Schedule-dependent interaction between paclitaxel and 5-fluorouracil in human carcinoma cell lines in vitro

Abstract

Summary We assessed the cytotoxic interaction between paclitaxel and 5-fluorouracil administered at various schedules against four human carcinoma cell lines, A549, MCF7, PAI and WiDr. The cells were exposed simultaneously to paclitaxel and to 5-fluorouracil for 24 h or sequentially to one drug for 24 h followed by the other for 24 h, after which they were incubated in drug-free medium for 4 and 3 days respectively. In another experiment, the cells were exposed simultaneously to both agents for 5 days. Cell growth inhibition was determined by MTT reduction assay. The effects of drug combinations at IC80 were analysed by the isobologram. The cytotoxic interaction of paclitaxel and 5-fluorouracil was definitely schedule dependent. Simultaneous exposure to paclitaxel and 5-fluorouracil for 24 h showed mainly subadditive effects in A549, MCF7 and WiDr cell lines, whereas it showed additive effects in PAI cells. Sequential exposure to paclitaxel followed by 5-fluorouracil showed additive effects in all cell lines. Sequential exposure to 5-fluorouracil followed by paclitaxel showed subadditive effects in A549, MCF7 and PAl cells. Whereas it showed additive effects in WiDr cells. These findings suggest that maximum cytotoxic effects can be obtained when paclitaxel precedes 5-fluorouracil. Interestingly, the continuous (5-day) exposure to paclitaxel and 5-fluorouracil had additive effects in A549, PAl and WiDr cells, indicating that the prolonged simultaneous administration of these agents may circumvent the antagonistic interaction produced by short-term simultaneous administration. These findings may be useful in clinical trials of combination chemotherapy with paclitaxel and 5-fluorouracil.

A phase II study of paclitaxel, weekly, 24-hour continuous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer

“…In vitro and in vivo data appear to support the use of paclitaxel in gastric cancer (Chang et al, 1996;Ajani et al, 1998;Cascinu et al, 1998). An additive cytotoxic effect has been reported in vitro for the sequence of paclitaxel followed by 5-FU whereas the exposure to 5-FU followed by paclitaxel showed subadditive effects (Kano et al, 1996). Based on these rationale we had previously performed a phase II trial examining the efficacy and toxicity of the combination of paclitaxel, 5-FU and folinic acid in 22 patients with chemonaive gastric cancer (Bokemeyer et al, 1997a).…”

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

“…One study comparing a weekly infusion of paclitaxel with an infusion once every 3 weeks documented similar efficacy with decreased adverse reactions (in particular, myelosuppression and peripheral neuropathy) with the weekly regimen in women with ovarian cancer (Andersson et al, 2000). A combination of paclitaxel and 5-FU has been demonstrated to have additive cytotoxicity against tumour cell lines in vitro, especially strong with sequential exposure (Kano et al, 1996). Moreover, Kondo et al (2005) reported a MST of 335 days in a phase I study of weekly paclitaxel plus 5-FU in patients with advanced gastric cancer.…”

Berberine modulates expression of mdr1 gene product and the responses of digestive track cancer cells to Paclitaxel

“…In addition, berberine blocked high (0.1 µM) dose Paclitaxel-induced cell cycle arrest at G2/M phase in OC2, SC-M1, COLO 205 and abrogated low (0.01 µM) dose Paclitaxel-elicited sub-G0/G1 apoptosis in OC2, SC-M1 cells (Figure 4). Many studies documented that combination of some chemotherapeutic drugs with Paclitaxel decreased the response of Paclitaxel (Akutsu et al, 1995;Kano et al, 1996aKano et al, , 1996b. Most of these drugs arrested tumour cells at S phase and the reduction of cells at G0/G1 or G2/M phases most likely contributed to reduced responses to Paclitaxel.…”