Multiple factors other than p53 influence colon cancer sensitivity to paclitaxel

Abstract

Purpose: To determine factors which influence the sensitivity of human colorectal carcinoma cell lines to paclitaxel. Methods: The paclitaxel sensitivity of ten human colorectal carcinoma cell lines, and a panel of RKO colon carcinoma cell lines, isogenic except for p53 status, were studied. The inhibitory concentrations causing a 50% decrease in growth (IC₅₀) were assayed after 3, 24, and 96 h after paclitaxel exposure. The doubling time (DT) and cell cycle parameters of cells were also measured. The expression of the multidrug resistance glycoprotein-1 (MDR-1), bcl-2 and bax was quantitatively assessed by immunoblotting. Results: Mean IC₅₀ values at 24 and 96 h drug exposure were about 1.5 logs lower than the IC₅₀ values at 3 h, regardless of the p53 status. No difference was found between the IC₅₀ values of wild-type and mutant p53 cells, or among the RKO panel of cells. Correlation analysis showed that: (1) resistance was associated with longer DTs, but this was generally abated by a 96-h exposure; (2) with a 3-h exposure, the combination of MDR, bcl-2 and bax parameters with DT (DT + MDR + bcl-2–bax) best correlated with IC₅₀ values (r=0.77); (3) with a 96-h exposure, in spite of the generally decreased IC₅₀ values, a combination of MDR-1, bcl-2 and bax parameters (MDR + bcl-2–bax) best correlated with the IC₅₀ values (r=0.71). Conclusions: These results suggest that the exposure duration, DT, and expression of MDR-1, bcl-2 and bax each contribute to paclitaxel sensitivity of human colorectal carcinoma cells. In assessing paclitaxel drug resistance, multiple factors should always be considered. There may be a therapeutic window for taxanes in colon cancer by optimizing pharmacokinetics and modulating MDR-1 and bcl-2 resistance factors.