Anti-cancer agents in medicinal chemistry
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Anticancer Agents Med Chem · Jun 2009
ReviewCan the status of the breast and ovarian cancer susceptibility gene 1 product (BRCA1) predict response to taxane-based cancer therapy?
Taxanes (paclitaxel and docetaxel) are currently used to treat ovarian, breast, lung, and head and neck cancers. Despite its clinical success taxane-based treatment could be significantly improved by identifying those patients whose tumors are more likely to present a clinical response. ⋯ We argue that levels of BRCA1 in tumors may provide a predictive marker for the response to treatment with taxanes. In addition, the study of the role of BRCA1 in the mechanism of action of taxanes might reveal alternative approaches to avoid resistance.
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Protein tyrosine kinases are enzymes which catalyze the phosphorylation of tyrosine residues and activate a downstream cascade of cellular signalling pathways which regulate cell proliferation, differentiation and apoptosis and a wide variety of cellular functions. Clinical developments over the past decade have identified several novel therapeutic agents which inhibit tyrosine kinase activity, either by direct receptor inhibition or indirect inhibition of tyrosine kinase controlled pathways. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), such as gefitinib and erlotinib have been studied extensively in patients with refractory non-small cell lung cancer (NSCLC). ⋯ Future clinical trials with targeted agents need to be carefully designed to incorporate correlative translational research elements that will allow selection of appropriate treatment strategies for individual patients. For assessment of phase III trial results in advanced disease, progression free survival may serve as a more appropriate end-point than response rate in an adequately designed trial in the appropriately selected population, although there should be no substitute for the overall survival and quality of life end points. The role of EFGR TKI in NSCLC will be discussed in detail and data from these studies will be used to illustrate the challenges in designing clinical trials and interpreting outcomes.
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Anticancer Agents Med Chem · Feb 2009
ReviewRole of tyrosine phosphatase inhibitors in cancer treatment with emphasis on SH2 domain-containing tyrosine phosphatases (SHPs).
Protein tyrosine phosphorylation is one of the key mechanisms involved in signal transduction pathways. This modification is regulated by concerted action of protein tyrosine phosphatases and protein tyrosine kinases. Deregulation of either of these key regulators lead to abnormal cellular signaling, which is largely associated with human pathologies including cancer. ⋯ In this review we describe the progressive efforts and challenges concerning the development of drugs targeting phosphatases as promising novel cancer therapies. We focus on two key regulatory SH2 domain-containing phosphatases, SHP-1 and SHP-2 and one of their substrates, signal regulatory protein alpha. Since SHPs have been linked to many different malignancies, protein tyrosine phosphatases could offer a great spectrum of new, targeted drugs.
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Anticancer Agents Med Chem · Jun 2008
ReviewInhibition of receptor tyrosine kinases in combination with chemotherapy for the treatment of breast cancer.
Although significant advances have been made in the treatment of breast cancer using chemotherapy, less than half of the patients treated for localized breast cancer benefit from adjuvant chemotherapy and most patients with metastatic cancer eventually develop disease that is chemotherapy resistant. Targeted agents, such as inhibitors of tyrosine kinases, offer the opportunity to reverse chemotherapy resistance and enhance response in patients with localized and advanced breast cancer. Such combined approaches have been established for the treatment of advanced breast cancer and are now demonstrating benefit in the adjuvant arena. This review summarizes the results of several trials involving the use of tyrosine kinase inhibition in combination with chemotherapy for the treatment of breast cancer and discusses future directions for breast cancer biotherapy.