Increased intracellular concentrations of doxorubicin in resistant lymphoma cells in vivo by concomitant therapy with verapamil and cyclosporin A

Abstract

The tumor cell uptake of doxorubicin was studied in vivo in cells from 2 patients with clinically resistant leukemic lymphomas treated with continous infusions of doxorubicin 9 mg/m2 and vincristine with oral dexamethason. After 24 hours, intravenous or oral verapamil was added and in one treatment course intravenous cyclosporin A was given. Plasma and intracellular doxorubicin concentrations and plasma concentrations of verapamil and norverapamil were determined with HPLC. In the 1st patient the intracellular uptake rate of doxorubicin was increased from 0.007 to 0.013 nmol/mg protein/h after the start of verapamil infusion. In the first treatment course of patient number 2, the intracellular concentration of doxorubicin was increased by 280% during a 6‐h infusion of verapamil. When this patient in the next treatment course was given oral verapamil, no significant effect on doxorubicin uptake was seen. However, when 100 mg of cyclosporin A was added in three intravenous injections at 8‐h intervals, the doxorubicin concentration in the tumor cells increased from 0.027 to 0.086 nmol/mg protein. In conclusion, this study shows that the intracellular concentrations of doxorubicin can be increased also in vivo during patient therapy by the addition of verapamil or cyclosporin A.

Doxorubicin‐induced cardiomyocyte toxicity – protective effects of endothelial cells in a tri‐culture model system

“…This equates to 315 and 20 nM, respectively, which is within the wide range used herein (0.01 nM to 100 μM). Furthermore, the documented intracellular concentration of doxorubicin within tumour cells range from 0.007 to 0.013 nmol/mg protein and 0.027 to 0.086 nmol/mg protein, before and after concomitant therapy with verapamil and cyclosporine (Tidefelt et al, ).…”

Cholesterol and Triglycerides Metabolism Disorder in Malignant Hemopathies

“…This drug efflux pump can be inhibited by verapamil, too, the research made in vitro proved that it can reduce multidrug resistance. In such a study conducted in two patients with leukemic lymphoma resistant to treatment, verapamil was able to increase the intracellular amount of doxorubicin (Tidefelt et al, 1994). It was found that verapamil was able to overcome the P-gp -mediated resistance to doxorubicin and vincristine in a canine cell line of B cell lymphoma (GL-1) (Uozurmi et al, 2005, as cited in .…”