The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat |
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Authors: | W. Van de Vrie A. M. Jonker R. L. Marquet A. M. M. Eggermont |
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Affiliation: | (1) Department of Surgical Oncology, Rotterdam Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands;(2) Laboratory for Experimental Surgery, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands;(3) Department of Pathology, Rotterdam Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands |
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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.Abbreviations CsA cyclosporin A - DOX doxorubicin - MDR multidrug resistance - PBS phosphate-buffered salineThis work was supported by the Dr Daniël den Hoed Foundation, Rotterdam, The Netherlands |
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Keywords: | Chemosensitizer Cyclosporin A Doxorubiein Multidrug resistance Toxicity |
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