Abstract
The fluorometric microculture cytotoxicity assay (FMCA) was employed for analysing the effect of different chemotherapeutic drug combinations and their single constituents in 44 cases of acute myelocytic leukaemia (AML). A large heterogeneity with respect to cell kill was observed for all combinations tested, the interactions ranging from antagonistic to synergistic in terms of the multiplicative concept for drug interactions. However, an 'additive' model provided a significantly better fit of the data compared to the effect of the most active single agent of the combination (Dmax) for several common antileukaemic drug combinations. When the two interaction models were related to treatment outcome 38% of the non-responders showed preference for the additive model whereas the corresponding figure for responders was 80%. Overall, in 248 of 290 (85%) tests performed with drug combinations, there was an agreement between the effect of the combination and that of the most active single component. Direct comparison of Dmax and the combination for correlation with clinical outcome demonstrated only minor differences in the ability to predict drug resistance. The results show that FMCA appear to report drug interactions in samples from patients with AML in accordance with clinical experience. Furthermore, testing single agents as a substitute for drug combinations may be adequate for detection of clinical drug resistance to combination therapy in AML.
Highlights
Chemotherapy for malignant disease has continuously improved over the past decades
We have previously described the fluorometric microculture cytotoxicity assay (FMCA) for drug sensitivity testing of cell lines and tumour cell samples from patients with acute myelocytic leukaemia (AML; Larsson et al, 1992a; Larsson & Nygren, 1990)
Cells were cryopreserved in culture medium containing 10% dimethyl sulfoxide (DMSO) and 50% foetal calf serum (FCS) by initial freezing for 24 h in - 70'C followed by storage in liquid nitrogen
Summary
44 leukaemic cell samples were obtained from peripheral blood or bone marrow from 40 adult patients with newly diagnosed or relapsed AML. Mononuclear cells were obtained by 1,077 g ml-' Ficoll-Isopaque (Pharmacia, Uppsala, Sweden) density gradient centrifugation. Viability was determined by trypan blue exclusion test and the density gradient centrifugation generally yielded cell suspensions of >85% leukaemic cells as judged by May-Grunwald-Giemsa stained cytocentrifugate preparations. Cells were cryopreserved in culture medium containing 10% dimethyl sulfoxide (DMSO) and 50% FCS by initial freezing for 24 h in - 70'C followed by storage in liquid nitrogen. Both fresh and cryopreserved samples were used in this study
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