PATTERNS OF CROSS-RESISTANCE TO THE ANTI-FOLATE DRUGS TRIMETREXATE, METOPRINE, HOMOFOLATE, AND CB3717 IN HUMAN LYMPHOMA AND OSTEO-SARCOMA CELLS RESISTANT TO METHOTREXATE

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (11) , 5286-5292
Abstract
Methotrexate(MTX)-resistant sublines of malignant human cells were selected in vitro by stepwise increase in drug concentration in the medium. By this procedure resistant sublines of Burkitt''s lymphoma cells (RAJI/MTX-R), T-cell leukemia cells (CEM/MTX-R), osteosarcoma TE-85/MTX-R, MG-63/MTX-R and SAOS-2/MTX-R cells were selected. A B-cell lymphoblastoid line, WI-L2/m4, that was 13,000-fold resistant, was also studied. Assay of cellular dihydrofolate reductase (DHFR) showed the following pattern of activity in resistant cell lines, relative to parental cell activity: RAJ/MTX-R, 550-fold increased; CEM/MTX-R, unchanged; TE-85/MTX-R, 4-fold increased; MG-63/MTX-R, 6-fold increased; SAOS-2/MTX-R, unchanged; and WI-L2/m4, 110-fold increased. Measurement of MTX membrane transport showed decreased uptake in CEM/MTX-R and SAOS-2/MTX-R, relative to parental cell lines. The other DHFR-overproducing cells all gave normal initial MTX uptake rates but increased total uptake. The DHFR-overproducing lines had significant cross-resistance to metoprine and trimetrexate; the 2 lines with defective MTX transport were not cross-resistant, and the CEM/MTX-R cells showed collateral sensitivity to these agents. Only minor cross-resistance to homofolic acid was found in MTX-resistant lines. The highly MTX-resistant RAJI/MTX-R and WI-L2/m4 cells showed minor cross-resistance to the dual inhibitor of thymidylate synthetase and DHFR, CB3717 (5- and 15-fold, respectively). Depending upon the mechanism of resistance, MTX-resistant human tumor cells may be effectively killed by antifolates with different routes of uptake into cells, or with a different enzyme target. Thus, there are at least 3 functionally distinct classes of folate antagonist with antitumor activity.