Antitumor efficacy of combination chemotherapy with UFT and cyclophosphamide against human breast cancer xenografts in nude mice.
The combination of cyclophosphamide (CPA) and 5-fluorouracil (5-FU) is currently regarded as the most effective therapy for the treatment of patients with advanced and recurrent breast cancer. We evaluated the augmentation of antitumor activity and toxicity by coadministration of CPA and UFT (1M tegafur--4M uracil) instead of intravenous 5-FU on H-31 human breast cancer xenografts in nude mice. The maximum tolerable dose (MTD) of UFT alone (24 mg/kg) and CPA alone (85 mg/kg) had a significant effect on H-31 tumors in mice with 86.6% and 83.0% inhibition rates of tumor growth, respectively, and without loss of body weight, diarrhea or myelosuppression. The combined administration with full and 83.3% MTD of UFT and CPA augmented the antitumor activity compared to that of UFT alone and CPA alone. The relative tumor volume of the UFT plus CPA-treated group to the UFT- and CPA-treated groups was 0.28 and 0.36 for the full MTD, and 0.51 and 0.67 for 83.3% MTD, respectively. When CPA was consecutively administered to the tumor-bearing mice for 14 days, there were no decreases in the activities of enzymes related to 5-FU metabolism, but there was an significant increase in the activity of ribonucleotide reductase, suggesting that anabolism of 5-FU derived from tegafur is accelerated to some extent by coadministration of CPA. In conclusion, these results suggest that combination therapy with oral UFT and CPA may be useful for the long-term treatment of cancer patients with advanced and recurrent breast cancers.
Haga
S
S
Department of Surgery, Tokyo Women's Medical College Daini Hospital, Japan.
Shimizu
T
T
Imamura
H
H
Watanabe
O
O
Kinoshita
J
J
Fukushima
M
M
Kajiwara
T
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000378:metabolism; D005641:Tegafur / Q000008:administration & dosage / Q000633:toxicity; D014183:Transplantation, Heterologous; D014498:Uracil / Q000008:administration & dosage / Q000633:toxicity
D009363:Neoplasm Proteins; D011743:Pyrimidines; D005641:Tegafur; D014498:Uracil; D012264:Ribonucleotide Reductases; D002945:Cisplatin