions); rectal (for cancers and precancerous lesions of the 
lower GI tract, particularly colorectal cancer and the anus); and topical 
or transdermal (for cancers and precancerous lesions of the skin and the 
oral mucosa). Although the above are preferred routes of administration, 
it is also possible to administer the compounds parenterally, for example 
by intravenous or intramuscular injection. Moreover, the compounds can be 
instilled by catheter or other device into the locality of the tumour as, 
for example, papillomas of the bladder, or into the vagina and uterus for 
cervical cancer. 
Oral formulations may be in the form of tablets, capsules or emulsions 
depending on the site of the cancer to be treated. In some cases, it may 
be necessary to provide a delayed release formulation to ensure that the 
active compound is not released until the formulation reaches the site 
where it is required. The formulations may additionally contain other 
ingredients and in tablets, one or more suitable carriers will generally 
be present. Typical carriers include lactose, saccharose, potato starch, 
calcium stearate and methylcellulose. 
Injectable preparations may contain a solution of GMDP or GMDP-A or, 
alternatively, the compounds may be encapsulated in liposomes to form an 
injectable preparation. 
Vaginal and rectal formulations may be formulated as pessaries and 
suppositories respectively. It is likely that these formulations will also 
contain other excipients and suitable carriers and excipients are well 
known to those skilled in the art of formulation. 
Transdermal and other topical formulations may be in the form of ointments, 
creams or lotions and, again, suitable carriers and excipients are well 
known in the art. 
Moreover, to improve permeation of compound into the skin, it may be 
preferable to employ particularly lipophilic analogues. Alternatively, 
skin-permeability modifying compounds may be present in the formulations, 
or electric potential may be employed to drive charged analogues into the 
skin. For transdermal formulations, the formulation may be incorporated 
into a transdermal patch or similar device. 
Vaginal, rectal, topical and transdermal formulations are all new and 
themselves form a further aspect of the invention. In this aspect of the 
invention there is provided a composition comprising a muramyl peptide 
compound and a pharmaceutically acceptable excipient or carrier, 
characterised in that the composition is adapted for administration by the 
topical, transdermal, rectal or vaginal routes. 
Topical and transdermal formulations are, as mentioned above, likely to be 
particularly useful in the prophylaxis of skin cancer and muramyl peptides 
may be included in topical sun screens as an additional protection against 
cancers of the skin. 
The precise dosage for administration will be judged by the clinician or 
physician. However, in general, an average daily dose would be in the 
range of from 0.1 to 100 mg per day (or per tablet or other unit dose). It 
is likely that a dosage range of from 0.5 mg to 50 mg per day (or per 
tablet or other unit dose) will be preferred and a daily dosage of around 
1.0 mg to 10 mg is considered to be optimal.