Unlike normal cells that have tight regulatory mechanisms controlling EGFR pathways, tumor cells often have dysregulated EGFR signaling through receptor overexpression and/or mutation

Unlike normal cells that have tight regulatory mechanisms controlling EGFR pathways, tumor cells often have dysregulated EGFR signaling through receptor overexpression and/or mutation. (gefitinib and erlotinib) and two that block extracellular ligand binding (cetuximab, and most recently panitumumab). In this review, we focus on how these different inhibitors impact EGFR signaling and the mechanisms by which they potentiate the effects of chemotherapy and radiation therapy. Numerous clinical trials have been conducted with these brokers either as monotherapy, in combination with chemotherapy, or concurrently with radiation. Unfortunately, many of the clinical trials reported so far have shown at best limited gains; therefore, understanding the actions of these brokers is essential to improving their efficacy in the treatment of cancers. EGFR (%)experiments with xenografts of human tumors expressing EGFR in athymic mice demonstrated dose-dependent growth inhibition [26]. This antibody, known as C225, was humanized to produce cetuximab (ErbituxR; ImClone System, Princeton, NJ). After the antibody binds to the EGFR, the receptor is usually internalized, then degraded, leading to receptor downregulation at the cell surface. The receptor is usually prevented from autophosphorylation and activation; therefore, downstream signaling is usually inhibited. However, studies by Mandic and studies have exhibited growth inhibition of multiple cell lines by gefitinib [31]. Studies using xenografts of human tumors derived from, ovarian, colon, lung, vulval, breast, and hormone-refractory prostate cancers showed that gefitinib potentiated the Leupeptin hemisulfate cytotoxic effects of many chemotherapeutic brokers [32]. However, as will be discussed later, clinical trials have shown only modest efficacy of gefitinib as both a single agent and as part of a combination regimen in the treatment of patients with NSCLC. Hence, even though FDA experienced in the beginning given wider approval to gefitinib for the treatment of NSCLC, because of these unimpressive results, it is now available only for patients who have failed both platinum-based and docetaxel chemotherapy and experienced previously benefited from gefitinib. Erlotinib (OSI-774, Tarceva?, OSI Pharmaceuticals in collaboration with Genentech and Roche) potently and reversibly inhibits EGFR tyrosine kinase Leupeptin hemisulfate activity of both wild-type EGFR and the constitutively Leupeptin hemisulfate active mutant EGFRvIII at concentrations at nanomolar concentrations analyzed patients with glioblastomas who had been treated with EGFR kinase inhibitors [35]. Their study demonstrated that patients with co-expression of EGFRvIII and PTEN were more likely to show a radiologic response to an EGFR inhibitor. Furthermore, glioblastoma cells co-expressing these two molecules were sensitive to erlotinib. A possible explanation is usually that loss of PTEN might activate the Akt pathway independently of EGFR and render it insensitive to EGFR inhibition. These results suggest that identification of patient populations with certain mutations may lead to specifically directed therapies. EGFR is usually overexpressed in 80% of NSCL and mutated in a smaller percentage. Leupeptin hemisulfate Pao and radiosensitivity [39, 72]. Other groups have confirmed that C225 or gefitinib prospects to enhanced killing in response to radiation and using diverse cell types including HNSCC, colon, ovarian, NSCLC, and breast malignancy lines [73-76]. How EGFR inhibitors increase sensitivity to radiation is not completely comprehended. The C225 antibody causes an increase in the proportion of cells in G1, which is a more radiosensitive phase, and a concomitant decrease in the proportion in the S phase, which is usually more radioresistant [71]. Gefitinib [77] and erlotinib [72] also cause this cell cycle redistribution, which could contribute to radiosensitivity. Another potential mechanism of radiosensitization is usually via increased apoptosis. Huang found some support for this hypothesis in their study Rabbit polyclonal to CDKN2A showing that patients with SCCHN achieved better local control with an accelerated radiotherapy routine, but only if their tumors overexpressed EGFR [86]. If ongoing studies continue to provide Leupeptin hemisulfate further evidence that EGFR overactivity may be responsible for the phenomenon of accelerated repopulation, then inhibition of downstream kinase activity may potentially be an alternative to accelerated radiotherapy for overcoming repopulation. In addition to the mechanisms discussed above that are apparent in vitro (increased apoptosis, cell cycle redistribution, decreased DNA repair and inhibition of accelerated repopulation), there may be additional factors that are only important in vivo. As discussed previously, EGFR inhibition has effects on VEGF/angiogenesis and migration/invasion that could increase radiosensitivity. Radiation itself can upregulate the expression of VEGF, and there.