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Enhancement of Antitumor Effects of 1-Hexylcarbamoyl-5-fluorouracil Combined with Hyperthermia on Ehrlich Ascites Tumor in Vivo and Nakahara-Fukuoka Sarcoma Cell in Vitro

Department of Oral and Maxillofacial Surgery I, Hiroshima University, School of Dentistry, Kasumi 1-2-3, Minami-Ku, Hiroshima 734, Japan

1-Hexylcarbamoyl-5-fluorouracil (HCFU) was found to be hydrolyzed to 5-fluorouracil (5-FU) depending on temperature. In this study, the antitumor effects of HCFU with hyperthermia were studied on Ehrlich ascites in tumor-bearing CD-1 mice and Nakahara-Fukuoka sarcoma cells. Concurrently, the change of 5-FU concentration in the Ehrlich tumor was also observed. In vivo, Ehrlich cells were transplanted in the foot pads of mice. HCFU (80 mg/kg) and 5-FU (40 mg/kg) (same molarity) were administered orally on the 3rd, 6th, and 9th days after transplantation and simultaneously hyperthermia (43.5°C, 45 min) was induced. The antitumor effect was evaluated by the tumor volume. On the 9th day after transplantation, HCFU (150 mg/kg) and 5-FU (75 mg/kg) were administered with or without hyperthermia (43.5°C, 45 min) and the tumor tissues were taken for 5-FU concentration analysis. In addition, Nakahara-Fukuoka sarcoma cells were incubated (42°C various times) with our without HCFU and 5-FU (both 1 x 10^-4 M) in vitro. The cytotoxicity was evaluated by colony forming assay. The most effective condition was found to be the combination of HCFU with hyperthermia in vitro and in vivo. The highest 5-FU concentration was observed by the treatment of HCFU combined with hyperthermia in vivo. Hence, HCFU could be clinically useful in thermochemotherapy.

¹ To whom request for reprints should be addressed.

Received 1/11/88. Revised 4/ 4/88. Accepted 4/ 8/88.