title: Methotrexate exacerbates tumor progression in a murine model of chronic myeloid leukemia.
abstract: Expression of drug-resistant forms of dihydrofolate reductase (DHFR) in hematopoietic cells confers substantial resistance of animals to antifolate administration. In this study, we tested whether the chemoprotection conferred by expression of the tyrosine-22 variant DHFR could be used for more effective therapy of the 32Dp210 murine model of chronic myeloid leukemia (CML). 32Dp210 tumor cells were found to be sensitive to methotrexate (MTX) in vitro, whereas cells expressing the tyrosine-22 DHFR gene were protected from MTX at up to micromolar concentrations. MTX administered at low dose (2 mg/kg/day) did not protect normal C3H-He/J mice from 32Dp210 tumor infused intravenously, with drug toxicity limiting the administration of higher doses. Animals engrafted with transgenic tyrosine-22 DHFR marrow were protected from greater MTX doses (up to 6 mg/kg/day). However, the increased doses of MTX afforded by drug-resistance gene expression surprisingly resulted in decreased survival of the transplanted tumor-bearing animals, with increased levels of tumor detected in peripheral blood. This apparent exacerbation of tumor progression by MTX was not observed in DHFR transgenic mice in which all cells and tissues contain the drug-resistance gene. This suggests that increased tumor progression in MTX-administered animals resulted from MTX sensitivity of a nonhematopoietic host component, thus allowing tumor expansion. We conclude that MTX exacerbates tumor progression in the 32Dp210 model of CML, and that based on this model alternate DHFR inhibitors combined with drug-resistant DHFR or other chemotherapeutic agent/drug-resistance gene combinations may be required for the application of drug-resistance gene expression to the treatment of CML.
authors.affiliation: Gene Therapy Program, Institute of Human Genetics, Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Sweeney
authors.forename: Miechaleen D
authors.initials: MD
authors.lastname: Diers
authors.forename: Joel L
authors.initials: JL
authors.lastname: Frandsen
authors.forename: Roland
authors.initials: R
authors.lastname: Gunther
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Verfaillie
authors.forename: R Scott
authors.initials: RS
authors.lastname: McIvor
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002470:Cell Survival; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005493:Folic Acid Antagonists / Q000633:toxicity*; D006400:Hematocrit; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D008727:Methotrexate / Q000633:toxicity*; D051379:Mice; D008809:Mice, Inbred C3H; D009929:Organ Size / Q000187:drug effects; D016019:Survival Analysis; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate