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Mode of action of anti tumor triazenes and triazines 5. correlation of the in vitro cyto toxicity and in vivo anti tumor activity of hexa methyl melamine analogs with their metabolism



Mode of action of anti tumor triazenes and triazines 5. correlation of the in vitro cyto toxicity and in vivo anti tumor activity of hexa methyl melamine analogs with their metabolism



Biochemical Pharmacology 33(7): 1131-1136



Experiments were conducted to ascertain whether the antitumor activity of hexamethylmelamine analogs correlated with their in vitro cytotoxicity and metabolism. Two analogs, namely pentamethylmelamine (PMM) and 2,2,4,4-tetramethylmelamine (TMM) and hexamethylmelamine (HMM) itself were active towards the murine ADJ PC6A (PC6) plasmacytoma; another 3: 2-chloro-4,6-bis(dimethylamino)-1,3,5-triazine (CBDT), 2,4-bis-(dimethylamino)-6-hydrazino-1,3,5-triazine (HBDT) and 2,4,6-trimethylmelamine (TriMM) were inactive against the same tumor. The cytotoxicity of these compounds was examined against a PC6 tumor cell line in vitro. In the absence of liver microsomal activation, only CBDT proved to be significantly cytotoxic at a concentration of 5 mM. In the presence of murine liver microsomes, the 3 active antitumor agents were all cytotoxic at this concentration, whereas HBDT and TriMM remained non-toxic. The degree of cytotoxicity correlated with the extent of metabolism for these analogs. The products of biotransformation of these compounds were stable precursors of formaldehyde (presumably N-hydroxymethyl intermediates) (FP) rather than formaldehyde itself. After injection of these 6 compounds to Balb/c mice, the levels of FP generated in the plasma were markedly greater for the 3 active antitumor agents than for the inactive analogs. No free formaldehyde was detected in the plasma after administration of any of the compounds. For these compounds, in vitro cytotoxicity correlates with in vitro biotransformation. Their antitumor activity correlates with plasma levels of FP generated by metabolism in vivo.

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