[Effect of cepharanthine on antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207)--5-fluorouracil delivery into tumor tissue].

A study on the antitumor effect and distribution to tumor tissue of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) when administered with cepharanthine was performed using RPMI 4788 human colon cancer cell line or murine Sarcoma-180 tumor cells in vitro and in vivo. Combined treatment with FT-207 or 5-fluorouracil (5-FU) and cepharanthine showed a marked anti-proliferative effect on DNA synthesis of RPMI 4788 cells when measured by 3H-thymidine incorporation in vitro. Combination of FT-207 (1 microgram/ml) and cepharanthine (1 microgram/ml or 5 micrograms/ml) exhibited a similar antitumor effect to FT-207 (25 micrograms/ml). Also the DNA synthesis of RPMI 4788 cells was inhibited by low dose of 5-FU with cepharanthine similarly by high dose of 5-FU alone. On the other hand, Sarcoma-180 tumor was transplanted to the back of mice, and FT-207 (50 mumole/kg; 10 mg/kg) and cepharanthine were orally coadministered once at day 7 after tumor transplantation. This combined therapy significantly inhibited the growth of Sarcoma-180 tumor. Furthermore, antitumor activity of FT-207 was enhanced significantly by coadministration of cepharanthine daily for 10 days. The concentration of FT-207 or 5-FU in the tumor tissue, normal tissues and serum were measured in mice with Sarcoma-180 tumor. The mice were given FT-207 and cepharanthine orally once at day 7 (I) or daily for 10 days (II) after transplantation of Sarcoma-180 tumor cells. No remarkable difference was found in the concentration of FT-207 between tumor tissue and serum. The concentration of 5-FU in the tumor tissue was significantly higher than that in the serum. The ratio of 5-FU concentration in the tumor tissue to that in the serum (T/S) was 15.9 (I) or 13.0 (II) in the two administration systems. Maximum concentration of 5-FU was found when cepharanthine and FT-207 were given simultaneously at the molar ratio of 0.5:1, and this combination ratio seemed to be optimal. These results suggest that 5-FU is delivered and selectively accumulated into the tumor tissue by the presence of cepharanthine, but not in serum, and this mechanism should be correlated with antitumor activity shown by combination of FT-207 and cepharanthine. This mechanism is one of the reasons why the 5-FU concentration in the tumor tissue increases much more than that in normal tissues after administration of FT-207 by cepharanthine. Accordingly clinical application of cepharanthine is considered to be a useful adjuvant chemotherapy for cancer.