Seminars in oncology
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A large number of new drugs have been approved over the past 10 years for the treatment of both common and rare gastrointestinal malignancies. Many other agents, however, have failed at a great cost of financial and patient resources. ⋯ Pharmaceutical companies must show therapeutic efficacy and achieve regulatory approval as well as success in the marketplace to recoup their investment. It is worth examining successful examples of drug development such as imatinib, delayed but eventually successful agents such as oxaliplatin, as well as failures such as SU-5416, and applying those lessons to current and future drug development.
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In 2006, approximately 38,890 patients in the United States will be diagnosed with kidney tumors. Roughly 90% of those will be renal cell carcinomas (RCCs). Of those patients, 30% will have metastatic disease at the time of diagnosis. ⋯ An improved understanding of the molecular basis of RCC has allowed for a more targeted approach to therapy. Several newer agents, including thalidomide, vitespin (heat shock protein [hsp] 96 vaccine), WX-G250, sorafenib, and sunitinib, are either currently under investigation in the adjuvant setting or being considered for future adjuvant trials. Here, we discuss the past, present, and future of adjuvant therapy for RCC patients at high risk for relapse following definitive surgical therapy.
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The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family that is abnormally activated in many epithelial tumors. Several mechanisms lead to the receptor's aberrant activation that is observed in cancer, including receptor overexpression, mutation, ligand-dependent receptor dimerization, and ligand-independent activation. Two classes of anti-EGFR agents are currently approved for the treatment of patients with cancer: cetuximab, a monoclonal antibody directed at the extracellular domain of the receptor, and gefitinib and erlotinib, oral, low-molecular-weight (MW), adenosine triphosphate (ATP)-competitive inhibitors of the receptor's tyrosine kinase. ⋯ Clinical and survival benefits with anti-EGFR agents have been demonstrated in additional tumor types such as head and neck and pancreatic carcinomas. New agents with clinical activity are entering the clinic and new combinatorial approaches with anti-EGFR agents are being explored. Major efforts are, belatedly, attempting to identify molecular markers that can predict patients more likely to respond to anti-EGFR therapy.
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Seminars in oncology · Aug 2006
ReviewRole of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway.
Improvements in our understanding of the molecular basis of cancer have led to the clinical development of protein kinase inhibitors, which target pivotal molecules involved in intracellular signaling pathways implicated in tumorigenesis and progression. These novel targeted agents have demonstrated activity against a wide range of solid tumors, are generally better tolerated than standard chemotherapeutics, and may revolutionize the management of advanced refractory cancer. The ubiquitous Raf serine/threonine kinases are pivotal molecules within the Raf/mitogen extracellular kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway, which regulates cellular proliferation and survival. ⋯ In this review, the role of Raf in normal cells and in cancer is discussed, and an overview is given of Raf inhibitors currently in development, focusing on sorafenib tosylate (BAY 43-9006 or sorafenib). Sorafenib is the first oral multi-kinase inhibitor to be developed that targets Raf kinases (Raf-1, wild-type B-Raf, and b-raf V600E), in addition to receptor tyrosine kinases associated with angiogenesis (vascular endothelial growth factor receptor [VEGFR]-2/-3, platelet-derived growth factor receptor [PDGFR]-beta) or tumor progression (Flt-3, c-kit). Preclinical and clinical sorafenib data that led to its recent approval for the treatment of advanced RCC are summarized, along with current thinking on sorafenib's mechanism of effect on the tumor and tumor vasculature in melanoma and RCC.
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Seminars in oncology · Jun 2006
ReviewAnthracycline-induced cardiotoxicity in adult hematologic malignancies.
Anthracyclines are a highly efficacious treatment for adult hematologic malignancies, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphoma. The consequences of anthracycline-induced cardiotoxicity have obliged hematologists to set empirical dose limits, above which the cardiotoxic risk is deemed unacceptable. ⋯ Through discontinuing further use of anthracyclines, relapsed patients previously treated with these agents may consequently be treated with second-line therapy that is less effective and possibly less well tolerated. Anthracycline-induced cardiotoxicity is potentially fatal and can significantly impair patients' quality of life, while also substantially increasing health care costs.