Cancer research
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Imatinib mesylate, a selective inhibitor of the Abl tyrosine kinase, is effective as a single-agent therapy for chronic myelogenous leukemia. However, resistance has been reported, particularly in patients with advanced-stage disease. ⋯ We analyzed the inhibitory activity of PD180970 against Abl kinase domain mutations and cells expressing clinically relevant mutations. Our data indicate that PD180970 is active against several Bcr-Abl mutations that are resistant to imatinib and support the notion that developing additional Abl kinase inhibitors would be useful as a treatment strategy for chronic myelogenous leukemia.
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More than half of all chronic cancer pain arises from metastases to bone, and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Several tumor types including sarcomas and breast, prostate, and lung carcinomas grow in or preferentially metastasize to the skeleton where they proliferate, and induce significant bone remodeling, bone destruction, and cancer pain. Many of these tumors express the isoenzyme cycloxygenase-2 (COX-2), which is involved in the synthesis of prostaglandins. ⋯ A selective COX-2 inhibitor was administered either acutely [NS398; 100 mg/kg, i.p.] on day 14 or chronically in chow [MF. tricyclic; 0.015%, p.o.] from day 6 to day 14 after tumor implantation. Acute administration of a selective COX-2 inhibitor attenuated both ongoing and movement-evoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors, and reduced tumor burden, osteoclastogenesis, and bone destruction by >50%. The present results suggest that chronic administration of a COX-2 inhibitor blocks prostaglandin synthesis at multiple sites, and may have significant clinical utility in the management of bone cancer and bone cancer pain.
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By virtue of its tissue-specific expression, carcinoembryonic antigen (CEA) is an important self, tumor-associated antigen, which is expressed by different human adenocarcinomas and also serves as a target for active-specific immunotherapy. Similar to humans, CEA expression in mice transgenic for the human CEA gene (CEA. Tg) occurs predominantly along the gastrointestinal tract. ⋯ No evidence of autoimmunity directed against normal tissues expressing CEA was observed in mice in which the CEA-based vaccine significantly reduced intestinal tumor load. The CEA. Tg/MIN mice present a clinically relevant model in which different CEA-based vaccine strategies can be tested on the spontaneous onset of intestinal tumorigenesis.
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Both nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX) 2-selective inhibitors such as celecoxib are being reported as having potent anticancer activity in laboratory models. Several reports have suggested that the mechanism of action of these agents in reducing tumor volume/burden is unrelated to their inhibition of prostaglandin synthesis. Many in vitro reports use supraphysiological concentrations of these drugs to demonstrate COX-independent activities on apoptosis or proliferation. ⋯ Celecoxib-treated tumors showed reduced proliferation and increased apoptosis of both tumor and stromal cells compared with vehicle controls. Specific inhibition of PGE2 activity by a neutralizing antibody mimicked the reduced tumor growth observed after celecoxib treatment, suggesting growth is PGE2 mediated. These data indicate that a major antitumor mechanism of action of celecoxib is inhibition of COX-2-derived prostaglandins, particularly PGE2, and suggest celecoxib as a novel therapeutic agent for human head and neck cancer.
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The regulation of biological functions including cell growth, viability, migration, and adhesion of small cell lung cancer (SCLC) cells depends largely on the autocrine or paracrine stimulation of growth factor receptors and chemokine receptors. Stem cell factor (SCF) and its receptor c-Kit have been identified as important regulators of SCLC viability and are coexpressed in approximately 40-70% of SCLC specimens. In vitro, the inhibition of c-Kit tyrosine kinase activity by the small molecule tyrosine kinase inhibitor STI571 (Gleevec) abrogates cell growth. ⋯ In contrast, the phosphatidylinositol 3-kinase inhibitor, LY294002, prevented these cells from adhering and completely blocked SCF- and/or SDF-1alpha-induced Akt or p70 S6 kinase phosphorylation. These results demonstrate that the CXCR4 receptor is functionally expressed in SCLC cells and may, therefore, be involved in the pathogenesis of SCLC in vivo. Inhibition of both the CXCR4 and the c-Kit downstream events could be a promising therapeutic approach in SCLC.