Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We sought to determine the expression and prognostic significance of HER2 and c-KIT proteins in nasopharyngeal carcinoma (NPC). In this retrospective study, immunohistochemical stains for HER2 and c-KIT were performed on formalin-fixed paraffin-embedded sections from 49 patients with NPC who were treated at our hospital from 1971 to 2000. The clinical and immunohistochemical data were correlated, including gender, ethnic origin, age, histological type, EBV status (EBER in situ hybridization), stage, and overall survival. HER2 expression was not found in the tested samples. C-KIT overexpression was found in 33% (16/49) of the patients. Nine of the 16 samples (56%) were strongly positive for c-KIT protein (staining of >50% of the tumor cells). C-KIT expression was associated with younger age. C-KIT was not found in patients with squamous carcinoma or in those with negative EBV status, although these two groups consisted of only five patients each. Although c-KIT-positive cases tended to be associated with slightly better survival, this was not statistically significant. C-KIT protein was expressed in one third of the NPC patients in this study, only in EBV-positive, undifferentiated, or nonkeratinizing carcinoma patients. Further study is needed to check whether c-KIT expression is correlated with c-KIT DNA mutations and to test the possibility of treatment with imatinib mesylate (Gleevec). HER2 protein was negative in the same tested specimens.
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PMID:Expression of HER2 and C-KIT in nasopharyngeal carcinoma: implications for a new therapeutic approach. 1455 87

Treatment of advanced renal cancer has made little progress in the past 30 yr. Most clinical efforts have incorporated cytokine-based therapy. The presumption has been that the cytokines may trigger a host immune response against the renal cancer. Only IFN-alpha and high-dose IL-2 seemed to have positive effects on patient outcomes. IFN has prolonged the lives of patients by a few months, and high-dose IL-2 is capable of inducing very prolonged remissions (>5 yr) for a small number of patients. Nephrectomy in the presence of metastatic disease has been established as an effective procedure for select patients, providing palliation and prolonging survival. Finally, enthusiasm has focused on the use of nonmyeloablative allogeneic stem cell transplantation and donor leukocyte infusion for the induction of graft versus tumor effects. Early results are both provocative and promising. A number of agents that target the critical gene products downstream from pVHL and hypoxia-inducible factor-1, such as vascular endothelial growth factor, PDGF, EGF receptor, and TGF-alpha, have recently become available. The new agents are capable of inhibiting specific cellular targets, and the biologic characteristics of clear cell carcinoma of the kidney support their application. If the correct targets are carefully selected for inhibition in tumors in which the targets are present (clear cell histologic features and loss of VHL expression), then results should resemble those others have observed with targeted therapy, such as the use of STI-571 (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors or anti-HER2/neu (Herceptin; Genentech, South San Francisco, CA) for treatment of breast cancer.
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PMID:Targeting of the VHL-hypoxia-inducible factor-hypoxia-induced gene pathway for renal cell carcinoma therapy. 1456 78

Rad51 is an essential component of the homologous DNA repair pathway and has been implicated as a determinant of cellular radiosensitivity. Gleevec is a relatively specific inhibitor of c-Abl, a tyrosine kinase that can play a role in the regulation Rad51. The aim of this study was to determine the effects of Gleevec on Rad51 levels and the radiosensitivity of two human glioma cell lines and a nonimmortalized normal human fibroblast cell line. Exposure of both glioma cell lines to radiation resulted in an increase in Rad51 expression; Gleevec treatment alone reduced Rad51 expression. When glioma cells were pretreated with Gleevec, radiation-induced Rad51 expression and nuclear foci formation were reduced. Accordingly, pretreatment of the glioma cells with Gleevec resulted in an enhancement in their radiosensitivity. These data indicate that Gleevec enhances radiation-induced tumor cell killing and suggest that the mechanism involves the reduction in Rad51 levels. In contrast to the glioma cell lines, radiation or Gleevec treatments had no effect on Rad51 expression or foci formation in the normal fibroblast cells. Consistent with these observations, Gleevec did not modify the radiosensitivity of the normal cell line. These results suggest that Rad51 expression is subject to different regulatory processes in the glioma and normal cell lines and further suggest that Rad51 may be an appropriate target for selectively enhancing the radiosensitivity of brain tumor cells.
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PMID:Gleevec-mediated inhibition of Rad51 expression and enhancement of tumor cell radiosensitivity. 1461 36

Transforming growth factor-beta (TGF-beta) has growth-stimulating effects on mesenchymal cells and several tumor cell lines. The signaling pathway for this effect is, however, not well understood. We examined how TGF-beta stimulates proliferation of MG63 human osteosarcoma cells. Two distinct type I receptors for TGF-beta, ALK-1 and ALK-5, were expressed and functional in MG63 cells. Of these two receptors, ALK-5 appears to be responsible for the growth stimulation because expression of constitutively active ALK-5, but not ALK-1, stimulated proliferation of MG63 cells. SB-431542 (0.3 microM), a novel inhibitor of ALK4/5/7 kinase, suppressed TGF-beta-induced growth stimulation. DNA microarray analysis as well as quantitative real-time PCR analysis of RNAs from TGF-beta-treated cells demonstrated that several growth factors, including platelet-derived growth factor AA, were induced in response to TGF-beta in MG63 cells. Gleevec (1 microM) as well as AG1296 (5 microM) inhibited TGF-beta-induced growth stimulation of MG63 cells, suggesting that platelet-derived growth factor AA was mainly responsible for the growth-stimulatory effect of TGF-beta. We also examined the mechanisms of perturbation of growth-suppressing signaling in MG63 cells. We found that expression of c-Myc, which is down-regulated by TGF-beta in many other cells, was up-regulated in MG63 cells, suggesting that up-regulation of c-Myc expression may be the mechanism canceling growth-suppressing signaling of TGF-beta in MG63 cells.
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PMID:SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells. 1463 5

Gastrointestinal stromal tumors (GISTs) are c-kit-positive tumors that may arise anywhere in the tubular gastrointestinal tract. Around 5% of the cases arise elsewhere in the abdominal cavity. Tumors originating in the omentum and mesentery have been reported.A 31-year-old woman presented with pelvic pain, a palpable pelvic mass, and elevated CA-125. Imaging showed innumerable pelvic and abdominal masses. Histopathology showed a GIST that was positive for c-kit and vimentin and negative for desmin and smooth muscle actin. The patient was started on imatinib mesylate. Six months after diagnosis the tumor has remained stable.GI stromal tumors (GIST) may initially present as pelvic mass with elevated CA-125. Imatinib mesylate is the current mainstay therapy for GISTs after surgery.
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PMID:Gastrointestinal stromal tumor presenting as a pelvic mass. 1467 90

Expression of KIT tyrosine kinase is critical for normal germ cell development and is observed in the majority of seminomas. Activating mutations in KIT are common in gastrointestinal stromal tumors and mastocytosis. In this study we examined the frequency and spectrum of KIT mutations in 54 testicular seminomas, 1 ovarian dysgerminoma and 37 non-seminomatous germ cell tumors (NSGCT). Fourteen seminomas (25.9%) contained exon 17 point mutations including D816V (6 cases), D816H (3 cases), Y823D (2 cases), and single examples of Y823C, N822K, and T801I. No KIT mutations were found in the ovarian dysgerminoma or the NSGCTs. In transient transfection assays, mutant isoforms D816V, D816H, Y823D, and N822K were constitutively phosphorylated in the absence of the natural ligand for KIT, stem cell factor (SCF). In contrast, activation of T801I and wild-type KIT required SCF. Mutants N822K and Y823D were inhibited by imatinib mesylate (Gleevec, previously STI571) whereas D816V and D816H were both resistant to imatinib mesylate. Biochemical evidence of KIT activation, as assessed by KIT phosphorylation and KIT association with phosphatidylinositol (PI) 3-kinase in tumor cell lysates, was largely confined to seminomas with a genomic KIT mutation. These findings suggest that activating KIT mutations may contribute to tumorigenesis in a subset of seminomas, but are not involved in NSGCT.
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PMID:KIT mutations are common in testicular seminomas. 1469 43

Imatinib mesylate (IM) binds to the BCR-ABL protein, inhibiting its kinase activity and effectively controlling diseases driven by this kinase. IM resistance has been associated with kinase mutations or increased BCR-ABL expression. However, disease progression may be mediated by other mechanisms that render tumor cells independent of BCR-ABL. To demonstrate this potential, IM-resistant cells were found in chronic myelogenous leukemia patients with continuous BCR-ABL gene expression but undetectable BCR-ABL protein expression. These cells were unresponsive to IM and acquired BCR-ABL-independent signaling characteristics. IM resistance in some patients may be mediated through loss of kinase target dependence.
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PMID:Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. 1474 84

Targeted protein-tyrosine kinase inhibitors (PTKIs) comprise a new, rapidly evolving class of low molecular weight anticancer drugs. Two members of this class, imatinib (Gleevec) and gefitinib (Iressa), are currently approved for market use in the United States. This review discusses the scientific history behind these two PTKI drugs, including the role of the targeted kinase in cancer etiology, the biochemistry of selective inhibition, the evaluation of clinical efficacy, and the mechanisms whereby drug resistance has emerged. Other PTKIs undergoing clinical evaluation are also described, including epidermal growth factor receptor kinase inhibitors (erlotinib, PKI166, and CI-1033) and PTKIs designed to disrupt tumor vascularization (SU5416, SU6668, SU11248, PTK787, and ZD6474). How might one apply current knowledge to the efficient development of new agents that would target as-yet-unexploited oncogenic PTKs such as chimeric anaplastic leukemia kinases or Janus kinases? Ideally, the targets should contain structurally distinct drug interaction epitopes, although it is not necessary that these epitopes be unique to a single target, because effective drugs may inhibit multiple kinases involved in an oncogenic process. Oral availability is a highly desirable feature because daily oral administration can maintain a sustained efficacious plasma concentration, whereas intermittent parenteral administration may not. Perhaps most importantly, one must verify the presence of an appropriate molecular target on a case-by-case basis before selecting a patient for PTKI therapy. Thus, the development of molecularly targeted diagnostic tools will be crucial to the ultimate success of molecularly targeted PTKI therapy.
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PMID:Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy. 1497 53

Platelet-derived growth factor (PDGF) and its cognate receptor are widely expressed on melanomas. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. Imatinib mesylate was previously reported to have specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Melanoma cells express abundant levels of the PDGF receptor (PDGFR). Nevertheless, c-Kit expression is progressively lost as the cells take on a more highly metastatic phenotype. To investigate the potential of imatinib mesylate as a therapy for melanoma, we studied its effect on the growth of melanoma cells using an in vivo mouse model. Melanoma cells with high malignant potential (PDGFR-positive, c-Kit-negative) or low malignant potential (PDGFR-positive, c-Kit-positive) were injected subcutaneously into athymic nude mice. Mice were treated with imatinib mesylate (100 mg/kg three times weekly) or with phosphate-buffered saline for 4 to 6 wk. PDGFR-alpha and -beta were expressed on all melanoma cell lines tested. The level of PDGFR expression correlated with the metastatic potential of the melanoma cells: higher levels of PDGFR-alpha were expressed on cells with higher metastatic potential, and higher levels of PDGFR-beta were expressed on cells with lower metastatic potential. There was no significant difference in tumor size between treated and control mice. Immunohistochemical studies demonstrated inhibition of PDGFR phosphorylation on the tumors from mice treated with imatinib mesylate but not from control mice, suggesting that the receptors were functional and that the concentration of drug used was appropriate. Our data demonstrated that imatinib mesylate blocked both PDGFR-alpha and PDGFR-beta in vivo. It did not, however, affect the growth of melanoma cells expressing PDGFR, regardless of whether the cells expressed c-Kit.
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PMID:Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not affect tumorigenicity in vivo. 1500 22

Three cases of gastrointestinal stromal tumors (GIST) are reported as typical examples of the broad clinical spectrum in which these rare tumors can be detected. The first case describes an 82-year-old patient with a hemorrhagic shock due to upper gastrointestinal bleeding from a GIST of the stomach. GIST most frequently present with either gastrointestinal bleeding, abdominal pain or a detectable mass on physical examination or by ultrasound imaging. Clinically asymptomatic tumor growth also occurs as demonstrated by the second case of a 44-year-old -woman with an incidental finding of GIST during surgery of the esophagus. The cases are used to discuss the consequences for therapy and prognosis resulting from the heterogeneity of this tumor entity; the relevant immunohistochemical markers used to distinguish between various tumor subtypes of gastrointestinal mesenchymal tumors (GIMT) are listed. Since gastrointestinal stromal tumors (GIST) represent the most common subgroup of GIMT, we focus on the clinicopathological prognostic factors of GIST. The third case of a 40-year-old patient with a malignant GIST recurrence after surgery and exhibiting secondary resistance after one year of successful therapy with the receptor tyrosine kinase inhibitor imatinib (Gleevec), antagonizing pathogenetically relevant constitutive c-KIT activation, illustrates the potential and limitations of the only effective drug treatment for advanced GIST.
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PMID:[Gastrointestinal stromal tumors: a broad clinical spectrum from incidental -discovery to acute gastrointestinal bleeding]. 1502 11


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