Relationship between paclitaxel activity and pathobiology of human solid tumors.
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), p53, 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 > or = 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 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-, p53- and Bcl-2-positive tumors.
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College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus 43210, USA.
Wientjes
M G
MG
Au
J L
JL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D006801:Humans; D007150:Immunohistochemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel