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Patterns of cross-resistance to the antifolate drugs trimetrexate, metoprine, homofolate, and CB3717 in human lymphoma and osteosarcoma cells resistant to methotrexate.

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 a subline of Burkitt's lymphoma cells (RAJI) was made 290-fold resistant (RAJI/MTX-R), T-cell leukemia cells (CCRF-CEM) were obtained 210-fold resistant (CEM/MTX-R), and 3 MTX-resistant human osteosarcoma lines were selected: TE-85/MTX-R (19-fold resistant; relative to wild-type); MG-63/MTX-R (8-fold resistant); and SAOS-2/MTX-R (200-fold resistant). We also studied a B-cell lymphoblastoid line, WI-L2/m4, that was 13,000-fold resistant. Assay of cellular dihydrofolate reductase (DHFR) showed the following pattern of activity in resistant cell lines, relative to parental cell activity: RAJI/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 all had significant cross-resistance to both metoprine and trimetrexate; the two 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 all 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). These studies demonstrated that, 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 three functionally distinct classes of folate antagonist with antitumor activity.
AuthorsH Diddens, D Niethammer, R C Jackson
JournalCancer research (Cancer Res) Vol. 43 Issue 11 Pg. 5286-92 (Nov 1983) ISSN: 0008-5472 [Print] United States
PMID6225514 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Folic Acid Antagonists
  • Quinazolines
  • metoprine
  • homofolic acid
  • CB 3717
  • Folic Acid
  • Tetrahydrofolate Dehydrogenase
  • Trimetrexate
  • Methotrexate
  • Pyrimethamine
Topics
  • Antineoplastic Agents (toxicity)
  • Biological Transport
  • Burkitt Lymphoma (drug therapy, metabolism)
  • Cell Line
  • Drug Resistance
  • Folic Acid (analogs & derivatives, therapeutic use)
  • Folic Acid Antagonists (therapeutic use)
  • Humans
  • Kinetics
  • Leukemia, Lymphoid (drug therapy, metabolism)
  • Lymphoma (drug therapy, metabolism)
  • Methotrexate (metabolism, therapeutic use)
  • Osteosarcoma (drug therapy, metabolism)
  • Pyrimethamine (analogs & derivatives, therapeutic use, toxicity)
  • Quinazolines (therapeutic use, toxicity)
  • Structure-Activity Relationship
  • T-Lymphocytes (drug effects)
  • Tetrahydrofolate Dehydrogenase (metabolism)
  • Trimetrexate

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