Gan Y, Wientjes M G, Au J L
College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus 43210, USA.
Clin Cancer Res. 1998 Dec;4(12):2949-55.
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.
我们之前报道了紫杉醇对取自患者的膀胱、乳腺、头颈部、卵巢和前列腺肿瘤组织培养物的抗增殖和凋亡作用的药效学。本研究检测了紫杉醇药效学与肿瘤病理生物学参数[即分期、分级、增殖状态、P-糖蛋白（Pgp）、p53和Bcl-2的表达]之间的关系。通过免疫组织化学方法检测Pgp、p53和Bcl-2蛋白。五种肿瘤类型的药物敏感性排序如下：抗增殖作用方面，前列腺≥头颈部=膀胱＞乳腺＞卵巢；凋亡作用方面，乳腺=卵巢=头颈部＞前列腺=膀胱。当将病理生物学参数视为单一参数时，抗增殖作用与肿瘤分期、分级、标记指数（LI）以及Pgp、p53和Bcl-2的表达呈负相关（所有情况均P＜0.05）。凋亡作用与Pgp表达、LI和肿瘤分级呈正相关（P＜0.01），但与肿瘤分期以及p53和Bcl-2的表达无关（P＞0.2）。多变量分析结果表明，肿瘤分期与Pgp和p53表达的组合（负相关）最能预测最大抗增殖作用，肿瘤LI与Pgp表达的组合（正相关）最能预测最大凋亡作用。总之，这些结果表明紫杉醇在人类实体瘤中的两种主要作用，即抗增殖和凋亡，与不同的肿瘤特性相关。第二个发现是，与未表达这些蛋白的肿瘤相比，表达Pgp、p53和Bcl-2的肿瘤中药物诱导的凋亡相同或更高，这支持了紫杉醇用于治疗Pgp、p53和Bcl-2阳性肿瘤。
