In vitro schedule-dependent interaction between paclitaxel and SN-38 (the active metabolite of irinotecan) in human carcinoma cell lines

Abstract

Paclitaxel and irinotecan are important new anticancer agents. The combination of these two agents has been considered for use against a variety of advanced solid tumors. Since the schedule-dependent effects of this combination may be crucial to its use, we studied the interaction of paclitaxel and SN-38 (the active metabolite of irinotecan) in various schedules in four human cancer cell lines in culture. Cell growth inhibition after 5 days was determined using an MTT assay. The effects of drug combinations at the IC80 level were analyzed by the isobologram method. Simultaneous exposure to paclitaxel and SN-38 for 24 h produced antagonistic (subadditive and protective) effects in the human lung cancer cell line A549, the breast cancer cell line MCF7, and the colon cancer cell line WiDr, and produced additive effects in the ovarian cancer cell line PA1. Sequential exposure to paclitaxel for 24 h followed by SN-38 for 24 h, and the reverse sequence, produced additive effects in all four cell lines. These findings suggest that sequential administration, not simultaneous administration, may be the appropriate schedule for the therapeutic combination of paclitaxel and irinotecan. Continued preclinical and clinical studies should provide further insights and assist in determining the optimal schedule for this combination in clinical use.

Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines

“…Lower ratios of the observed data/the predicted minimum values mean that the combinations are more synergistic. 33 The observed data of PKC412 in combination with cytarabine, doxorubicin, idarubicin, etoposide, 4-hydroperoxy-cyclophosphamide and vincristine are 70-100% of the predicted minimum values in most of FLT-3 mutation-positive cell lines (Table 2). There is no obvious difference in the ratios of the observed data/the predicted minimum values between the combinations.…”

“…the data on the boundary (mode I or mode II lines) between the additive area and supra-additive area (or subadditive and protective areas)). 33 Combinations with significant values (Po0.05) were defined as having a synergistic effect (or an antagonistic effect), and those with insignificant values (P40.05) were defined as having an additive/synergistic effect (or an additive/antagonistic effect). All statistical analyses were performed using the StatView 4.01 software program (Abacus Concepts, Berkeley, CA, USA).…”

Synergistic antitumor activity of pro‐apoptotic agent PAC‐1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299

“…18 In other reports, several sequential combination procedures had been used. Examples include addition of the first drug for 24 h followed by the second drug for a further 48 h, 26 treatment of the first drug for 24 h followed by its removal and addition of the second drug for a further 48 h, 27 targeted therapy for 72 h followed by chemo treatment for 24 h or chemo treatment for 24 h followed by targeted therapy for 48 h, 28 and the first drug for 24 h followed by a second single or add-on drug for 24 h. 29,30 Different means of administration of the drugs may affect the anti-proliferative outcome. Here we used PAC-1 treatment for 48 h and Cis treatment for 24 h (72 h total).…”

In vitro cytotoxic effects of fludarabine (2-F-ara-A) in combination with commonly used antileukemic agents by isobologram analysis

“…The mean value of the observed data was compared with that of the predicted maximum values and that of the predicted minimum values for an additive effect. 42 If the mean value of the observed data was equal to or smaller than that of the predicted maximum values and equal to or larger than that of the predicted minimum values, the combination was regarded as an additive.…”