Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

Abstract

Aims To study anthracycline-induced apoptosis in leukemic cells isolated from patients with acute myelogenous leukemia (AML) in vitro and to compare intracellular anthracycline concentrations causing apoptosis in vitro with those obtained in vivo during anthracycline treatment. Methods Mononuclear blood cells from AML patients were isolated before (n=20) and after anthracycline infusion (n= 24). The pre-treated cells were incubated in vitro with daunorubicin (DNR) and/or idarubicin (IDA). Anthracycline concentrations were determined by high-performance liquid chromatography, and apoptosis was detected by propidium iodine staining using a flow cytometer. Results There was a clear concentration-response relationship between intracellular anthracycline levels and apoptosis albeit with a large interindividual variation. Intracellular levels >1200 μM always led to high apoptosis development (>60%) in vitro. The intracellular concentrations of DNR in vivo (n=24) were more than tenfold lower than the concentrations needed to induce effective apoptosis in vitro, although a significant relation between in vivo concentrations and clinical remission was found. We also found a significant relation between apoptosis induction in leukemic cells by IDA in vitro and clinical remission. Conclusions Our results indicate that intracellular anthracycline levels in vivo are suboptimal and that protocols should be used that increase intracellular anthracycline levels.

Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target

“…IDA is a synthetic analog of DNR and one of the most effective inhibitors of DNA topoisomerase. Alex et al found a significant relation between apoptosis induction in leukemic cells by IDA in vitro and the disease remission measured by the percent of residual leukemic cells in bone marrow [29]. In this study, we found the sequential combination treatment of DAC and IDA efficiently inhibited the formation of AML cell clones and tumor growth in a subcutaneous AML mouse model.…”

Structural modifications in the sugar moiety as a key to improving the anticancer effectiveness of doxorubicin

“…After proving the favourable toxicity profile of investigated compounds there have been attempts to determine the ability of derivatives to induce apoptosis. Apoptosis plays an important role in the cytotoxic activity of first-and second-generation anthracyclines in the therapy of solid cancer [52] and leukaemia [53]. There are reports describing the role of DOX in the generation of morphological alterations in the nuclei [54,55].…”

Human Carbonyl Reductases

“…Hence, attenuation of CBR1 activity using pharmacologic inhibitors could improve the therapeutic response to DAUN and DOX and reduce the side effects in patients undergoing chemotherapy [45,95,96,101]. Additionally, CBR1 may be implicated in the large interpatient variabilities in the pharmacokinetics of both DAUN and DOX [105][106][107]. The reasons for these interindividual variabilities in DAUN and DOX pharmacokinetics remain unclear [45,105], and the consequences of such differences in pharmacokinetics are unpredictable with regard to toxicity and outcome of therapy [45,108].…”