Uptake and metabolism of 5,8-dideazaisofolic acid in human colon carcinoma cells.

Abstract

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.

• Authors: A F Sobrero, J J McGuire, J R Bertino
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 37 Issue 6 Pg. 997-1001 (Mar 15 1988) ISSN: 0006-2952 [Print] England
• PMID: 2451526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Folic Acid Antagonists
• Quinazolines
• Polyglutamic Acid
• 5,8-dideazaisofolic acid
• Thymidylate Synthase
• Methotrexate

Topics

• Adenocarcinoma (metabolism)
• Biotransformation
• Colonic Neoplasms (metabolism)
• Folic Acid Antagonists (metabolism)
• Humans
• Methotrexate (metabolism, pharmacokinetics)
• Polyglutamic Acid (metabolism)
• Quinazolines (metabolism, pharmacokinetics)
• Thymidylate Synthase (antagonists & inhibitors)
• Tumor Cells, Cultured (metabolism)