Abstract:
The increased use of sunscreens, while limiting damage to the DNA, may promote cancer growth by preventing vitamin D synthesis in the skin. According to the present invention, the beneficial effects of UV radiation are obtained by incorporating vitamin D into the topical sunscreen. Application of the sunscreen prevents the harmful effects of UV radiation and the included vitamin D is activated by the skin to calcitriol for cancer prevention. Because calcitriol also promotes cellular growth and differentiation, the topical sunscreen with vitamin D may be of benefit for photoaging.

Description:
CROSS REFERENCES  
       [0001]     This application claims priority to U.S. patent application Ser. No. 10/956,993, filed Sep. 29, 2004. 
     
    
     BACKGROUND  
       [0002]     1. Field of the Invention  
         [0003]     The present invention relates to methods and products for preventing cancer through topical application of cancer inhibitors. More particularly, it relates to the use of sunscreens containing vitamin D 3 , vitamin D derivatives (natural or synthetic), or cod-liver oil to inhibit skin cancers and other dermatological disorders related to ultraviolet light exposure.  
         [0004]     2. Discussion of Related Art  
         [0005]     It is common knowledge that we are experiencing an epidemic of skin cancer. Non-melanoma (basal and squamous cell carcinoma) skin cancer has increased by 3-8% per year since the 1960&#39;s, and the lifetime risk of malignant melanoma has increase from 1/500 in 1960 to 1/75 (estimated) in 2000. There is some evidence that vigorous use of sunscreens may reduce the incidence of nonmelanoma cancer. Sunscreens seek to block the ultraviolet light, which causes sunburn and is a probable cause of skin cancers. Sunscreens are rated with an sun-protective-factor (SPF) which is essentially a measure of protection against sunburn or ultraviolet B radiation. High SPF sunscreens have been available for almost 30 years and broader spectrum sunscreens, which also block some longwave ultraviolet light, for almost 15 years. There is some evidence that vigorous use of sunscreens may reduce the incidence of non-melanoma skin cancer, but it difficult to reconcile this with the non-melanoma skin cancer epidemic. The situation with melanoma is less clear. Some studies show a protective effect and others show that sunscreens may increase the risk of melanoma. There are no adequate animal models for basal cell carcinoma or melanoma. So, testing of the effects of sunscreens with respect to skin cancer is difficult  
         [0006]     Among the various hypotheses put forth to explain the failure of sunscreens, especially in the prevention of melanoma, is that sunscreens inhibit epidermal synthesis of vitamin D 3  (cholecalciferol), and that this promotes the growth of cancer. Calcitrol is a potent regulator of cell growth and differentiation. It also has an inhibitory effect on cellular death and new blood vessel growth, i.e., into tumors). Low vitamin D levels have been associated with breast, prostate, and colon cancer. New vitamin D analogues have been shown to be very effective in preventing chemical tumorgenesis in nice.  
         [0007]     Vitamin D 3  is synthesized by epidermal keratinocytes on exposure to UVB, but must undergo activation first by 25-hydroxylation and then 1-alpha hydroxylation to convert it to 1,25-dihydroxyvitamin D 3 , or calcitriol, the active form of vitamin D. Traditionally, these conversions have been thought to occur in the liver and kidney exclusively. Professor Michael F. Holick at Boston University has suggested that the UV blocking characteristics of sunscreens has inhibited the natural production of vitamin D 3  by the skin. He has created a controversy among the dermatological community by suggesting some unprotected exposure to natural or artificial sunlight for short periods of time in order to increase vitamin D production. Additionally, he has several patents, such as U.S. Pat. No. 5,422,099, relating to topical application of vitamin D precursors in conjunction with exposure to sunlight. The general consensus among dermatologists is that all UV radiation is problematic due to its connections with melanomas and other skin cancers. Furthermore, other sources of vitamin D, such as diet and supplements, can be used to provide a sufficient daily dose without production by the skin.  
       SUMMARY OF THE INVENTION  
       [0008]     The present invention provides a method of inhibiting skin cancers, precancers, photoaging and other dermatological disorders through use of vitamin D 3 . According to one aspect of the invention, vitamin D 3  is provided as an ingredient in a topical sunscreen. According to another aspect of then invention, cod-liver oil is provided as an ingredient in a topical sunscreen as a source of vitamin D 3 . A topical sunscreen containing vitamin D 3  or cod-liver oil is applied to portions of the skin subject to exposed to sunlight. 
     
    
     DETAILED DESCRIPTION  
       [0009]     According to traditional dogma, hepatic and renal activation of vitamin D 3  are necessary to produce calcitriol. However, it has been known for many years that the skin is capable of converting vitamin D 3  to calcitriol on its own, in addition to creating vitamin D 3  through exposure to sunlight. Bikle D D, Nemanic M K, Gee E, et al., 1,25 dihydroxyvitamin D 3  Production by Human Keratinocytes, Kinetics and Regulation,  J Clin Invest  1986, 557-66; Bikle D D, Nemanic M K, Whitney J D et al., Neonatal Human Foreskin Keratinocytes Produce 1,25 dihydroxyvitamin D 3   . Biochemistry  1986; 25:1545-&amp; Matsumoto K, Azuma Y, Kiyoki M, et al. Involvement of Endogenously Produced 1,25 dihydroxyvitamin D3 in the Growth and Differentiation of Hunan Keratinocytes,  Biochim Biophvs Acta  1997,1092:311-8.  
         [0010]     Recent studies have shown that melanoma patients have normal calcitriol serum levels, normal 25-hydroxyvitamin D 3  serum levels, and normal dietary vitamin D intake. Cornwell M L, et al., Prediagnositc Serum Levels of 1,25 dihydroxyvitamin D and Malignant Melanoma,  Photodermatol Photoimmunol Photomed  1992, 9:109-12; Reichrath J, et al., No Evidence for Reduced 25-hydroxyvitamin D Serum levels in Melanoma Patients, Cancer Causes Control, 2004, 15:97; and Weinstock M A, et al., Case-Control Study of Melanoma and Dietary Vitamin D: Implications for Advocacy of Sun Protection and Sunscreen Use,  J Invest Dermatol,  1992; 98:809-11. However, it is known that calcitriol inhibits the growth and invasion of melanoma cells and invasion. Colston K, et al., 1,25-Dihydroxyvitamin D 3  and Malignant Melanoma The Presence of Receptors and Inhibition of Cell Growth in Culture,  Endocrinology,  1981; 108: 1083-6. Evans S R, et al., Vitamin D Receptor and Growth Inhibition by 1,25 dihydroxyvitamin D 3  in Human Malignant Melanoma Cell Lines,  J Surg Res,  1996; 61:127-33. Yudon, K et al., 1 alpha, 25 Dihydroxyvitamin D 3  Inhibits In Vitro Invasiveness Through The Extracellular Matrix and In Vivo Pulmonary Metastasis of B16 Mouse Melanoma,  J Lab. Clin Med  1999, 133:120-8. Furthermore, melanoma cells can express the in D rector and can activate vitamin D 3 . Frankel, T L, et al., The Synthesis of Vitamin D Metabolites By Human Melanoma Cells,  J Clin Endocrimol Metab,  1983, 57:627-631. Polymorphisms of the vitamin D receptor are also associated with an increased susceptibility to and worsened progress in melanoma Halsall J A, et al., A novel Polymorphism in the IA Promoter Region of the Vitamin D Receptor Is Associated With Altered Susceptibility and Prognosis in Malignant Melanoma,  Br J Cancer,  2004: 16:765-70. Hutchinson P E, et al., Vitamin D Receptor Polymorphisms Are Associated With Altered Prognosis in Patients With Melanoma,  Clin Cancer Res,  2000; 6:498-504.  
         [0011]     Thus, serum vitamin D levels and dietary intake appear to be of little importance in preventing melanomas despite the inhibiting effect of calcitriol. However, the ability of the epidermis to generate calcitriol, as suggested by the various studies, explains the conflicting data. Activation of vitamin D 3  to calcitriol within the epidermis puts the anti-tumor activity of calcitriol at the site of tumor formation and at the time of tumor formation in high concentration. As shown by K. Matsumoto, most of the calcitriol remains within the keratinocyte. This is also suggested by the fact that individuals who sunbathe do not experience elevated calcium levels (an obvious effect of both topical and circulating calcitriol). It also explains the increase in skin cancer despite widespread use of sunscreens. Exposure to UV radiation can increase the risk of cancer. On the other hand, it causes the skin to produce vitamin D which has a cancer inhibiting effect. The use of sunscreens prevents the formation of vitamin D in the skin. Accordingly, protection against sunburn seems not to be protection against skin cancer due to variations in vitamin D formation and activation.  
         [0012]     The present invention resolves the conflict by providing another source of vitamin D to the skin. Specifically, vitamin D 3  (cholecalciferol) or other biologically active vitamin D derivatives are added to topical sunscreens. When the sunscreen is applied, it inhibits the UV radiation and its cancer causing effects. On the other hand, the vitamin D 3  is provided to the skin. The skin can activate the vitamin D 3  to calcitriol to provide the anti-cancer effects at the epidermis. Thus, the benefits of vitamin D formation from UV radiation can be achieved without the harmful exposure.  
         [0013]     The amount and form for adding vitamin D 3  to topical sunscreens in order to best achieve the benefits is still subject to research and testing. However, synthetic or natural sources of vitamin D 3 , such as cod-liver oil, can be used. The topical application of vitamin D is safe and beneficial. Schering-Plough&#39;s “A&amp;D Ointment,” a preparation for diaper rash, has been available over the counter for decades. It contains approximately the adult recommended daily allowance of vitamin D (10 mcg or 400 units) per ounce. An ounce is approximately the amount necessary to cover an adult body. Vitamins A, E, and C are currently added to some sunscreens. Thus, vitamin D 3  could also be added. Since vitamin D 3  is lipid soluble, the sunscreen should contain lipids. Otherwise, any sunscreen formulation can be used with the present invention.  
         [0014]     Because of its effects on growth and differentiation, vitamin D and its analogs are of potential benefit in the treatment of photoaging. Nagpal S, et al. Vitamin D analogs: mechanism of action and therapeutic applications. Curr Med Chem 2001; 8:1661-79. Thus, the addition of vitamin D 3  to sunscreen may also inhibit photoaging.  
         [0015]     Having disclosed at least one embodiment of the present invention, various adaptations, modifications, additions, and improvements will be readily apparent to those of ordinary skill in the art. Such adaptations, modifications, additions and improvements are considered part of the invention which is only limited by the several claims attached hereto.