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. 1994 Sep;120(9):533–538. doi: 10.1007/BF01221030

The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat

W Van de Vrie 1,2, A M Jonker 3, R L Marquet 2, A M M Eggermont 1,2,✉
PMCID: PMC12201596  PMID: 7913932

Abstract

the feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubiein without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%–33% higher doses, because of the enhanced toxicity of the combination treatment.

Key words: Chemosensitizer, Cyclosporin A, Doxorubiein, Multidrug resistance, Toxicity

Abbreviations

CsA

cyclosporin A

DOX

doxorubicin

MDR

multidrug resistance

PBS

phosphate-buffered saline

Footnotes

This work was supported by the Dr Daniël den Hoed Foundation, Rotterdam, The Netherlands

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