Chemopreventive Effect of N -Homocysteine Thiolactonyl Retinamido Cobalamin on Carcinogenesis by Ethyl Carbamate in Mice

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.