Relationship between Paclitaxel Activity and Pathobiology of Human Solid Tumors1

We previously reported the pharmacodynamics of antiproliferative and apoptotic effects of paclitaxel in histocultures of bladder, breast, head and neck, ovarian, and prostate tumors obtained from patients. This study examined the relationship between paclitaxel pharmacodynamics and tumor pathobiological parameters [i.e., stage, grade, proliferation status, expression of P-glycoprotein (Pgp), PS3, and Bcl-2]. Pgp, p53, and Bcl-2 proteins were detected by immunohistochemical methods. The drug sensitivity rank order of the five tumor types is as follows: prostate head and neck = bladder > breast > ovarian for the antiproliferative effect and breast = 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, grade, labeling index (LI), and expression of Pgp, p53, and Bcl-2 (P < 0.05 in all cases). The apoptotic effect was positively correlated with Pgp expression, LI, and tumor grade (P < 0.01) but was not related to tumor stage and expression of p53 and Bcl-2 (P > 0.2). Results of multivariate analysis indicated that the maximum antiproliferative effect was best predicted by the combination of tumor stage and expression of Pgp and p53 (inverse correlation) and that the maximum apoptotic effect was best predicted by the combination of tumor LI and Pgp expression (positive correlation). In summary, these results indicate that the two major effects of paclitaxel in human solid tumors, i.e., antiproliferation and apoptosis, correlate with different tumor properties. The second finding Received 3/6/98; revised 9/3/98; accepted 9/1 1/98. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with I 8 U.S.C. Section 1 734 solely to indicate this fact. 1 This study was supported in part by National Cancer Institute (NIH, Department of Health and Human Services) Grants R37CA49816 and R01CA63363 and by a gift from Bristol Myers Squibb Co. The Ohio State University Comprehensive Cancer Center Tissue Procurement Service was supported in part by National Cancer Institute Grant P3OCA 16058. 2 To whom requests for reprints should be addressed, at College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210. Phone: (614) 292-4244; Fax: (614) 688-3223; E-mail: Au. 1 @osu.edu. that drug-induced apoptosis was equal or higher in tumors that expressed Pgp, p53, and Bcl-2 compared to tumors that did not express these proteins supports the use of paclitaxel in treating Pgp-, p53and Bcl-2-positive tumors.