Work

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

Year: 1988

Type: article

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.

Source: Biochemical Pharmacology

DOI: 10.1016/0006-2952(88)90500-x

Authors: Alberto F. Sobrero, John J. McGuire, Joseph R. Bertino

Institution: Yale University

Language: English

Topic: Folate and B Vitamins Research

Subfield: Rheumatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,590