Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells

Abstract

We examined the effect of daunorubicin (DNR), the new anthracycline derivative idarubicin (IDR), and verapamil on two leukemia cell lines that displayed the multidrug resistant (MDR) phenotype and used laser flow cytometry to quantitate intracellular anthracycline content. The vinblastine-resistant human lymphoblastic leukemia cell line CEM-VBL demonstrated minimal DNR uptake; simultaneous incubation with verapamil and DNR increased intracellular DNR uptake fourfold. IDR uptake was 10 times more rapid in these cells and simultaneous incubation with IDR and verapamil resulted in only a 1.2-fold increase of intracellular IDR. Similar results were observed in the vincristine-resistant human myeloid leukemia cell line HL-60/RV+. Intracellular retention of DNR and IDR was also measured in each cell line. In CEM-BVL cells, 38% of the original DNR concentration remained after a 2-hour resuspension in fresh medium compared with 71% of the original IDR concentration. In HL- 60/RV+ cells, 36% of the DNR concentration remained compared with 51% of the IDR concentration. After incubation of CEM-VBL and HL-60/RV+ cells with DNR for 1 hour followed by resuspension in fresh medium plus verapamil, intracellular DNA retention increased 5- and 5.2-fold, respectively. However, incubation of these cells for 1 hour with IDR followed by resuspension in fresh medium plus verapamil resulted in only a 1.6- and 2.4-fold increase in intracellular IDR retention. Lastly, clonogenic experiments were performed to correlate intracellular anthracycline content with cytotoxicity. DNR alone had a minimal effect on the clonogenic growth of CEM-VBL cells, whereas the combination of DNR plus verapamil resulted in approximately 80% growth inhibition. However, incubation of these cells with IDR alone resulted in greater than 95% growth inhibition. These results suggest that IDR may be more effective than DNR in leukemia cells that display the MDR phenotype.

P‐glycoprotein (PGP), lung resistance‐related protein (LRP) and multidrug resistance‐associated protein (MRP) expression in acute promyelocytic leukaemia

“…Notably, the only case that substantially increased the baseline PGP expression at first relapse was the only one who received DNR instead of idarubicin or mitoxantrone as first-line therapy. This observation, although occasional and requiring confirmation, suggests that, compared with idarubicin or mitoxantrone, DNR, the toxicity and transport of which has the strongest relationship with PGP action, may also have the highest activity in stimulating PGP expression (Berman & McBride, 1992;Michieli et al, 1993). In addition, it must be stressed that the patient who showed an increased PGP expression at first relapse received the highest dose of arabinosyl cytosine (AC), which has been shown to have a high activity in inducing PGP expression .…”

In vitro evaluation of the efficacy of idarubicin in human tumour cells from patients with low‐grade non‐Hodgkin's lymphoma

“…Both experimental (Berman & McBride, 1992) and clinical studies (Berman et al, 1989) have provided evidence of incomplete, if any, cross-resistance between Ida and Dox or Dnr. Our study confirmed these findings, but only in cells from previously treated patients.…”

“…Idarubicin (Ida) is the newest anthracycline and lacks a methoxy group in position 4 of the daunorubicin (Dnr) chromophore ring (Robert, 1993). In contrast to Dnr, Ida is cytotoxic in Pgp-positive cells in vitro (Berman & McBride, 1992;Tidefelt et al, 1994) and in vivo (Nü ssler et al, 1997).…”

Dexamethasone, cyclophosphamide, idarubicin and etoposide (DC‐IE): a novel, intensive induction chemotherapy regimen for patients with high‐risk multiple myeloma

“…In DC-IE the cell cycle active agents, idarubicin and etoposide, were administered over a 72 h period during the expected increase in proliferation induced by cyclophosphamide. In vitro data suggests that the cellular uptake of idarubicin may not be affected by expression of the MDR1 gene, and therefore may bypass this mechanism of drug resistance (Berman & McBride, 1991).…”