Bulletin du cancer
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The development of molecular targeted therapies requires some specific methodological approaches. Dose-limiting toxicities are rare in phase I studies the maximal tolerated dose is rarely established. ⋯ All of them are indicated in specific situations. The discontinuation treatment studies and the validation of biomarkers (as surrogate endpoints or as classifiers) are the two main particularities of phase III studies designed for the assessment of molecular targeted therapies.
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The epothilones are a new class of non-taxane tubulin polymerization agents obtained by natural fermentation of the myxobacteria Sorangium cellulosum. The cytotoxic activities of the epothilones, like those of the taxanes, have been linked to stabilization of microtubules, but they also have important differences. ⋯ Ixabepilone was evaluated in vivo in a panel of human and rodent tumour models, the majority of which were chosen because of their known, well-characterized resistance to paclitaxel, and seems able to overcome the over-expression of multidrug resistance and to be unaffected by mutations in the beta tubulin gene. The interest of ixabepilone was clinically confirmed in clinical studies of phase II which demonstrated a strong activity at the patients with metastatic breast cancer resistant to taxanes and in patients suffering of other types of chemoresistant tumors.
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Imatinib mesylate (Gleevec, Glivec, Novartis, Basel, Switzerland) is a small molecule inhibitor of the tyrosine kinase c-abl, c-kit and the platelet derived growth factor receptor (PDGFR). Imatinib was developed for the treatment of chronic myeloid leukaemia (CML) but was approved both in Europe and the US fro the treatment of CML and gastrointestinal stromal tumors (GIST). Given its activity against both c-kit and PDGFR kinases and its remarkable safety profile, imatinib has been 'tried' in several solid tumors; results however have often been deceiving. We review the current data regarding the activity of imatinib in solid tumors, including GIST.
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Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) is now an entire part of treatment of peritoneal dissemination of colorectal malignancy, and it's possible to hope prolonged survival. This treatment is more and more codified. ⋯ Last big published series results show a decrease of morbidity and mortality and interest of using new drugs like oxaliplatine. Indications have to be more homogeneous and based on evidences.
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Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. ⋯ Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.