Modulation of target enzyme associated with the action of antifolates.
The cytotoxicity and molecular effects of antifolate thymidylate synthase inhibitor, ICI-D1694, against human ileocecal carcinoma, were evaluated. The drug concentration for 50% inhibition of cell growth by ICI-D1694 is 73 nM and 3 nM following 2 hr and 72 hr exposure, respectively. The drug induces high level of DNA single strand breaks in a time dependent manner, but subsequent to maximum inhibition of thymidylate synthase. Drug effects can be reversed by thymidine and leucovorin at > 1 microM concentrations. Leucovorin action is primarily at the cell membrane level, competing with the transport and activation of ICI-D1694. Thymidine, however, exerts its competitive effect primarily at the level of thymidylate synthase.
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Grace Cancer Drug Center and Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263.
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D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity; D002277:Carcinoma / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005069:Evaluation Studies as Topic; D006801:Humans; D007414:Intestinal Neoplasms / Q000378:metabolism*; D002955:Leucovorin / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology* / Q000633:toxicity; D013876:Thiophenes / Q000494:pharmacology* / Q000633:toxicity; D013936:Thymidine / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; C068874:raltitrexed; D002955:Leucovorin; D013936:Thymidine