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)

Gleevec, a selective tyrosine kinase inhibitor, retarded the growth of anaplastic thyroid cancer cell lines in vitro and in vivo through selective inhibition of ABL tyrosine kinase activity. In the present study, we investigated the ability of Gleevec to modulate the in vitro and in vivo radiation response of anaplastic thyroid cancer cells. Cell growth assays, colony formation assays and xenograft models were used to quantify the radiosensitizing effect of Gleevec in cells of the anaplastic thyroid cancer cell lines ARO and FRO. FACS, Western blotting and histochemical techniques were employed to study the mechanisms of radiation response after exposure to Gleevec. Gleevec (7.0 microM) increased the anti-proliferative effect of radiation on the growth ARO and FRO cells in vitro. Clonogenic analysis demonstrated that Gleevec reduced cell survival after irradiation. Gleevec combined with radiation produced an increase in tumor growth inhibition compared to treatment with either modality alone in mice bearing anaplastic thyroid cancer xenografts. The drug suppressed radiation-induced ABL activation and promoted CDKN1A (p21(cip1)) accumulation in irradiated anaplastic thyroid cancer cells. Gleevec had an additional effect on radiation-induced apoptosis in cells of both cell lines and potentiated the induction of terminal growth arrest accompanied by the expression of senescence-associated beta-galactosidase. The antitumor effect of Gleevec is potentiated in adjunctive therapy with radiation not only due to inhibition of proliferative cell growth with transient cell cycle arrest and apoptosis, but also due to the terminal growth arrest associated with senescence, suggesting that tumor cell senescence is a mechanism for tumor targeting therapy in combination with ionizing radiation.
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PMID:Inhibition of ABL tyrosine kinase potentiates radiation-induced terminal growth arrest in anaplastic thyroid cancer cells. 1639 60

Fanconi's anemia (FA) is an autosomal recessive inherited syndrome with a predisposition to malignancy. The association between FA and solid pediatric tumors is extremely rare. The authors report a rare case of VACTERL syndrome associated with FA and multiple solid pediatric tumors occurring in a very young girl. This child had numerous congenital anomalies (horseshoe kidney, cerebella hypoplasia, microcephaly, sacral agenesis) and esophageal atresia, which was repaired in neonatal period. Such association led quickly to the diagnosis of FA. At age of 11 months, she developed simultaneously a renal tumor in a horseshoe kidney and bilateral adrenal tumors. The left adrenal mass was removed, and partial nephrectomy was performed. Histological analysis concluded to adrenal neuroblastoma and nephroblastoma. We also evaluated the c-kit expression in these tumors to propose a therapeutic alternative to chemotherapy by oral agent STI-571 (Gleevec; Novartis, East Hanover, NJ). Strong cytoplasmic immunostaining of c-kit was found in both tumors. Unfortunately, she quickly developed a posterior cerebellar fossa tumor and died 1 month later. This clinical situation is very rare but suggests that young patients with FA and solid pediatric tumors may belong to a particular subgroup of FA. Further studies are necessary to test if STI-571 treatment could be efficient in such patients with pediatric tumors.
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PMID:Bilateral adrenal neuroblastoma and nephroblastoma occurring synchronously in a child with Fanconi's anemia and VACTERL syndrome. 1641 81

Imatinib (STI571, Gleevec/Glivec) and other small-molecule tyrosine kinase inhibitors are highly effective in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and, for example, eosinophilia-associated chronic myeloproliferative disorders. This molecularly targeted approach disrupts abnormal tyrosine kinase dependent signalling pathways, thus providing a preferred treatment option for selected neoplastic disorders with activating mutations of Abelson-, Abl-related-, Kit-, and platelet-derived growth factor receptor A and B genes. Loss of response to imatinib may be due to an acquired resistance of emerging mutant tumor cell clones. Therapy is generally well tolerated. However, toxicities including edema, skin rashes, fatigue, nausea and myelosuppression have been reported. Philadelphia/Bcr-Abl-negative clonal chromosomal abnormalities may develop. Bone marrow trephines obtained from CML patients in complete remission with prolonged pancytopenia secondary to imatinib generally show marrow hypoplasia. Morphological features may be in keeping with either aplastic anemia or myelodysplasia developing in Philadelphia-negative hematopoiesis. Single or multilineage myelodysplasia may be accompanied by an excess of blasts and rarely evolves into acute leukemia in CML patients. Severe adverse hematological effects of imatinib are extremely rare. Current questions involve the molecular mechanisms of hematological side effects of tyrosine kinase inhibitors with special regard to the emergence of distinct aberrant clones.
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PMID:[Hematological side effects of tyrosine kinase inhibition using imatinib]. 1642 5

Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor alpha (PDGFRalpha) gene. Both PDGFRalpha and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
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PMID:Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. 1706

Gastrointestinal stromal tumors (GISTs) are currently defined as c-Kit-positive mesenchymal tumors with specific histological characteristics. CD117 (c-Kit protein) is a growth factor receptor with tyrosine kinase activity and product of the protooncogene c-Kit. The most frequent sign is gastrointestinal haemorrhage, which occurs in approximately one third of patients. The evaluations which are necessary for diagnosis include clinical examination, immunohistochemistry analysis, endoscopic examination, X-ray, abdominal CT scan, ultrasound, MRI, exploratory surgery, biopsy or fine-needle aspiration of the tumor. Current data suggest a major role of a new tyrosine kinase inhibitor, imatinib mesylate (Glivec), for patients with metastatic or advanced disease. Surgical resection is the treatment of choice and offers the only chance for cure.
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PMID:[Gastrointestinal stromal tumors. Actual diagnosis and treatment]. 1660 75

Mouse bone marrow cells transduced with retroviral vectors encoding either of two oncogenic Bcr-Abl isoforms (p210(Bcr-Abl) and p185(Bcr-Abl)) induce B cell lympholeukemias when transplanted into lethally irradiated mice. If the activity of the Arf tumor suppressor is compromised, these donor cells initiate a much more highly aggressive and rapidly fatal disease. When mouse bone marrow cells expressing Bcr-Abl are placed in short-term cultures selectively designed to support the outgrowth of pre-B cells, only those lacking one or two Arf alleles can initiate lympholeukemias when inoculated into immunocompetent, syngeneic recipient mice. Although the ABL kinase inhibitor imatinib mesylate (Gleevec) provides highly effective treatment for BCR-ABL-positive chronic myelogenous leukemia, it has proven far less efficacious in the treatment of BCR-ABL-positive acute lymphoblastic leukemias (ALLs), many of which sustain deletions of the INK4A-ARF (CDKN2A) tumor suppressor locus. Mice receiving Arf-/- or Arf+/- p210(Bcr-Abl)-positive pre-B cells do not achieve remission when maintained on high doses of oral imatinib therapy and rapidly succumb to lympholeukemia. Although cells expressing the Bcr-Abl kinase can proliferate in the absence of IL-7, they remain responsive to this cytokine, which can reduce their sensitivity to imatinib. Treatment of Arf-/-, p210(Bcr-Abl)-positive pre-B cells with imatinib together with an inhibitor of JAK kinases abrogates this resistance, suggesting that this combination may prove beneficial in the treatment of BCR-ABL-positive acute lymphoblastic leukemia.
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PMID:Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. 1661 32

The aim of this study was to analyze epidemiology and outcome of 40 patients with gastrointestinal stromal tumor (GIST) expressed CD 117. All epidemiological data (age, sex, location) and survival data were analyzed retrospectively. The tumors occurred in 17 men and 23 women. Stomach was the most common site of localization (47.5%). Of the 37 patients without Gleevec treatment, 18 benignant cases (66.6%) showed long-term survival (2 to 8 years) and 9 malignant cases (33.3%) were diagnosed. 10 cases were still being in followed (< 2 years). Gastric tumor's survival was better than extragastric tumor's survival without statistically significance (p>0.05). Our experience confirms that GIST is an aggressive tumor. 33.33% of them are malignant with recurrence or metastatic potential. Additionnally, epidemiologic factors (age, sex and location) do not have a predictive value.
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PMID:[Gastrointestinal stromal tumor: epidemiology and outcome study in 40 cases]. 1663 9

Targeted cancer therapies exploit the continued dependence of cancer cells on oncogenic mutations. Such agents can have remarkable activity against some cancers, although antitumor responses are often heterogeneous, and resistance remains a clinical problem. To gain insight into factors that influence the action of a prototypical targeted drug, we studied the action of imatinib (STI-571, Gleevec) against murine cells and leukemias expressing BCR-ABL, an imatinib target and the initiating oncogene for human chronic myelogenous leukemia (CML). We show that the tumor suppressor p53 is selectively activated by imatinib in BCR-ABL-expressing cells as a result of BCR-ABL kinase inhibition. Inactivation of p53, which can accompany disease progression in human CML, impedes the response to imatinib in vitro and in vivo without preventing BCR-ABL kinase inhibition. Concordantly, p53 mutations are associated with progression to imatinib resistance in some human CMLs. Our results identify p53 as a determinant of the response to oncogene inhibition and suggest one way in which resistance to targeted therapy can emerge during the course of tumor evolution.
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PMID:Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. 1665 19

Most gastrointestinal stromal tumors (GISTs) possess a gain-of-function mutation in c-KIT. Imatinib mesylate, a small-molecule inhibitor against several receptor tyrosine kinases, including KIT, platelet-derived growth factor receptor-alpha, and BCR-ABL, has therapeutic benefit for GISTs both via KIT and via unknown mechanisms. Clinical evidence suggests that a potential therapeutic benefit of imatinib might result from decreased glucose uptake as measured by positron emission tomography using 18-fluoro-2-deoxy-d-glucose. We sought to determine the mechanism of and correlation to altered metabolism and cell survival in response to imatinib. Glucose uptake, cell viability, and apoptosis in GIST cells were measured following imatinib treatment. Lentivirus constructs were used to stably express constitutively active AKT1 or AKT2 in GIST cells to study the role of AKT signaling in metabolism and cell survival. Immunoblots and immunofluorescent staining were used to determine the levels of plasma membrane-bound glucose transporter Glut4. We show that oncogenic activation of KIT maximizes glucose uptake in an AKT-dependent manner. Imatinib treatment markedly reduces glucose uptake via decreased levels of plasma membrane-bound Glut4 and induces apoptosis or growth arrest by inhibiting KIT activity. Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation. Overall, these findings contribute to a clearer understanding of the molecular mechanisms involved in the therapeutic benefit of imatinib in GIST and suggest that a drug-mediated decrease in tumor metabolism observed clinically may not entirely reflect therapeutic efficacy of treatment.
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PMID:Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. 1670 77

A 68-year-old woman presented with an extremely rare intracranial metastasis from a gastrointestinal stromal tumor (GIST) manifesting as left hemiparesis 2 years after resection of a sacral tumor adjacent to the coccygeal bone. Magnetic resonance imaging revealed an intracranial tumor in the right parietal lobe. Craniotomy was performed to completely remove the tumor. Although the tumor was located extra-axially, only internal carotid angiography showed mass staining. Seven months after surgery, the tumor recurred. Repeat craniotomy was performed to remove the recurrent tumor. Immunohistochemical analysis showed that the tumor cells were positive for c-kit and CD34, and the tumors were identified as intracranial metastasis of GIST. Following the second intracranial surgery, the patient developed severe lower back pain caused by metastatic tumor invading the lumbar spine and ureter. To avoid surgical complications and to reduce tumor volume, imatinib mesylate (Gleevec) was administered. The severe pain was relieved, although the tumor was not reduced. In this case, the extra-axial tumor was fed only by the internal carotid artery.
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PMID:Perisacral gastrointestinal stromal tumor with intracranial metastasis. Case report. 1672 20


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