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 less than 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 less than 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 less than 0.01). The results show that
N-homocysteine thiolactonyl retinamido cobalamin has chemopreventive activity against chemical
carcinogenesis by
ethyl carbamate in mice.