Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer.
Stable transfection of human ovarian carcinoma cells with survivin cDNA caused a four- to sixfold increase in cell resistance to taxotere and taxol (two-sided Student's t test, p < 0.05), with a concomitant reduction in the apoptotic response to taxol, but did not affect cell sensitivity to cisplatin or oxaliplatin. Such findings were indirectly supported by similar observations obtained with clinical tumours. In fact, high levels of survivin protein expression (>30% positive cells), detected by immunohistochemistry in 90/124 (73%) advanced ovarian carcinomas, were significantly associated with clinical resistance to a taxol/platinum-based regimen but unrelated to tumour shrinkage following cisplatin-including combinations (non-taxol based). In the 95 patients receiving a taxol/platinum-based regimen, survivin overexpression correlated with a lower clinical or pathologic complete remission rate than absent/low protein expression (43 vs 75%, p = 0.0058 by logistic regression adjusted for tumour stage, histological grade and p53 expression). Conversely, in the 29 cases treated with cisplatin-containing regimens (not taxol based), survivin expression was unrelated to tumour response. Cellular studies and clinical data suggest a direct link between survivin expression and tumour cell susceptibility to taxol.
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009154:Mutation; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000187:drug effects; D000077022:Survivin; D043823:Taxoids; D014162:Transfection; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000077022:Survivin; D043823:Taxoids; D000077150:Oxaliplatin; D000077143:Docetaxel; D010770:Phosphotransferases; D017239:Paclitaxel; D002945:Cisplatin