Antitumour imidazotetrazines--IV. An investigation into the mechanism of antitumour activity of a novel and potent antitumour agent, mitozolomide (CCRG 81010, M & B 39565; NSC 353451).
8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4-(3H )-one- mitozolomide (CCRG 81010, M & B 39565, NSC 353451) is a potent inhibitor of the growth of a number of experimental tumours and can potentially decompose to give either an isocyanate or the monochloroethyltriazene (MCTIC). In vitro CCRG 81010 is not cross-resistant with the bifunctional alkylating agents against the Walker carcinoma. To investigate the mechanism of the antitumour activity of CCRG 81010 a comparison has been made with BCNU and MCTIC on precursor incorporation into macromolecules in TLX5 mouse lymphoma cells. Whereas BCNU produces a rapid and extensive inhibition of both (methyl 3H) thymidine and [5-3H]uridine incorporation into acid-insoluble material, neither CCRG 81010 or MCTIC have an early effect on precursor incorporation. Inhibition of precursor uptake is also not produced by concentrations of 2-chloroethylisocyanate that inhibit intracellular glutathione reductase activity. The potential carbamoylating activity of CCRG 81010 has also been assessed by comparing its effect with that of BCNU and 2-chloroethyl isocyanate on enzymes known to be inhibited by carbamoylation. Such enzymes, glutathione reductase, chymotrypsin and gamma-glutamyltranspepidase are not inhibited by CCRG 81010 under conditions where BCNU and 2-chloroethyl isocyanate show complete inhibition of enzyme activity, suggesting an absence of carbamoylating species. The results suggest that the most likely antitumour metabonate produced from CCRG 81010 is the triazene MCTIC.
D000241:Adenosine / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002279:Carcinoma 256, Walker; D002330:Carmustine / Q000494:pharmacology; D002478:Cells, Cultured; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology*; D008223:Lymphoma; D051379:Mice; D009588:Nitrogen Mustard Compounds; D013936:Thymidine / Q000378:metabolism; D014529:Uridine / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007093:Imidazoles; D009588:Nitrogen Mustard Compounds; D000620:Aminoimidazole Carboxamide; C040369:mitozolomide; D005980:Glutathione Reductase; D005723:gamma-Glutamyltransferase; D002918:Chymotrypsin; D000241:Adenosine; D002330:Carmustine; D013936:Thymidine; D014529:Uridine