Advantage of combined treatment of CPT-11 and 5-fluorouracil

The combined chemotherapy of SN-38, active metabolite of CPT-11, and 5-FU in vitro was examined using human cell lines and primarily cultured cells obtained at surgery. The percent survival of the Suit-2 cell line treated with a single modality of SN-38 at the concentration of 0.95-61 nM was 70% to 86%, while, when treated with SN-38 and 5-FU, the percent survival of these cells decreased at even 1 microM of 5-FU. The enhanced ratios (percent survival at 0 nM SN-38/percent survival at 61 nM SN-38) at 1 microM and 4 microM of 5-FU were 1.56 and 1.33, respectively. The enhanced ratio became lower when the concentration of 5-FU was increased. When topoisomerase I activity in Suit-2 cells incubated with 5-FU was examined, 5-FU at a high dose (> or = 4 microM) in the medium caused a strong inhibition of the relaxation of Suit-2 DNA by topoisomerase I, but 5-FU at low dose (< or = 2 microM) barely inhibited topoisomerase I activity. These results indicated that topoisomerase I synthesis in the Suit-2 cell line might be suppressed by a high dose of 5-FU in the medium but not by a clinically achievable level of 5-FU. The cancer cells obtained from clinical cancer tissues were treated with these drugs at a clinically achievable dose in the medium. Judging from the results of a sensitivity test, in 7 out of 10 cases, the percent survivals under the combined treatment were lower than those estimated under the single modality treatment. Therefore, by the addition of 5-FU, the antitumor effect of CPT-11 would seem to be further enhanced.