Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methionine (MET)-dependent cell lines require MET to proliferate, and homocysteine (HCY) does not act as a substitute for this requirement. From six O6-methylguanine-DNA methyltransferase (MGMT)-efficient (mer+) cell lines tested, two medulloblastomas (Daoy and D-341) and a lung non-small-cell adenocarcinoma with metastatic potential (H-1623) were most sensitive to MET deprivation, while two glioblastomas (U-138, D-263) and a small-cell lung carcinoma H-1944 were moderately to weakly dependent. Regardless of the degree of MET dependence, all of these lines down-regulated their MGMT activity within 48-72 h of transfer from MET+HCY- to MET-HCY+ media, long before the eradication of the culture. Reduction of MGMT activity was due to a decline of both MGMT mRNA and protein levels. However, the reduction was not related to the methylation status of the MGMT promoter at the SmaI site or the HpaII sites in the body of the gene; such sites have been shown to be associated in MGMT regulation and in defining the mer phenotype. MET-dependent, mer+ tumour cells cultured in MET-HCY+ were more sensitive to BCNU (IC50 = 5-10 microM) than those cultured in MET+HCY-(IC50 = 45-90 microM), while MET-independent or mer- cell lines were unaffected. This indicates that reduction of MGMT, imposed by the absence of MET, renders mer+ tumour cells more susceptible to alkylating agents. The relatively selective suppression of MGMT activity in mer+ MET-dependent tumour cells, in combination with the inability of such cells to proliferate in the absence of MET, may lead to the development of more effective treatment strategies for mer+ MET-dependent tumours.
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PMID:Regulation of O6-methylguanine-DNA methyltransferase by methionine in human tumour cells. 906 96

Single nucleotide polymorphisms (SNPs) in the metabolic pathways of S-adenosylmethionine have been related to global hypomethylation and a lower number of hypermethylated CpG islands of tumor suppressor genes. Hypermethylation of checkpoint and DNA repair genes has been shown to be indicative of chemosensitivity. In the present study, we have examined the SNP of methylenetetrahydrofolate reductase (MTHFR) C677T, which affects DNA methylation patterns and is linked to elevated plasma homocysteine levels in 208 patients with gemcitabine/cisplatin-treated stage IV non-small-cell lung cancer (NSCLC). No differences in response rate were observed according to the MTHFR genotype. However, time to progression was 7.4 months for 68 patients with CC genotype, 5.5 months for 108 patients with heterozygous CT genotype, and 5.2 months for 28 patients with TT genotype. These findings can lead us to distinguish different outcome patterns among patients with stage IV NSCLC whose similar clinical prognostic factors would otherwise indicate similar outcomes. Carriers of the MTHFR 677T allele could benefit from supplementation with folic acid and vitamin B12. The Spanish Lung Cancer Group has undertaken a phase III randomized trial to elucidate this concept.
Clin Lung Cancer 2004 May
PMID:Effect of the methylenetetrahydrofolate reductase C677T polymorphism on patients with cisplatin/gemcitabine-treated stage IV non-small-cell lung cancer. 1521 35

Though the methodology and designs of epidemiological studies and analyses of medical databases have improved, associations between modifiable exposures and the disease in observational epidemiological studies remain partly biased. Mendelian randomization principle, which is the random distribution of parental genes to offspring in meiosis during gametogeneis and at conception, represents a chance for methodology of evaluation of the causal relations between the external cause and the disease. The use of this principle assumes the association between the disease and the genetic polymorphism which reflects the biological relation between the suspected exposure and the disease, and is generally less prone to the phenomenon of confounding and reverse causation that can impair the interpretation of results in conventional observational studies. Authors describe explanatory options of the Mendelian randomization principle using examples in folic acid--homocysteine--coronary heart disease, and isothiocyanate versus lung carcinoma. Though the use of Mendelian randomization principle has its limitations, it offers new possibilities to test causal relations and clearly shows that means invested into the Human genome project can contribute to the understanding and prevention of adverse effects of modifiable exposure to the human health.
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PMID:[Genotype-disease association and possibility to reveal environmentally modifiable disease causes: the use of mendelian randomization principle]. 1749 Dec 44

Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.
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PMID:Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. 2333 22

Introduction Human immunodeficiency virus (HIV) patients are at risk of developing thrombosis than general population. There are several intersecting mechanisms associated with HIV infection and antiviral therapy that are emerging, which may lead to vasculopathy and hypercoagulability in these patients. Methods We analyzed the HIV patients who followed up with our Vascular Medicine outpatient clinic with venous thromboembolism (VTE) over the past 3 years and followed them prospectively. The patients included were those who had minimum, regular follow-up of 3 months, with a Doppler scan in the beginning and last follow-up. Patients were analyzed for age, gender, race, site of thrombosis, coagulation factors, lipid panel, type of antiretroviral treatment, past or present history of infections or malignancy, CD4 absolute and helper cell counts at the beginning of thrombosis, response to treatment and outcome. Patients with HIV with arterial thrombosis were excluded. Results A total of eight patients were analyzed. The mean age was 49.87 years (range, 38-58 years). All were male patients with six patients having lower limb thrombosis, one patient with upper limb thrombosis related to peripheral inserted central catheter (PICC), and one patient had pulmonary embolism with no deep vein thrombosis. Most common venous thrombosis was popliteal vein thrombosis, followed by common femoral, superficial femoral and external iliac thrombosis. Two patients had deficiency of protein S, two had high homocysteine levels, one had deficiency of antithrombin 3, and one had increase in anticardiolipin Immunoglobulin antibody. All patients were taking nucleoside and nonnucleoside inhibitors but only two patients were taking protease inhibitors. There was history of lymphoma in one and nonsmall cell lung carcinoma in one patient. Three patients had past history of tuberculosis and one of these patients also had pneumocystis carinii pneumonia. The mean absolute CD4 counts were 383.25 cells/UL (range, 103-908 cells/UL) and helper CD4 counts were 22.5 cells/UL (range, 12-45 cells/UL). All were anticoagulated with warfarin or enoxaparin. There was complete resolution of deep vein thrombosis in two patients (one with PICC line thrombosis in 3 months and other with popliteal vein thrombosis in 1 year). There was extension of clot in one patient and no resolution in others. Seven patients are still alive and on regular follow-up. Conclusion Thrombosis in HIV patients is seen more commonly in middle aged, community ambulant male patients. Left lower limb involvement with involvement of popliteal vein is most common. Deficiency of protein S and hyperhomocystenaemia were noted in these patients. Most of these patients did not respond to therapeutic anticoagulation, but the extension of the thrombosis was prevented in majority of cases.
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PMID:Risk of Venous Thromboembolism in Patients Infected with HIV: A Cohort Study. 2443 91