Sensitivity and resistance to chemotherapy in acute leukemia: correlation with in vitro drug uptake and lack of potentiation by verapamil

Abstract

The calcium channel blocker verapamil has been reported to circumvent acquired resistance to different antitumor agents in tumor cell lines in vitro. We studied its effect on in vitro uptake of m-AMSA and adriamycin in fresh leukemic cells from 11 leukemia patients. Six previously untreated patients were sensitive to m-AMSA (obtained remission). Four were clinically resistant to m-AMSA, and two of these also to adriamycin. Leukemic cells were incubated in pharmacological doses of 14C-adriamycin and 14C-m-AMSA for up to 2 h. Samples were supplemented with verapamil (750 ng ml-1) 30 min prior to the addition of m-AMSA or adriamycin. Drug uptake was measured at 15 min intervals up to 2 h and drug retention was measured during 30 min after the end of incubation, following washing and resuspension in fresh medium without cytotoxic drugs. Adriamycin uptake was the same irrespective of verapamil in all four cell samples, two of which were derived from patients resistant to adriamycin. The cellular m-AMSA uptake was higher in cells from clinically sensitive than from resistant patients (510 +/- 155 fg cell-1 vs 275 +/- 125 fg cell-1; P less than 0.01). Retention of m-AMSA 30 min after incubation was higher in cells from sensitive compared to resistant patients (187 +/- 78 vs 25 +/- 7; P less than 0.05). Our data suggest: (1) in vitro uptake greater than or equal to 350 fg cell-1 and subsequent retention greater than 75 fg cell-1 correlate to clinical sensitivity to the drug; and (2) neither m-AMSA nor adriamycin uptake could be significantly increased by verapamil.