Biological properties of fluoroglutamate-containing analogs of folates and methotrexate with altered capacities to form poly (gamma-glutamate) metabolites.
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.
McGuire
J J
JJ
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Hart
B P
BP
Haile
W H
WH
Magee
K J
KJ
Rhee
M
M
Bolanowska
W E
WE
Russell
C
C
Galivan
J
J
Paul
B
B
Coward
J K
JK
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D005467:Floxuridine / Q000494:pharmacology; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006133:Growth Substances / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D002955:Leucovorin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011099:Polyglutamic Acid / Q000378:metabolism*; D051381:Rats; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D006133:Growth Substances; C097768:beta,beta-difluorofolic acid; C036539:fluoresceinated methotrexate; C097767:gamma-fluorofolic acid; D005467:Floxuridine; D011099:Polyglutamic Acid; D005492:Folic Acid; D002955:Leucovorin; D008727:Methotrexate