Effects of paclitaxel, docetaxel and their combinations on subcutaneous lymphomas in inbred Sprague–Dawley/Cub rats

• Published in: European journal of pharmaceutical sciences 2006-12, Vol.29 (5), p.442-450
• Main Authors: Otová, Berta, Václavíková, Radka, Danielová, Vlasta, Holubová, Jaroslava, Ehrlichová, Marie, Horský, Stanislav, Souček, Pavel, Šimek, Petr, Gut, Ivan
• Format: Article
• Language: English
• Subjects: Animals; Anticancer; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Bioavailability; Biological and medical sciences; Body Weight; Cell Line, Tumor; Docetaxel; Drug Therapy, Combination; Efficiency; Gene Expression Regulation; General pharmacology; Humans; Intestines - metabolism; Lymphoma, T-Cell - blood; Lymphoma, T-Cell - drug therapy; Lymphoma, T-Cell - metabolism; Medical sciences; Metabolism; Mice; Microsomes, Liver - metabolism; P-glycoprotein; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - blood; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Subcutaneous Tissue - pathology; Taxoids - administration & dosage; Taxoids - blood; Taxoids - pharmacology; Taxoids - therapeutic use
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2006.08.007

We investigated, whether the effects on paclitaxel, docetaxel or their combinations on T-cell lymphomas in Sprague–Dawley/Cub rats were mainly caused by their different efficiency or combination of different mechanism of action, or limited by metabolic inactivation by P450 enzymes or drug efflux caused by P-glycoprotein (P-gp). Docetaxel most effectively prolonged the survival of rats and the time of lymphoma appearance, inhibited their intravital size and weight after sacrifice. Paclitaxel was poorly effective and combined administration had intermediate effects. Blood levels of both drugs were similar. Repeated administration of paclitaxel, but not docetaxel, decreased its area under concentration, but the effect disappeared 6 h after dosing and was not sufficient to explain lower effects of paclitaxel. The faster metabolism of docetaxel than paclitaxel in vitro did not limit its higher efficiency and repeated administration of paclitaxel did not induce its metabolism to decrease its blood levels sufficiently. Likewise, undetectable expression of P-gp protein in tumours could not explain lower effects of paclitaxel, which is a better substrate of P-gp. Docetaxel was three-fold more effective than paclitaxel against P388D1 lymphoma cell line, used as a model of the T-cell lymphoma and combined action was dominated by the effects of docetaxel. Thus, docetaxel was effective against T-cell lymphomas and may be a potential anticancer drug in similar indications.