Resistance to drugs associated with the multidrug resistance phenotype following selection with high-concentration methotrexate.
To study patterns of resistance at extreme but nevertheless clinically relevant drug concentrations, we developed a series of methotrexate-selected CCRF-CEM sublines, all of which were highly resistant to this antifolate (relative resistance, 10(2)- to greater than 10(5)-fold). The least methotrexate-resistant subline was completely sensitive to drugs associated with the multidrug resistance phenotype. However, more highly methotrexate-resistant sublines were significantly cross-resistant to vincristine, vinblastine, and dactinomycin (maximum relative resistance, 40-fold). These sublines were not cross-resistant to doxorubicin, daunorubicin, and teniposide. Regression analysis indicated that relative resistance to methotrexate was correlated with relative resistance to vincristine (r = 0.96) and vinblastine (r = 0.99). Such cross-resistance in highly methotrexate-resistant cells may have important clinical implications.
Children's Leukaemia and Cancer Research Unit, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia.
M
M
Haber
C
C
Reed
M
M
Kavallaris
M D
MD
Norris
B W
BW
Stewart
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype; D012044:Regression Analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D003609:Dactinomycin; D014750:Vincristine; D014747:Vinblastine; D008727:Methotrexate