Relationship between paclitaxel activity and pathobiology of human solid tumors

We previously reported the pharmacodynamics of antiproliferative and apopto tic effects of paclitaxel in histocultures of bladder, breast, head and nec k, ovarian, and prostate tumors obtained from patients. This study examined the relationship between paclitaxel pharmacodynamics and tumor pathobiolog ical parameters [i.e., stage, grade, proliferation status, expression of P- glycoprotein (Pgp), p53, and Bcl-2], Pgp, p53, and Bcl-2 proteins were dete cted by immunohistochemical methods, The drug sensitivity rank order of the five tumor types is as follows: prostate greater than or equal to head and neck = bladder > breast > ovarian for the antiproliferative effect and bre ast = ovarian = head and neck > prostate = bladder for the apoptotic effect . When the pathobiological parameters were considered as single parameters, the antiproliferative effect was inversely correlated with tumor stage, gr ade, labeling index (LI), and expression of Pgp, p53, and Bcl-2 (P < 0.05 i n all cases). The apoptotic effect was positively correlated with Pgp expre ssion, LI, and tumor grade (P < 0.01) but was not related to tumor stage an d expression of p53 and Bcl-2 (P > 0.2), Results of multivariate analysis i ndicated that the maximum antiproliferative effect was best predicted by th e combination of tumor stage and expression of Pgp and p53 (inverse correla tion) and that the maximum apoptotic effect was best predicted by the combi nation of tumor LI and Pgp expression (positive correlation). In summary, t hese results indicate that the two major effects of paclitaxel in human sol id tumors, i.e., antiproliferation and apoptosis, correlate with different tumor properties. The second finding that drug-induced apoptosis was equal or higher in tumors that expressed Pgp, p53, and Bcl-2 compared to tumors t hat did not express these proteins supports the use of paclitaxel in treati ng Pgp-, p53- and Bcl-2-positive tumors.