Folates provoke cellular efflux and drug resistance of substrates of the multidrug resistance protein 1 (MRP1)

Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration inf

Drug combination testing in acute lymphoblastic leukemia using the MTT assay

Drug resistance assays may be useful to identify drug interactions. For this purpose, we studied three drug combinations, each at 8-12 concentrations, with the MTT assay in acute lymphoblastic leukemia (ALL) samples from 34 children obtained at initial diagnosis. This resulted in a total of 518 comparisons between expected and observed leukemic cell survivals. The combinations prednisolone (PRD) with vincristine (VCR), PRD with mafosfamide (MAF), and PRD with daunorubicin (DNR) were tested without technical difficulties, and without an increased assay variation as compared to single drugs. We observed a marked heterogeneity in drug interactions between patients, between combinations, and between different concentrations within one specific combination. Between PRD + VCR, synergism was found in 46%, antagonism in 18%, and additivity in 36% of the 228 observations. Between PRD + MAF, synergism was found in 51%, antagonism in 20%, and additivity in 29% of the 140 observations. Between PRD + DNR, synergism was found in 35%, antagonism in 31%, and additivity in 34% of the 150 observations. PRD + VCR and PRD + MAF showed more often synergism than PRD + DNR, while antagonism was observed more frequently between PRD + DNR (p < 0.05). However, the magnitude of antagonism was not much different between the three drug combinations, nor was there a significant antagonistic interaction in any of the drug combinations tested, if all samples were considered together. We conclude that the MTT assay can be used to study drug interactions in vitro in ALL samples. The type of interaction was different between patients, and depends on the drug combination and concentrations. The combinations PRD + VCR and PRD + MAF generally showed additive and even synergistic interactions. The cytotoxicity of PRD + DNR was generally not markedly higher than that of the most active single drug

In vitro cytotoxicity of mitoxantrone, daunorubicin and doxorubicin in untreated childhood acute leukemia

Mitoxantrone (MIT) has not been studied as a single agent in children with untreated leukemia. The antileukemic activity of MIT in these patients and its activity in relation to clinical and cell biological features is unknown. We studied the in vitro cytotoxicity of MIT, daunorubicin (DNR) and doxorubicin (DOX) in untreated childhood acute lymphoblastic leukemia (ALL, n=131) and acute nonlymphoblastic leukemia (ANLL, n=20) samples, using the MTT assay. There were marked interindividual differences in resistance to all three drugs. A strong, significant cross-resistance was found in ALL between MIT, DNR and DOX. ALL samples of the T-lineage, a prognostically unfavorable immunophenotype, however, were significantly more resistant to DNR and DOX, but not to MIT, than common or pre-B ALL samples. ALL cells from children with a prognostically unfavorable age at diagnosis, especially those < 2 years, showed a relative resistance to all three drugs compared to the intermediate age-group. This was found within all patients, but also within the common or pre-B ALL cases only. Sex, white blood cell count, or FAB type was not related to in vitro drug resistance. None of the three drugs showed an overall preferential activity in ALL or ANLL. We conclude that the in vitro antileukemic activity of MIT, DNR and DOX is related to certain clinical and cell biological features. There were no major differences between the three drugs in antileukemic activity, except that T-ALL samples were more resistant than common or pre-B ALL samples to DNR and DOX, while MIT was equally active in these two immunophenotypes