Effects of paclitaxel, docetaxel and their combinations on subcutaneous lymphomas in inbred Sprague-Dawley/Cub rats.
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 6h 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.
Otová
Berta
B
Institute of Biology and Medical Genetics, 1st Faculty of Medicine and General Teaching Hospital Charles University, 128 00 Prague, Czech Republic.
Václavíková
Radka
R
Danielová
Vlasta
V
Holubová
Jaroslava
J
Ehrlichová
Marie
M
Horský
Stanislav
S
Soucek
Pavel
P
Simek
Petr
P
Gut
Ivan
I
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D001835:Body Weight; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040521:Subcutaneous Tissue / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel