Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of nucleoside diphosphate kinase (NDK) genes has been implicated as a negative regulator of murine and human tumor metastases and is critical to proper development in Drosophila melanogaster. Molecular mechanisms for the role(s) of NDK in these complex processes have not yet been elucidated, but several reports have suggested that these and many other signal transduction pathways may be activated by NDK acting directly on a regulatory GTP-binding protein(s). To test this hypothesis, we examined the ability of NDK to catalyze the phosphorylation of the GDP bound to the following three members of the superfamily of regulatory GTP-binding proteins: Gt, Ha-ras p21, and ARF. We have found no evidence to support the hypothesis that NDK can directly activate any GTP-binding protein. Rather, evidence is presented which clearly shows that all of the GTP formed upon incubation of GTP-binding proteins with NDK is the result of NDK utilizing free GDP as substrate. The GDP bound to the regulatory proteins is not a substrate for NDK under conditions in which free nucleotides are rapidly and efficiently phosphorylated. The importance of appropriate controls for dissociation of GDP from the regulatory proteins both during the NDK reaction and during the analysis of product is demonstrated. We believe there is currently no experimental evidence to support the hypothesis that NDK can directly activate a regulatory GTP-binding protein.
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PMID:Regulatory GTP-binding proteins (ADP-ribosylation factor, Gt, and RAS) are not activated directly by nucleoside diphosphate kinase. 132 60

Interleukin-2 (IL-2) mediates the regression of metastatic cancer, but clinical application has been limited by the induction of dose-dependent toxicities in normal tissues. The most clinically significant toxicities occur secondary to a vascular leak syndrome and include acute respiratory failure and hemodynamic instability. Because previous studies suggested a role for pentoxifylline in attenuating the toxic effects of IL-2, we hypothesized that pentoxifylline would inhibit alterations in the microvasculature induced by IL-2 and would ultimately reduce IL-2-induced toxicity. To determine the validity of this hypothesis, we prepared four groups of rats for in vivo microvascular observation. In the first group, a bolus intravenous injection of IL-2 (1 x 10(6) units/kg) acutely induced hypotension, tachypnea, hypoxia, increased lung water, decreased microvascular blood flow, and increased leukocyte-endothelial adherence. No significant changes occurred in animals treated by pentoxifylline alone or the control IL-2 vehicle-alone group. However, pentoxifylline inhibited many of the IL-2-induced systemic and microvascular effects, such as hypotension, tachypnea, increased lung water, hypoxia, and increased leukocyte-endothelial adherence, but not tachycardia or increased microvascular protein leakage. These data support our hypothesis that systemic toxicities induced by IL-2 are associated with alterations in the microcirculation, which may be ameliorated by pentoxifylline.
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PMID:Pentoxifylline inhibits interleukin-2-induced leukocyte-endothelial adherence and reduces systemic toxicity. 185 30

In contrast to pulmonary parenchyma metastases or lymphangitic carcinomatosis, neoplastic emboli of small pulmonary arteries and capillaries frequently go unrecognized and are only discovered at autopsy. Five patients (48 +/- 12 years old) were admitted to 3 intensive care units for severe acute respiratory failure and died between the first and the tenth day following hospitalization. Each patient had a history of rapidly progressive dyspnea, and physical examination showed clinical evidence of right ventricular failure. The lungs were clear on chest X-rays and the ECG revealed sinus tachycardia with a right QRS axis. The mean partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) were, respectively, 50.8 +/- 9.1 mm Hg and 22.2 +/- 2.4 mm Hg. A swan-Ganz catheter, inserted into 4 patients, revealed pulmonary arterial hypertension (55, 43, 37, 28) with capillary wedge pressure within the normal limits and cardiac output normal or low (3.0, 3.8, 4.4, 5.0 l/min). Pulmonary angiograms from each patient showed decreased distal lung perfusion without any proximal defects suggestive of pulmonary embolism. The inferior vena cava always appeared clear. Malignant cells were found upon autopsy (4 cases) in the lumina of the pulmonary arterioles and the primary site of the cancer was determined in 3 patients (2 hepatomas and 1 pancreatic carcinoma). The last patient had a known breast cancer with bone marrow metastases and clinical, hemodynamic and angiographic evidence of neoplastic emboli. The clinical course of neoplastic emboli can suggest acute pulmonary embolism, but the diagnosis can only be advanced after pulmonary angiography, especially if the patient is to have a cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Acute respiratory distress caused by distal neoplastic pulmonary emboli]. 209 8

A 65-year-old man presented with renal cell carcinoma of the right kidney with a tumor thrombus extending up the vena cava to the right atrium. Cardiopulmonary bypass, profound hypothermia and total circulatory arrest were used to create a bloodless field for excision of the renal cell carcinoma and its tumor thrombus. Acute respiratory failure and deep jaundice developed after the operation and the patient was transferred to the intensive care unit for critical care. After respiratory therapy and nutritional support, the liver function was restored. The endotracheal tube was weaned one month later. The patient has had total resolution of all symptoms and there is no evidence of tumor recurrence of distant metastases after 6 months follow-up.
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PMID:Removal of renal cell carcinoma extending into the right atrium using cardiopulmonary bypass, profound hypothermia and circulatory arrest. 813 47

Twenty eight patients with germ cell testicular cancer pulmonary metastases received primary chemotherapy including bleomycin, etoposide, and cisplatin (BEP). Complete response was achieved in 21 (75%) patients, in 11 of them CR was achieved following chemotherapy alone. Postchemotherapy surgery of residual mass was performed in 12 (42.9%) patients with normalized serum tumor markers. Retroperitoneal lymph node dissection was performed in one patient, pulmonary surgery in four, and both postchemotherapy treatments in 7 patients. Overall cure rate was 89.3%, 26 (92.9%) patients are still alive at a mean follow-up of 19.7+ months (range, 3-34+ months) after the treatment start. Two (7.1%) patients died: one of them due to disease progression during chemotherapy, and the second one due to postoperative complication (acute respiratory failure). Relapse of disease was observed in one patient 21 months following CR achievement, and sequential chemotherapy was introduced. Authors recommend surgical remove of all radiologically detected residual deposits, because the available imaging methods are not adequate for determining the histologic composition of residual mass, which is decisive for further therapy and has prognostic value.
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PMID:Management of germ cell testicular cancer with pulmonary metastases. 884 60

Pulmonary metastases from choriocarcinoma can very rarely give rise to a 'miliary' pattern on the chest X-ray. A 23-year-old woman with a diffuse nodular pattern on chest X-ray died due to acute respiratory failure and cor pulmonale. At autopsy, choriocarcinoma of the uterus was found. In the lungs, multiple macrovascular tumour emboli within branches of pulmonary muscular arteries in the region of segmental/subsegmental bronchi were detected. There was no evidence of pulmonary parenchymal metastases, pneumonia or tuberculosis. The 'miliary' pattern of pulmonary metastases described in cases of choriocarcinoma may be due to large vessel intra-arterial tumour emboli rather than disseminated parenchymal metastases.
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PMID:A case of pulmonary tumour embolism mimicking miliary tuberculosis. 1102 95

Malignant melanoma (MM) is thought to arise by sequential accumulation of genetic alterations in normal melanocytes. Previous cytogenetic and molecular studies indicated the 9p21 as the chromosomal region involved in MM pathogenesis. In addition to the CDKN genes (p16/CDKN2A, p15/CDKN2B and p19(ARF), frequently inactivated in familial MM), widely reported data suggested the presence within this region of other melanoma susceptibility gene(s). To clearly assess the role of the 9p21 region in sporadic melanoma, we evaluated the presence of microsatellite instability (MSI) and loss of heterozygosity (LOH) in primary tumours as well as in synchronous or asynchronous metastases obtained from the same MM patients, using 9 polymorphic markers from a 17-cM region at 9p21. LOH and MSI were found in 27 (41%) and 11 (17%), respectively, out of 66 primary tumours analysed. In corresponding 58 metastases, MSI was found at higher rate (22; 38%), whereas a quite identical pattern of allelic deletions with 27 (47%) LOH+ cases were observed. Although the CDKN locus was mostly affected by LOH, an additional region of common allelic deletion corresponding to marker D9S171 was also identified. No significant statistical correlation between any 9p21 genetic alteration (LOH, MSI or both) and clinicopathological parameters was observed.
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PMID:Definition of the role of chromosome 9p21 in sporadic melanoma through genetic analysis of primary tumours and their metastases. The Melanoma Cooperative Group. 1110 70

Tumors often display unrestricted cell cycling attributable to a dysfunctional G(1)-S checkpoint. One of the mechanisms leading to such a defect is the inactivation of the cyclin-dependent kinase inhibitor p16(INK4a). Although inactivation of p16(INK4a) is observed in a wide range of tumors, including cutaneous melanoma, genetic alteration of p16(INK4a) is reportedly uncommon in uveal melanoma. Here we show that the p16(INK4a) promoter is hypermethylated in 6 of 12 uveal melanoma cell lines and in 7 of 22 primary uveal melanomas analyzed. Five of seven patients with a methylated primary tumor died of metastatic disease compared with 2 of 15 patients with a nonmethylated primary tumor. We also show that all uveal melanoma cell lines with a hypermethylated p16(INK4a) promoter have lost p16(INK4a) expression but have maintained the expression of p14(ARF). Treatment of uveal melanoma cell lines with 5-aza-2'-deoxycytidine results in demethylation of p16(INK4a) and in reexpression of p16(INK4a) mRNA, which is maintained upon withdrawal of the 5-aza-2'-deoxycytidine. In conclusion, p16(INK4a) promoter methylation appears to be a common event in uveal melanoma and is accompanied by the loss of p16(INK4a) expression.
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PMID:Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma. 1143 74

CDKN2A (INK4a/ARF) is frequently disrupted in various types of human cancer, and germline mutations of this locus can confer susceptibility to melanoma and other tumours. However, because CDKN2A encodes two distinct cell cycle inhibitory proteins, p16INK4a and p14ARF (p19Arf in mice), the mechanism of tumour suppression by CDKN2A has remained controversial. Genetic disruption of Cdkn2a(p19Arf) (hereafter Arf) alone predisposes mice to tumorigenesis, demonstrating that Arf is a tumour-suppressor gene in mice. We mutated mice specifically in Cdkn2a(p16Ink4a) (hereafter Ink4a). Here we demonstrate that these mice, designated Ink4a*/*, do not show a significant predisposition to spontaneous tumour formation within 17 months. Embryo fibroblasts derived from them proliferate normally, are mortal, and are not transformed by oncogenic HRAS. The very mild phenotype of the Ink4a*/* mice implies that the very strong phenotypes of the original Ink4a/ArfDelta2,3 mice were primarily or solely due to loss of Arf. However, Ink4a*/Delta2,3 mice that are deficient for Ink4a and heterozygous for Arf spontaneously develop a wide spectrum of tumours, including melanoma. Treatment of these mice with the carcinogen 7,12-dimethylbenzanthracene (DMBA) results in an increased incidence of melanoma, with frequent metastases. Our results show that, in the mouse, Ink4a is a tumour-suppressor gene that, when lost, can recapitulate the tumour predisposition seen in humans.
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PMID:Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. 1154 30

Inactivation of the neurofibromatosis-1 (NF1) gene de-regulates RAS and cooperates with mutation or loss of the p53 tumor suppressor to induce tumorigenesis. p19(ARF) acts upstream of p53 in an oncogene checkpoint to induce apoptosis in response to activated RAS and other factors that stimulate proliferation. Therefore, we bred p19(ARF-/-) to NF1(+/-) mice to determine if loss of these genes collaborates in tumorigenesis. As expected from the embryonic lethality of NF1 null mice, no mice lacking both p19(ARF) and NF1 were born. Unexpectedly, the loss of one allele of NF1 did not greatly shorten the time to tumor formation in a p19(ARF) null background. The tumor types observed were characteristic of p19(ARF) null animals, not those associated with neurofibromatosis or those observed with NF1(+/-)/p53(+/-) mice. However, seven out of 12 animals developed multiple tumors, some with metastases. This multiple tumor phenotype was not previously observed with p19(ARF)-null mice and suggests a distinct form of cooperation between the loss of these tumor suppressors.
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PMID:Loss of neurofibromatosis-1 and p19(ARF) cooperate to induce a multiple tumor phenotype. 1211 76


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