This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Panetta, J. C. Articles by Evans, W. E. Search for Related Content PubMed PubMed Citation Articles by Panetta, J. C. Articles by Evans, W. E.

Methotrexate Intracellular Disposition in Acute Lymphoblastic Leukemia

A Mathematical Model of -Glutamyl Hydrolase Activity¹

Departments of Pharmaceutical Sciences [J. C. P., A. W., M. V. R., W. E. E.] and Hematology-Oncology [C-H. P.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105-2794, and Colleges of Pharmacy and Medicine, University of Tennessee, Memphis, Tennessee 38101 [C-H. P., M. V. R., W. E. E.]

Methotrexate (MTX) is an antifolate that is widely used for the treatment of childhood acute lymphoblastic leukemia (ALL) and a number of other malignant and nonmalignant diseases. Within cells, MTX is metabolized to more active methotrexate polyglutamates (MTXPG), and these polyglutamates are subsequently cleaved in lysosomes by -glutamyl hydrolase (GGH). GGH is reported to act as either an endopeptidase or an exopeptidase, exhibiting species differences in these functions. To better define the in vivo functions of GGH in human leukemia cells, we characterized GGH activity with different MTXPG substrates (MTX with three to five glutamates) in human T- and B-lineage leukemia cell lines, and in primary leukemia cells from newly diagnosed patients with ALL. Parameters estimated from fitting a series of hypothetical mathematical models to the data revealed that the experimental data were best fit by a model where GGH simultaneously cleaved multiple glutamyl residues, with highest activity at cleaving the outermost or two outermost residues from a polyglutamate chain. The model also revealed that GGH has a higher affinity for longer chain polyglutamates. Together, these findings provide new insights to the intracellular disposition of MTX in human ALL cells, and provides a mechanism-based model for characterizing differences among patients and genetic subtypes of ALL.

This article has been cited by other articles:

				R. C. Cho, P. D. Cole, K.-J. Sohn, G. Gaisano, R. Croxford, B. A. Kamen, and Y.-I. Kim Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells Mol. Cancer Ther., November 1, 2007; 6(11): 2909 - 2920. [Abstract] [Full Text] [PDF]