In vitro analysis of drug resistance in tumor cells from patients with acute myelocytic leukemia

Abstract

A 72 hours fluorometric microculture cytotoxicity assay (FMCA) was used for the study of chemotherapeutic drug resistance in tumor cell suspensions from patients with acute myelocytic leukemia (AML). A marked heterogeneity with respect to sensitivity was observed for a panel of cytotoxic drugs tested in 76 samples from 60 patients with treated or untreated AML. Primary resistance to vincristine (Vcr) and prednisolone in untreated AML was observed as well as 'acquired' resistance to several other antileukemic drugs. Cross resistance patterns for AML active drugs revealed significant positive relationships between anthracyclines, VP16 and amsacrine (Amsa), whereas mitoxantrone (Mitox) was more weakly correlated. Sensitivity to cytosine arabinoside was unrelated to the anthracyclines, VP16, Amsa and Mitox but showed a significant relationship to 6-thioguanine. Several resistance modifying agents, including the novel non-immunosuppressive cyclosporin A analogue PSC 833, were able to potentiate the effects of doxorubicin and Vcr at concentrations achievable in the clinic. However, the pattern of activity was heterogenous and the frequency of responsive samples was higher in relapse compared to de novo cases. Individual in vitro/in vivo correlations based on quartile distributions of all accumulated drug sensitivity data from AML patients indicated a high specificity with respect to the identification of drug resistance. The results suggest that the FMCA may provide clinically valuable information on chemotherapeutic drug resistance in AML.