THE CHEMOSENSITIZER CYCLOSPORINE-A ENHANCES THE TOXIC SIDE-EFFECTS OFDOXORUBICIN IN THE RAT

The feasibility of using chemosensitizers in the circumvention of P-gl ycoprotein-mediated multidrug resistance has been shown in many studie s. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same exp erimental design we investigated the side-effects of the combination t reatment. During the 35-day experiment doxorubicin treatment caused do se-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppress ion (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulti ng, in ascites, pleural effusion, hypercholesterolaemia and hypertrigl yceridaemia. These toxicities were enhanced by the addition of the che mosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no si gns of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrena l gland and large intestine. CsA had a low toxicity profile, as it onl y caused a transient rise in bilirubin. In conclusion, the chemosensit izer CsA enhanced the side-effects of the anticancer drug doxoruhicin without altering the toxicity pattern. There was no evidence of a ther apeutic gain by adding CsA to doxorubicin, compared to single-agent tr eatment with doxorubicin in 25%-33% higher doses, because of the enhan ced toxicity of the combination treatment.