Abstract
Mechanisms of resistance to the active metabolite 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) of the drug 5-(3,3-dimethyl-1-triázeno)imidazole-4-carboxamide (DTIC) were studied in three human cell lines with differing amounts of the repair enzyme O6-alkylguanine-DNA alkyltransferase (O6AT). The lines were HT29 (Mer+Rem+), A549 (Mer+Rem-) and VA13 (Mer-). The ability to repair O6 methyl-guanine was directly related to resistance to MTIC (HT29 ID50 650 mumol l-1, A549 ID50 210 mumol l-1, VA13 ID50 15 mumol l-1. MTIC produced DNA single strand breaks over the range of one log of cell kill, but depletion of cellular NAD levels could not be detected until there was greater than 95% cell kill. Inhibitors of the repair enzyme adenosine diphosphoribosyl transferase (ADPRT) potentiated killing by 2-fold in the Mer+ cell lines but not the Mer- line. The enhancement was directly proportional to an increase in DNA strand breaks but not a change in their half-life. Therefore resistance to the clinically used methylating agent MTIC can be partly overcome by inhibiting ADPRT but a role for ADPRT as a suicide mechanism in response to alkylating agent damage is unlikely.
Highlights
One of the few active drugs in the treatment of malignant melanoma (Comis, 1976) and a component of sarcoma treatment regimens (Gottlieb et al, 1976) is the substituted triazene 5-(3,3-dimethyl- 1 -triazeno)imidazole-4-carboxamide (DTIC)
Because de novo or secondary resistance to DTIC is a common problem, we have investigated the mechanisms of resistance to killing and ways to potentiate cytotoxicity in human tumour cell lines
Cell survival was measured in HT29 (Mer+Remn), A549 (Mer+Rem-) and VA13 (Mer-) cell lines
Summary
One of the few active drugs in the treatment of malignant melanoma (Comis, 1976) and a component of sarcoma treatment regimens (Gottlieb et al, 1976) is the substituted triazene 5-(3,3-dimethyl- 1 -triazeno)imidazole-4-carboxamide (DTIC). The mechanism of action is thought to involve metabolic N-demethylation to give the cytotoxic monomethyl triazene 5-(3-methyl- I -triazeno)imizadole-4-carboxamide (MTIC), which can methylate N-7 sites of guanine in DNA (Preussman & von Hodenburg, 1970)
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