Experiments on the theory of photochemical formation of carcinogens from skin fats.
Irradiation products of skin surface fats, including digitonin-precipitable sterols, isocholesterols, and total unsaponifiable fractions, were painted on the ears of white mice for periods of from 15 to 18 months, but failed to produce precancerous or cancerous changes that could be noted histologically. Therefore, the theory of photochemical formation of carcinogenic compounds on the surface of the skin by ultraviolet irradiation could not be substantiated by this method.
Cholesterol content of skin, blood, and tumor tissue in rats irradiated with ultraviolet light.
The production of malignant tumors by ultraviolet radiation has been reported by several investigators. Herlitz, Lundill, and Wahlgren (l), Findlay (2), and Putschar and Holtz (3) have produced malignant growths in mice and rats by irradiation. Roffo (4) reported an extensive series of experiments in which he exposed rats to ultraviolet radiation, beginning with a 5 minute daily dose, and gradually increasing to 20 hours daily. Tumors developed on the eyes, ears, and back of the head in 6 to 8 months. Beard, Boggess, and von Haam (5), applying the technique of Roffo, have verified these observations, producing sarcomas and carcinomas on the eyes, ears, and heads of rats. In the field of tumor chemistry, cholesterol has been of particular interest. Kahn (6) showed that malignant tumors contain large amounts of cholesterol and its esters, while blood serum was lower than normal in cholesterol. Bolaffi (7) reported an increase of cholesterol esters in the whole organism of tumor mice. Bergheim (8), using histological methods, found larger amounts of cholesterol in malignant tumors than in benign ones. Yasuda and Bloor (9) likewise report that malignant tumors contain a much higher percentage of fatty substances-neutral fat, phospholipid, and cholesterol-than less malignant ones. Roffo (10-12) has emphasized that cholesterol must play a predominant part in the formation of tumors. This is based on his observations that cholesterol is greatly increased in neoplastic tissue, particu-
Antitumor activities of (2"R)-4'-O-tetrahydropyranyl-adriamycin (THP) and its combination with other antitumor agents on murine tumors.
(2''R)-4'-O-Tetrahydropyranyladriamycin (THP) is a new derivative of doxorubicin (adriamycin, ADM). The concentrations of THP and ADM required to inhibit by 50% the growth of a cultured L1210 cells was 0.003 microgram/ml and 0.016 microgram/ml, respectively. Various therapeutic designs of combinations of THP with other antitumor agents were investigated in vivo using the L1210 murine leukemia. The combination of THP with cytosine arabinoside (Ara-C), cyclocytidine hydrochloride (Cyclo-C), 6-mercaptopurine (6-MP) and cyclophosphamide (EX) showed a great effectiveness following daily intraperitoneal treatment from days 1 to 10. High therapeutic effects were also obtained with the combinations of THP with Ara-C, Cyclo-C, vincristine (VCR) and EX following intravenous combination therapy one day following implantation of L1210 leukemia. Schedule dependency and its therapeutic efficacy of THP were examined. THP showed almost the same antitumor activity on the solid-type sarcoma-180 or solid-type Ehrlich carcinoma as ADM by intraperitoneal or intravenous treatment. THP showed some superior activity to ADM in the advanced stage of L1210 leukemia. High antitumor activity of THP on murine leukemia L1210 has been reported by Tsuruo et al. (Cancer Res. 42: 1462-1467, 1982) and was also confirmed. THP gave many mice cures, especially in the intravenous treatment.