R. B. Vincent, C. Rutty, G. Abel
1984
Citations
1
Influential Citations
19
Citations
Quality indicators
Journal
British Journal of Cancer
Abstract
5-(3-Dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) is an antitumour agent which has limited use in the treatment of malignant melanoma. DTIC is known to undergo oxidative N-demethylation to give 5-(3-monomethyl-1-triazeno)imidazole-4-carboxamide (MIC) via an intermediate carbinolamine 5-(3-hydroxymethyl, 3-monomethyl-1-triazeno)imidazole-4-carboxamide (HMIC). MIC undergoes rapid chemical decomposition yielding a methyl carbonium ion which can methylate DNA. Thus the antitumour activity of DTIC is dependent upon metabolism of the drug. In view of the marked species differences in the N-demethylation of pentamethylmelamine (PMM) described earlier (Rutty et al, Cancer Chemother. Pharmacol. 8, 105, 1982), the metabolism of DTIC in mouse, rat and man was examined. The plasma half life (t1/2 s) of DTIC in the rat (29.6mins) was significantly greater than in the mouse (8.6mins), and greater still in 4 patients studied to date (57–100mins). Of greater significance were the peak levels of the cytotoxic metabolites HMIC and MIC found in the plasma of mice (33.8µM) which were very much higher than in either rat (2.0µM) or man (6.7µM). Correspondingly, DTIC shows marked activity versus a mouse plasmacytoma, but is without activity against the Walker 256 tumour grown in the rat. These findings suggest that the poor clinical activity of DTIC is at least in part due to the low level of metabolism of the drug in man.