Vol.53 No.11 November 2005

Experimental chemoendocrine therapy using S-1 and tamoxifen on human breast carcinoma xenografts

Takaya Yamada¹⁾, Miki Tongu²⁾, Osamu Hiraku³⁾, Asako Hashimoto¹⁾, Koichiro Atsuda^2,4), Tatsuo Suzuki¹⁾, Yukio Suzuki¹⁾, Fumiki Asanuma⁵⁾ and Yoshinori Yamada⁵⁾

¹⁾Biomedical Laboratory, Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku, Tokyo, Japan
²⁾Department of Pharmacy, Kitasato Institute Hospital
³⁾Laboratory Animal Center, Center for Basic Research, Kitasato Institute
⁴⁾College of Pharmacy, Kitasato University
⁵⁾Department of Surgery, Kitasato Institute Hospital

Abstract

The antitumor activity of combined chemoendocrine therapy, fluoropyrimidine derivatives and tamoxifen (TAM), was examined with three human breast carcinoma xenografts, MCF-7, R-27, and Br-10, which are estrogen receptor (ER) positive tumors. Treatments based on maximum tolerated doses were initiated in four groups: control, 5-fluorouracil (5-FU) 60 mg/kg i.p. every four days for a total of three times, S-1 20 mg/kg (as tegafur) p.o. five times a week for three weeks, and TAM 5 mg/kg p.o. six times a week for three weeks. The antitumor activity of each agent were assessed by the T/C (treated/control) ratio of relative mean tumor weight. Values for 5-FU with MCF-7, R-27 and Br-10 were 68.6, 80.4, and 52.7%, and those for S-1 were 49.0, 60.0, and 29.6%, showing higher antitumor activity than 5-FU. For TAM, values were 50.5, 62.3, and 39.8%. The activity of combination therapy, 5-FU+TAM and S-1+TAM, was tested with R-27 which showed the lowest sensitivity to each of the three agents. Values were 51.9% for 5-FU+TAM and 28.7% for S-1+TAM. Determination in thymidylate synthase (TS) inhibition and dihydropyrimidine dehydrogenase (DPD) activity then measured to examine the role of 5-FU metabolism in the antitumor effect enhancement, which showed no statistically significant difference between treatment groups, S-1 alone and S-1+TAM. 5-FU concentrations in the tumor also showed no statistically significant differences between groups. It is negative that 5-FU in the tumor is modified by TAM and another mechanism might contribute to the enhancement of antitumor effect with this combination. S-1+TAM appears to be a promising combination against advanced or recurrent hormone receptor positive breast cancer.

Key word

breast cancer, animal model, tamoxifen, combination therapy, S-1

Received

July 13, 2005

Accepted

September 27, 2005

Jpn. J. Chemother. 53 (11): 679-685, 2005