Biological properties of fluoroglutamate-containing analogs of folates and methotrexate with altered capacities to form poly (gamma-glutamate) metabolites.

Abstract

Fluoroglutamate-containing analogs of folates and methotrexate (MTX) with altered capacities for poly (gamma-glutamate) metabolism were synthesized to probe the biological roles of polyglutamates. Compared to folic acid, DL-e,t-gamma-fluorofolic acid, a compound that is a poor substrate for polyglutamylation, was approximately 25-fold less potent in promoting growth of folate-depleted H35 rat hepatoma cells. DL-beta,beta-Difluorofolic acid, a compound that forms diglutamates more readily than does folic acid, was at least equivalent to folic acid in potency. Leucovorin (LV), a reduced folate, was 30-fold more potent than folic acid in promoting growth, whereas the analogous form of DL-e,t-gamma-fluorofolate, DL-e,t-gamma-fluoroleucovorin (DL-e,t-gamma-FLV) was only 4-fold more potent than folic acid. Both LV and DL-e,t-gamma-FLV protected or "rescued" cells from the growth inhibitory effects of MTX; however a 37- to 46-fold higher concentration of the fluoro analog was required. Folic acid, DL-e,t-gamma-fluorofolic acid, LV, and DL-e,t-gamma-FLV each potentiated the growth inhibitory effect of 5-fluoro-2'-deoxyuridine on CCRF-CEM human leukemia cells; higher concentrations of fluorinated analogs again were required. Stereochemically pure L-t-gamma-fluoromethotrexate (L-t-gamma-FMTX), a poor substrate for polyglutamylation, was evaluated as a cell growth inhibitor. In continuous exposure, L-t-gamma-FMTX), was 7-fold less potent than MTX as an inhibitor of CCRF-CEM growth. Results with these fluorinated folate and MTX analogs offer insight into the importance of polyglutamate metabolism to these biological and pharmacological effects.

• Authors: J J McGuire, B P Hart, W H Haile, K J Magee, M Rhee, W E Bolanowska, C Russell, J Galivan, B Paul, J K Coward
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 52 Issue 8 Pg. 1295-303 (Oct 25 1996) ISSN: 0006-2952 [Print] England
• PMID: 8937438 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Growth Inhibitors
• Growth Substances
• beta,beta-difluorofolic acid
• fluoresceinated methotrexate
• gamma-fluorofolic acid
• Floxuridine
• Polyglutamic Acid
• Folic Acid
• Leucovorin
• Methotrexate

Topics

• Animals
• Cell Division (drug effects, physiology)
• Floxuridine (pharmacology)
• Folic Acid (analogs & derivatives, chemical synthesis, pharmacology)
• Growth Inhibitors (chemical synthesis, pharmacology)
• Growth Substances (chemical synthesis, pharmacology)
• Humans
• Leucovorin (analogs & derivatives, chemical synthesis, pharmacology)
• Methotrexate (analogs & derivatives, chemical synthesis, pharmacology)
• Polyglutamic Acid (metabolism)
• Rats
• Tumor Cells, Cultured