Historical Perspective on the Role of Sunlight and Vitamin D on Bone Health and Cancer Prevention

The correlation between decreased morbidity and mortality of cancer and exposure to sunlight is known. The many biological functions of vitamin D that contribute to cancer prevention have only recently begun to be appreciated. Once activated 1,25-dihydroxyvitamin D [1,25(OH)2D3] functions as a potent inhibitor of normal and cancer cellular proliferation. Vitamin D deficiency in mice led to a 60% increase in colon tumor growth, compared to vitamin D-sufficient mice. The ligand binding domain of the Vitamin D receptor was shown to accommodate a class of 1,25(OH)2D3-analogs that possess an additional side-arm. These novel Gemini analogs were evaluated in vitro and in vivo. Select Gemini analogs were 100 times or more effective in inhibiting colon tumor growth in mice, compared to their parent compound. Correcting vitamin D deficiency may decrease the risk of developing colon cancer, while the novel Gemini 1,25(OH)2D3-analogs have the potential for therapeutic application in human colon cancer. Historical Perspective on the Role of Sunlight and Vitamin D on Bone Health and Cancer Prevention More than 100 years before vitamin D was identified, its sun-derived effects on bone health had been reported by Sniadecki in 1822. He suggested that the children living in Warsaw had a high prevalence of rickets due to lack of sun exposure (1). In 1889, Palm reported a similar correlation between sunlight deficiency and rickets. Upon analyzing the prevalence of rickets in London, Manchester, the British Midlands and the Netherlands, compared to China, Mongolia and Tibet, Palm realized that rickets increased with increasing latitude and degree of urbanization (2). It was, however, not until the 1920’s that sunlight was widely recognized as having a protective effect against rickets (3,4) In 1919, Huldschinsky (5) first introduced the idea of using ultraviolet (UV) radiation from a mercury arc lamp as a therapy for rickets in children. Later, Hess and Unger conducted experiments irradiating rats and subsequently infants with a carbon arc lamp (6). They concluded that adequate exposure to UV radiation resulted in a "definite and dependable cure of [rickets]." Similarly, in 1936 Peller (7) analyzed the relationship between morbidity and mortality of cancer and exposure to radiation. He concluded that exposing the skin to enough UV radiation to induce skin cancer caused a decrease in the incidence of more malignant tumors in organs that were "not at all accessible to treatment." Peller described this method of inducing skin cancer (a more easily treatable cancer) for the sake of preventing the development of more malignant cancers as a novel strategy to decrease cancer mortality. To support his theory of the protective effects of UV radiation against the development of more malignant cancers, Peller and Stephenson proceeded to analyze the incidence of cancer in a population with increased exposure to solar UV radiation, the United States Navy. Compared to agematched controls, the rate of skin cancer in the US Navy was eight times higher, while the total number of deaths from other cancers was 60% less than the civilian population (8). In 1941, Apperley also analyzed the incidence and mortality rate of cancer with respect to sun exposure. As a model, he compared total cancer mortality to the percentage of American and Canadian state populations engaged in agriculture. He demonstrated a highly significant correlation between reduced cancer mortality in adults and a career in agriculture. Apperley’s analysis led him to conclude that cancer mortality could be reduced "by inducing partial or 2515 Correspondence to: M.F. Holick, Vitamin D, Skin & Bone Research Laboratory, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, U.S.A. Tel: 001-617-638-4546, e-mail: [email protected]