Uptake and metabolism of 5,8-dideazaisofolic acid in human colon carcinoma cells.
The uptake and metabolism of radiolabeled 5,8-dideazaisofolic acid (IAHQ) (N-[p- ([(2-amino-4-hydroxy-6-quinazolinyl)amino]methyl)benzoyl]-L-glutamic acid), a new antifol targeted to thymidylate synthase, has been investigated in the human colon adenocarcinoma cell line HCT-8. [3H]IAHQ uptake was very slow, requiring days to achieve the intracellular level achieved in minutes by [3H]methotrexate. This slow transport of IAHQ was consistent with the long exposures required to achieve cytotoxicity. Intracellular [3H]IAHQ was converted in a concentration-dependent manner to poly-gamma-glutamate derivatives containing between two and four additional glutamate residues. These results are consistent with our hypothesis that IAHQ is a "pro-drug" which must be converted to polyglutamate derivatives before it is a sufficiently potent inhibitor of thymidylate synthase to induce a pyrimidineless state and cell death.
D000230:Adenocarcinoma / Q000378:metabolism; D001711:Biotransformation; D003110:Colonic Neoplasms / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000378:metabolism*; D006801:Humans; D008727:Methotrexate / Q000378:metabolism / Q000493:pharmacokinetics; D011099:Polyglutamic Acid / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism* / Q000493:pharmacokinetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured / Q000378:metabolism
D005493:Folic Acid Antagonists; D011799:Quinazolines; D011099:Polyglutamic Acid; C035530:5,8-dideazaisofolic acid; D013940:Thymidylate Synthase; D008727:Methotrexate