Differential alteration of cisplatin cytotoxicity and myelotoxicity by the paclitaxel vehicle cremophor EL.
Cremophor EL (CR), the paclitaxel vehicle, has previously been reported to alter the pharmacokinetics and/or pharmacodynamics of some anticancer drugs including paclitaxel. Several experimental and clinical studies suggested that cisplatin (CDDP) in combination with paclitaxel results in less hematological toxicity than anticipated. To reveal the role of CR in this important pharmacological interaction, we evaluated the interaction of CR with CDDP in vitro and in vivo using experimental Ehrlich ascites carcinoma (EAC) tumor. CR (1 microg/ml) significantly enhanced the in vitro cytotoxicity of CDDP in cultured EAC cells. This enhancement was not associated with a parallel increase in CDDP cellular uptake. In tumor-bearing mice, CR (2.5 ml/kg, i.v.) given in combination with CDDP (7 mg/kg, i.v.) did not significantly change CDDP pharmacokinetics, antitumor activity or nephrotoxicity. On the other hand, CDDP-induced hematological toxicity was significantly reduced by CR. This protective effect was related to CR-induced inhibition of cellular CDDP accumulation in bone marrow. This study presents evidence that CR may play an important role in the pharmacological interaction between CDDP and paclitaxel. The present data may suggest formulation of CDDP with CR for systemic treatment. Further studies are yet necessary to establish the clinical value of CR as a modifier for CDDP therapeutic index.
Badary
O A
OA
Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt.
Abdel-Naim
A B
AB
Khalifa
A E
AE
Hamada
F M
FM
D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D002626:Chemistry, Pharmaceutical; D002945:Cisplatin / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D014677:Pharmaceutical Vehicles / Q000494:pharmacology; D013501:Surface-Active Agents / Q000494:pharmacology*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D014677:Pharmaceutical Vehicles; D013501:Surface-Active Agents; C000515:cremophor EL; D005990:Glycerol; D002945:Cisplatin