Role of folylpolygutamate synthetase (FPGS) in antifolate chemotherapy; a biochemical and clinical update.
Even though folate antimetabolites were introduced over forty years ago, they continue to be the backbone of many active chemotherapeutic regimens used by medical and pediatric oncologists. The recognition of polyglutamylation by folylpolyglutamate synthetase (FPGS) as an important metabolic step in the "activation" of classical antifolates and novel drugs aimed at thymidylate synthase (TS) and de novo purine synthesis, has resulted in renewed interest in this class of drugs. In addition, the emergence of secondary neoplasms in patients treated with alkylating agents and topoisomerase inhibitors in contrast to the exceptional safety record of antimetabolites, underscores the need for clinical trials that incorporate new strategies with known active antimetabolites and novel promising agents. In that context, FPGS is an important target for further laboratory and clinical investigations.
Synold
T W
TW
Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, California, USA.
Willits
E M
EM
Barredo
J C
JC
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001711:Biotransformation; D005492:Folic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D010453:Peptide Synthases / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005492:Folic Acid; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase