Molecular mechanisms of apoptosis and chemosensitivity to platinum and paclitaxel in ovarian cancer: biological data and clinical implications.
Apoptosis is a genetically regulated biological process that plays a major role in chemotherapy-induced tumor cell killing. It may be triggered by two major intracellular signaling cascades, the mitochondrial pathway and the death receptor pathway, both leading to caspase activation and cleavage of specific cellular substrates. The p53 gene is involved in the regulation of apoptosis. Caspase activation following wild-type p53 induction is associated with the release of the apoptogenic factors cytochrome c and Smac/DIABLO from the mitochondria, that is in turn controlled by the pro-apoptotic and anti-apoptotic Bcl-2 family proteins. In ovarian cancer p53 status is a strong predictor of response to platinum-based chemotherapy. Patients whose tumors have p53 mutations experience a lower chance of achieving a complete response following platinum-based regimens when compared to patients without p53 mutations. Conversely, experimental and clinical data seem to show that paclitaxel enhances apoptosis through a p53-independent pathway, that probably involves the Bax gene. Whereas patients with wild-type p53 tumors have a good chance to respond to platinum, patients with mutant p53 tumors may have a clinical benefit from the addition of paclitaxel to platinum-based chemotherapy. Therefore determining p53 status can be useful in predicting therapeutic response to specific drugs. Moreover the understanding of cellular mechanisms regulating apoptosis might offer a strong rationale for the combination of chemotherapy with other biological treatments.
Gadducci
A
A
Department of Procreative Medicine, University of Pisa, Italy.
Cosio
S
S
Muraca
S
S
Genazzani
A R
AR
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016158:Genes, p53 / Q000187:drug effects*; D006801:Humans; D008967:Molecular Biology; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010984:Platinum / Q000008:administration & dosage / Q000009:adverse effects; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D016896:Treatment Outcome
D019253:Proto-Oncogene Proteins c-bcl-2; D010984:Platinum; D017239:Paclitaxel