Docetaxel alone or orally combined with 5-fluorouracil and its derivatives: effects on mouse mammary tumor cell line MM2 in vitro and in vivo.
Although docetaxel (Taxotere; TXT), a taxoid anticancer drug, is clinically and experimentally very effective against breast cancer, its antitumor effect is of very short duration. We addressed whether 5-fluorouracil (5-FU) and its derivatives can act synergistically with TXT against mammary tumors, with placing particular stress on their use by oral route. Mouse mammary tumor cell line, MM2, was propagated in culture and as ascites in mice. Carmofur (HCFU) and doxifluridine (5'-DFUR) were used as 5-FU derivatives. In vitro, the cytotoxic effects of antitumor drugs on MM2 cells were examined by MTS assay. In vivo, mice inoculated i.p. with MM2 cells were treated with i.p. injection of TXT and/or oral administration of 5-FU or its derivatives, and observed for curing tumor. In vitro, the synergistic effects were observed in the combination of TXT and 5-FU or HCFU, but not in that of TXT and 5'-DFUR. In vivo, all of these combinations cured tumors far more effectively than TXT alone. The discrepant result of the combination of TXT and 5'-DFUR between in vitro and in vivo was ascribed to up-regulation of pyrimidine phosphorylase in tumor cells in vivo by TXT. Thus, 5-FU, its masked compounds like HCFU and its prodrugs like 5'-DFUR can act synergistically with TXT in the therapy of cancer even when administered by the oral route.
Takeda
Y
Y
Department of Surgery, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. ytake@ims.u-tokyo.ac.jp
Yoshizaki
I
I
Nonaka
Y
Y
Yanagie
H
H
Matsuzawa
A
A
Eriguchi
M
M
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008809:Mice, Inbred C3H; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011355:Prodrugs / Q000008:administration & dosage; D043823:Taxoids; D013939:Thymidine Phosphorylase / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation
D011355:Prodrugs; D043823:Taxoids; D005467:Floxuridine; D000077143:Docetaxel; D013939:Thymidine Phosphorylase; C017367:carmofur; D017239:Paclitaxel; D005472:Fluorouracil; C025034:doxifluridine