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The present study reports the modulatory influences of combined oral contraceptive formulations, Ovral (0.05 mg ethinylestradiol plus 0.5 mg norgestrel per pill) and Noracycline (0.05 mg ethinylestradiol plus 0.1 mg lynestrenol per pill), on methylcholanthrene (MCA)-induced carcinogenesis in the uterine cervix of Swiss albino mouse. Placement of cotton thread impregnated with beeswax containing approximately 300 micrograms of MCA yielded cervical tumors in 0.0%, 8.6% and 26% animals, respectively, in 30, 60 and 90 days. Concomitant treatments with doses D1 (1/2000th of a pill), D2 (1/200th of a pill) and D3 (1/20th of a pill) of Ovral yielded cervical tumors in 0.0%, 0.0% and 4.5% mice at 30 days, 0.0%, 6.2% and 10% mice at 60 days and in 3.3% (P less than 0.05), 3.4% (P less than 0.05) and 47% mice at 90 days, respectively. Likewise, concomitant treatments with doses D1 (1/2000th of a pill), D2 (1/200th of a pill) and D3 (1/20th of a pill) of Noracycline yielded cervical tumors in 0.0%, 0.0%, 16.6% mice at 30 days, 4%, 3.7% and 54% (P less than 0.05) mice at 60 days and 3.2% (P less than 0.05), 20% and 63% (P less than 0.05) of mice at 90 days, respectively. Both Ovral and Noracycline displayed biphasic action on MCA-induced cervical carcinogenesis in mice. At lower dose levels (D1 and D2), they were inhibitory while at the higher dose level (D3) they were augmentatory in their actions. Both pills also significantly enhanced the incidence of cervical hyperplasia.

A single intramedullary administration of each dose (15 approximately 20 mg) of 4-nitroquinoline 1-oxide, 3-methylcholanthrene, or 7,12-dimethylbenz[alpha]anthracene was applied to the mandible, diaphysis, or distal metaphysis of the femur of rabbits. The highest incidence in production of osteosarcoma was obtained from the group in which 4-nitroquinoline 1-oxide was applied to the distal metaphysis (75%, including one case of chondrosarcoma). Tumors hardly appeared in any of the groups when given 3-methylcholanthrene or 7,12-dimethylbenz[alpha]anthracene. Histologically, three kinds of entities were recognized from the quantitative difference of the reactive tissues which appeared around carcinogens. It is estimated that the condition of entity III induces the highest incidence of osteosarcoma if chemical carcinogens are given into the bone marrow of experimental animals.

The tumorigenic effect of a diet containing the alpha-isomer of benzene hexachloride (alpha-BHC) on the liver of various animals was examined. It was found that alpha-BHC induced liver tumors in male and female mice but not in rats or hamsters in the present observations. Histological changes in the liver of mice induced by alpha-BHC were also much greater than those induced in rats or hamsters. Male animals were more susceptible to the tumorigenic action of alpha-BHC than females. Among different strains of mice, the DDY showed greatest susceptibility and the C57BL/6 showed the least. Induction oflpha-BHC was not inhibited by concomitant feeding of 1-naphthyl isothiocyanate or p- hydroxypropiophenone. However, 3-methylcholanthrene slightly inhibited their induction by alpha-BHC.

For the purpose of inducing experimental lung cancer, carcinogens were applied into the bronchus of the rabbit. Experiments were divided into 2 groups, I and II, depending on the methods of application of chemical carcinogens into the bronchus. In Experiment I, carcinogens (4-nitroquinoline 1-oxide and/or 3-methylcholanthrene) in rabbit plasma or distilled water were instilled in the lower bronchus and, in Experiment II, 3-methylcholanthrene in Tween 60 was swabbed on the maon bronchus through a specially made bronchoscope. (1) In Experiment I, 163 of 366 rabbits having received over 4 instillations of the chemical carcinogens and surviving for more than 30 days developed lung cancer. However, in Experiment II, only 2 of 65 rabbits surviving more than 60 days developed lung cancer. (2) In Experiment II, 39 (60%) of 65 rabbits were found to have developed amyloidosis. However, in Experiment I, 86 (approx. 23%) of 366 rabbits developed amyloidosis. Amyloidosis was observed to occur in the kidneys, spleen, liver, and adrenals in both experiments.

Repeated topical application of 3-methylcholanthrene to the backs of BALB/c mice lowered the tissue levels of lathosterol and provitamin D3, intermediates in one of the cholesterol biosynthetic pathways (the delta 7 pathway), though the activities of lathosterol 5-desaturase and provitamin D3 7-reductase were similar to those of control animals. These results seemed to indicate that carcinogen treatment exerted a depressive effect at some earlier step(s) than lathosterol synthesis. However, the content of cholesterol in mouse skin was not lowered in these animals, suggesting that another biosynthetic pathway might be activated. When diazacholesterol, which is known to inhibit the conversion of desmosterol to cholesterol, was administered together with the carcinogen, a marked accumulation of desmosterol was observed compared to animals given only diazacholesterol. Since desmosterol is an intermediate in the pathway in which the delta 24 double bond is reduced at the final step (the delta 24 pathway), this seemed to suggest that the delta 24 pathway was activated by carcinogen treatment.

The effect of feeding and lighting on the regulation of aryl hydrocarbon hydroxylase activity in liver, small intestine, and lung from C3H/He, DBA/2, and Swiss albino mice was investigated. A circadian rhythm of aryl hydrocarbon hydroxylase activity in the liver from DBA/2 mice was observed under the controlled lighting conditions, showing higher activity at the end of the light period of a day and lower activity in the dark period. Contrasting to the change of the enzyme activity in mice fed freely in the continuous dark period, inconsistent and variable results of the enzyme activity and its induction by 3-methylcholanthrene were observed in the mice that were fed during the continuous light period, depending on the sex and strain of the mice used. Different responses in the induction of aryl hydrocarbon hydroxylase to different routes of 3-methylcholanthrene administration were found between the liver and small intestine of the mice, but not in the lung. The higher levels of the enzyme activity induced in the liver and small intestine were detected after the intraperitoneal and intragastric administration of 3-methylcholanthrene. The significance of controlled feeding schedules for obtaining reproducible experimental results in the regulation of aryl hydrocarbon hydroxylase activity in the mice was discussed.