NEW DRUG THERAPIES FOR CANCER
Imantinib mesylate (Gleevec) is a rationally designed inhibitor of the tumor-specific bcr-abl kinase. The Philadelphia chromosome, present in nearly all patients with chronic myelogenous leukemia (CML), is pro-duced by a chromosomal rearrangement linking the bcr and the abl genes. The bcr-able kinase is therefore a unique drug target in leukemic cells, and imantinib se-lectively and potently inhibits this kinase. Remissions in CML patients are achieved with high frequency and very low toxicity, and this compound may become a front-line agent for treating this cancer. Unfortunately, drug resistance has already been observed in the clinic as a result of mutations in the bcr-abl kinase, and this magic bullet does not appear to be curative for CML patients. Extension of the use of imantinib to other tu-mor types with overexpression of c-kit kinase or platelet-derived growth factor kinase is undergoing de-velopment because of its observed activity against these kinases.
The introduction of herceptin (Trastuzumab) into clin-ical practice for the treatment of breast cancer marks a major advance in the use of monoclonal antibody can-cer therapy. Herceptin is a humanized antibody di-rected against the HER-2 antigen that is overexpressed on the tumor cell surface in approximately 25% of breast cancer patients. HER-2/neu/erbB2 overexpres-sion marks an aggressive estrogen receptor–negative form of breast cancer. Therefore, a therapeutic agent selective for this target is particularly valuable. Herceptin is administered by intravenous infusion and in conjunction with paclitaxel can extend survival in patients with HER-2/neu/erbB2 overexpressing meta-static breast cancer. Herceptin use is associated with in-fusion- related hypotension, flushing and bronchocon-striction, and skin rash but no bone marrow toxicity. Herceptin appears to sensitize patients to cardiotoxic-ity, an important concern in patients also receiving doxorubicin.
Iressa (ZD1839) is an orally active tyrosine kinase in-hibitor selective for the epidermal growth factor (EGF) receptor tyrosine kinase. Iressa is undergoing clinical trials in the treatment of various solid tumors, including head and neck cancer, breast cancer and non-small cell lung cancer. Its antitumor activity is derived from the fact that the EGF receptor and EGF signaling are
frequently overactivated in sensitive tumors. The major side effects include diarrhea and skin rash. Bone mar-row toxicity has not been a dose-limiting problem.
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