Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy. *(E-mail: menard@istitutotumori.mi.it)
Platinum-based therapy has demonstrated efficacy in the treatment of several types of epithelial tumors [13], although responses to almost all chemotherapeutic drugs have been heterogeneous. It is this heterogeneity in clinical response that motivates researchers in efforts to identify tumor biological markers useful in identifying patients who will actually benefit from a specific treatment. The differential expression of molecules likely to be involved in the sensitivity of the tumor cells to therapy might explain the varying responses of tumor patients to diverse therapeutic procedures, and might provide important tools for investigating this aspect in the clinic. Cytotoxic chemotherapeutic agents are generally thought to be effective on proliferating tumors [4, 5]. The report by Sultana et al. on cervical cancer patients in this issue of Annals of Oncology [6] indicates that cervical tumors showing a high proliferation rate (determined on Ki-67 antigen labeling index) have a better response to platinum-based therapy. Note that a marked decrease in proliferation was observed in surgical specimens obtained after the treatment of responder patients, while proliferation remained unchanged in non-responders. This finding reinforces the notion that highly proliferative cells are more sensitive to drugs.
The extent of apoptosis in tumor cells is also thought to be relevant for induction of drug cytotoxicity. Sultana et al. have attempted to dissect the apoptotic pathway activated by the platinum chemotherapy regimen. Their paper reports new information concerning the role of the pro-apoptotic Bax molecule in the response to platinum, i.e. before therapy 44% of cervical cancer samples from patients classified as responders were found to express Bax versus only 17% in the non-responders group. Furthermore, Bax expression in responders but not in non-responders increased after chemotherapy. All these data are consistent with in vitro studies indicating that cells transfected with a Bax construct show increased sensitivity to cisplatin and etoposide [7]. In contrast, levels of the antiapoptotic Bcl-2 molecule decreased dramatically after treatment in the responder patients, contributing to tumor cell apoptosis. Cancer cells often become resistant to chemotherapy or irradiation through mutations in the p53 tumor suppressor gene, which prevents induction of apoptosis in response to cellular damage [810]. Besides mutation, p53 inactivation may result from viral infection, such as with human papilloma virus (HPV), a high-risk factor associated with the development of cervical cancer [1113]. In the analysis by Sultana et al., induction of apoptosis after platinum treatment was assessed in HPV-positive patients; cervical cancer cells of such patients are likely to be resistant to chemotherapy-induced apoptosis since p53 is inactivated by this virus [13], although pretreatment with an antiviral agent to restore p53 function restores the sensitivity to therapy [14]. In the report by Sultana et al., HPV-positive cervical tumors were shown to undergo apoptosis upon expression of Bax, a molecule directly regulated by functional p53 [15, 16]. Most likely, tumor cells rescue p53 inactivation by recruiting alternative pathways; alternatively, HPV reduces, but does not completely silence, p53 activity.
While all of these studies contribute to a better understanding of the mechanism of drug action, no single parameter identified as associated with therapy response is actually useful in the clinical planning of therapeutic management for patients. Even markers strongly associated with therapy response in the study by Sultana et al. never definitively discriminate responders from non-responders, so that some patients misclassified based on the predictive markers might not be appropriately treated if planning depends on marker expression. Preliminary analyses of gene expression profiles that consider the entire pattern of expression by a given tumor with respect to drug responsiveness have revealed no clear indications thus far. One possibility is that drug response is related not only to the tumor genetic profile, but also to the patients phenotype, as revealed by the spectrum of side- effects due to differences, for example, in drug metabolism, polymorphism of detoxification enzymes, or other factors. New information about the human genome is sure to allow consideration and characterization of the complete patient phenotype (i.e. differences in polymorphic genes) to provide a more defined picture.
S. Ménard*, M. Campiglio & A. Balsari
Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy (*E-mail: menard@istitutotumori.mi.it)
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