FSee 708 Kinase Inhibitors for Cancer

cyclophosphamide, doxorubicin, and vincristine sulfate (CAV); cyclophosphamide, doxorubicin, and etoposide (CAE); etoposide and cisplatin (EP); and cyclophosphamide, etoposide, and vincristine (CEV). Depending on the extent of the disease, non-small cell lung carcinoma can be removed by surgical resection or treated with radiation therapy in combination with chemotherapy (e.g., gemcitabine hydrochloride together with cisplatin and vinorelbine). In addition to the preceding treatment modalities, photodynamic therapy is use for the care of patients with inoperable lung cancer or with distant metastasis.

Surgery is the treatment of choice for colorectal cancer and, depending on the stage of the disease, chemotherapy and radiation are used as adjuvant treatment.76 For example, a cocktail of different agents (fluorouracil, leucovorin, and irinotecan) is used for metastatic colorectal cancer. An important advance in the treatment of colorectal cancer has been reported recently with bevacizumab, which is a humanized vascular endothelial growth factor (VEGF) antagonist. This protein blocks VEGF-induced signaling in endothelial cells and partially inhibits VEGF-driven angiogenesis. Bevacizumib in combination with intravenous 4-fluorouracial was approved in February 2004 by the US Food and Drug Administration (FDA) for the treatment of patients with first-line or previously untreated metastatic colorectal cancer.77 The antibody showed improved survival benefit compared to chemotherapy alone. Additional clinical trials in breast cancer (phase II/III, E-2100; treatment of metastatic breast cancer) and non-small cell lung cancer (phase II/III, E-4599; advanced non-squamous NSCLC in combination with carboplatin and paclitaxel) are ongoing and results from these studies are expected in late 2005 or early 2006.

Treatment options for prostate cancer include surgery and radiotherapy (e.g., external beam or radioactive seed implants, called brachytherapy; see above).78 Hormonal treatment, chemotherapy, and radiation (or a combination of them) are used for metastatic diseases and as supplemental/additional therapies for early stage tumors. Hormonal treatment, which controls the progression of the disease by shrinking the size of the primary tumor and reduces symptoms (e.g., pain), involves the use of antiandrogens to block production of testosterone, a hormone that prostate cancer cells use to grow. Examples of drugs used for this specific treatment include flutamide, leuprolide acetate, bicalutamide, and goserelin acetate. Bone metastasis is often associated with prostate cancer. The secondary tumor causes the breakdown of bone tissue releasing substantial amounts of calcium into the bloodstream. In order to treat the excess calcium in the blood (hypercalcemia), bisphosphonates (e.g., zoledronic acid), are used to decrease bone loss, increase bone density, and reduce the risk of bone fractures.

A deeper understanding of the molecular events leading to tumor formation, invasion, angiogenesis, and metastasis has provided a new mechanistic basis for oncology drug discovery: targeted anticancer therapy.79 The rationale behind this approach is relatively simple: specific inhibitors of proteins involved in aberrant signaling mechanisms would interfere with cancer progression, altering the natural course of the disease while sparing normal tissues. Although numerous disappointments have been harvested, we start to see how a new generation of targeted cancer agents - both low-molecular-mass inhibitors (e.g., imatinib, gefitinib, erlotinib)80 and humanized monoclonal antibodies (e.g., trastuzumab, cetuximab, becacizumab)77'81'82 - can provide incremental improvements over existing drug treatments. In addition to the identification of more effective anticancer agents, other areas under development include gene therapy (administration of tumor suppressor genes), immunotherapy (to boost the body's immune system to better fight off or destroy cancer cells), and improved radiation therapy approaches (the use of neutrons to cause cell damage in an oxygen-independent manner).83 Of special interest is the recent results obtained with CP-675206, a fully human immunoglobulin G2 (IgG2) antibody that is directed against human cytotoxic T lymphocyte-associated antigen 4 (CTLA4). This antibody enlists the immune system to attack malignant tumor cells responsible for the disease. CP-675206 is currently in clinical trials for the treatment of prostate cancer (phase II in combination with neoadjuvant androgen ablation) and advanced melanoma (phase I/II). In this last indication, midtrial results have shown a 43% response rate, a major breakthrough in comparison with the current response rates for the two FDA-approved therapies for metastatic melanoma (from 6% to 15%).

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