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Methotrexate: An Effective Agent for Treating Cancer and Building Careers. The Polyglutamate Era

Section of Hematology-Oncology, Department of Medicine, Committee on Clinical Pharmacology and the Cancer Research Center, University of Chicago, Chicago, Illinois, USA

Correspondence: Richard L. Schilsky, M.D., University of Chicago, Cancer Research Center, 5841 South Maryland Avenue, AMB O-119, MC 1140, Chicago, IL 60637, USA. Telephone: 312-702-6180; Fax: 312-702-9311.

This paper chronicles developments in the laboratory of Dr. Bruce Chabner during the period 1978-1981. Initial work demonstrated that methotrexate is taken up by human breast cancer cells by a high-affinity, carrier-mediated, energy-dependent transport system similar to that described in murine leukemia cells. Conversion of methotrexate to a high molecular weight polyglutamate metabolite was also demonstrated to occur in human breast cancer cells. Polyglutamates became the predominant form of intracellular drug, both free in the cytosol and bound to dihydrofolate reductase, during a 24 h exposure to clinically achievable methotrexate concentrations. Intracellular retention of polyglutamates led to prolonged suppression of thymidine synthesis and loss of cell viability after removal of extracellular drug. This work identified methotrexate polyglutamates as biologically active enzyme inhibitors in human tumor cells and launched a series of investigations on the interaction of these derivatives with folate-requiring enzymes.

Key Words. Methotrexate • Polyglutamate • Leucovorin • Stereoisomers • 5-fluorouracil • 5-ethynyluracil