Abstract
Abstract
Because of abnormalities of metabolism of homocysteine thiolactone and methionine in malignant cells, and because of the chemopreventive activity of N-homocysteine thiolactonyl retinamide against chemical carcinogenesis by ethyl carbamate in mice, the cobalamin derivative of this retinamide was prepared and tested for chemopreventive activity. The substance, N-homocysteine thiolactonyl retinamido cobalamin, was found to have a different UV-visible absorption spectrum from that of 5′-deoxyadenosyl cobalamin or N-homocysteine thiolactonyl retinamide. Spectral analysis suggests a ratio of 2 mol of retinamide/mol of cobalamin within the molecule. To demonstrate chemopreventive activity, ethyl carbamate was given in a dose of 2 mg/animal to A/J mice (15–18 g) weekly over a period of 10 weeks to induce pulmonary tumors. A total dose of N-homocysteine thiolactonyl retinamido cobalamin of 60 mg/kg, given for a total of 16 weeks, decreased by one fourth (P < 0.05) the number of pulmonary tumors induced by ethyl carbamate. An equimolar dose of 5′-deoxyadenosyl cobalamin (40 mg/kg) increased the number of tumors by one third (P < 0.001), and an equimolar dose of N-homocysteine thiolactonyl retinamide (20 mg/kg) had no effect on the number of pulmonary tumors. No mortality was observed in the experiment. When the ethyl carbamate was given in a single dose of 20 mg/animal, all three substances produced significant mortality in doses of 0.75–30 mg/kg. In the survivors of this experiment, doses of 0.75–30 mg/kg of N-homocysteine thiolactonyl retinamido cobalamin decreased the number of pulmonary tumors induced by ethyl carbamate to 52–82% of controls (P < 0.01). The results show that N-homocysteine thiolactonyl retinamido cobalamin has chemopreventive activity against chemical carcinogenesis by ethyl carbamate in mice.
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