In vitro and in vivo chemosensitizing effect of cyclosporin A on an intrinsic multidrug-resistant rat colon tumour

Abstract

Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumour model. CC531 is a rat colon carcinoma that expresses Pgp, as was shown with the monoclonal antibody C-219. In vitro the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and cyclosporin A (CsA), while the sensitivity to cisplatin was not enhanced. In a daunorubicin accumulation assay verapamil and CsA enhanced the daunorubicin content of CC531 cells. In vivo CsA was injected intramuscularly for 3 consecutive days at a dose of 20 mg kg-1 day-1. This resulted in whole-blood CsA levels above 2 mumol/l, while intratumoral CsA levels amounted to 3.6 mumol/kg. In a subrenal capsule assay the maximal tolerable dose of doxorubicin (4 mg/kg) significantly reduced tumour growth. Doxorubicin at 3 mg/kg was not effective, but in combination with CsA this dose was as effective as 4 mg/kg doxorubicin. These experiments show that adequate doses of the chemosensitizing drug CsA can be obtained in vivo, resulting in increased antitumoral activity of doxorubicin in vivo. The in vitro and in vivo data together suggest that the chemosensitization by CsA is mediated by Pgp. This finding may have implications for the application of CsA and CsA-like chemosensitizers in the clinical setting.

Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

“…In previous studies, calcium antagonists such as verapamil (4) and small interfering RNA (siRNA) targeting multidrug resistance protein 1 (MDR1) messenger RNA (mRNA) were observed to modulate MDR1/P-glycoprotein (P-gp)-dependent MDR by downregulating the expression of MDR1 mRNA and P-gp (5). However, calcium antagonists may cause heart failure and hypotension (6), and the clinical benefit of siRNA targeting MDR1 mRNA has not been reported thus far.…”

Specific reversal of MDR1/P-gp-dependent multidrug resistance by RNA interference in colon cancer cells

“…To improve the effect of chemotherapy in the treatment of colon cancer, one of the major challenges is how to reverse MDR in colon cancer cells. In previous studies, calcium antagonists such as verapamil (5), antisense oligonucleotides (6) and hammerhead ribozymes (7) were found to modulate MDR1/P-gp-dependent MDR by down-regulating the expression of the MDR1 mRNA and P-gp. However, calcium antagonists may cause heart failure and hypotension (8), and the clinical benefit of antisense oligonucleotides and hammerhead ribozymes has not been realized.…”

Pharmacokinetics of the multidrug-resistance-converting drug dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of tumor-bearing Wag / Rij rats

“…Solid tumors of the CC531 colon adenocarcinoma tumor model were used according to a previously described method [7,15]. Tumors of the intrinsic MDR cell line (CC531) were grown in donor Wag/Rij rats.…”

“…The aim of the present study was to explore the pharmacokinetics of dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of Wag/Rij rats bearing an intrinsic MDR CC531 colon adenocarcinoma as a solid tumor under the renal capsule [1,15].…”