The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat.
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 doxorubicin 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.
Van de Vrie
W
W
Department of Surgical Oncology, Rotterdam Cancer Institute, The Netherlands.
Jonker
A M
AM
Marquet
R L
RL
Eggermont
A M
AM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D004351:Drug Resistance; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013921:Thrombocytopenia / Q000139:chemically induced
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D016572:Cyclosporine