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)

Non-invasive predictive assays which can confirm the presence or absence of hypoxic cells in human tumours show promise for understanding the natural history of tumour oxygenation, and improving the selection of patient subsets for novel radiotherapeutic strategies. Sensitiser adducts have been proposed as markers for hypoxic cells. Misonidazole analogues radiolabelled with iodine-123 have been developed for the detection of tumour hypoxia using conventional nuclear medicine techniques. In this pilot study, we have investigated one such potential marker, 123I-iodoazomycin arabinoside (123I-IAZA). Patients with advanced malignancies have undergone planar and single-photon emission computed tomographic (SPECT) imaging after intravenous administration of 123I-IAZA. We have observed radiotracer avidity in three out of ten tumours studied to date. Normal tissue activity of variable extent was also seen in the thyroid and salivary glands, upper aerodigestive tract, liver, intestine, and urinary bladder. Quantitative analysis of those images showing radiotracer avidity revealed tumour/normal tissue (T/N) ratios of 2.3 (primary small cell lung carcinoma), 1.9 (primary malignant fibrous histiocytoma) and 3.2 (brain metastasis from small cell lung carcinoma) at 18-24 h post injection. These preliminary data suggest that the use of gamma-emitter labelled 2-nitroimidazoles as diagnostic radiopharmaceuticals is feasible and safe, and that metabolic binding of 123I-IAZA is observed in some, but not all tumours. The inference that tumour 123I-IAZA avidity could be a non-invasive measure of tumour hypoxia deserves independent confirmation with needle oximetry.
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PMID:Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: preliminary report of a clinical study. 131 Feb 53

Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (i.e. deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemistry of reduction of nitro heterocycles. 293 68

The Radiation Therapy Oncology Group (RTOG) investigated the use of misonidazole as an hypoxic cell sensitizer in a Phase III prospective randomized trial employing radiotherapy, 600 cGy twice weekly to a total of 3600 cGy with and without misonidazole in the treatment of locally advanced non-metastatic squamous cell, adeno, or large cell carcinoma of the lung. Between January 1980 and July 1983, 117 patients from 21 institutions were enrolled. One-hundred eight patients were evaluable; 53 in the combined treatment arm and 55 in the radiation alone arm. Grade 3 or worse complications associated with radiation occurred in 17% of patients. Esophageal toxicity accounted for the majority of complications. Two (4%) patients in the radiotherapy plus misonidazole group experienced grade 3 peripheral neurotoxicity. Complete or partial responses were produced in 58% of the patients with radiotherapy alone and 36% of those treated with radiotherapy plus misonidazole (p = 0.08). At the time of first progression, over 50% of the patients had persistent local disease. Median survival was 7 months regardless of treatment. Misonidazole in the dose and schedule employed did not enhance the effect of radiotherapy on either local tumor control or overall survival in patients with advanced lung cancer.
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PMID:Large fraction irradiation with or without misonidazole in advanced non-oat cell carcinoma of the lung: a phase III randomized trial of the RTOG. Radiation Therapy Oncology Group. 303 41

MTDQ, and its watersoluble derivative MTDQ-DA, have been tested in combination with radiation using the murine plasmacytoma X5563 and the Lewis lung carcinoma. Neither of the two compounds showed any effect on the single dose radiation response as measured by tumour growth delay. In addition no effect of MTDQ-DA on the response of the X5563 plasmacytoma to fractionated radiation was observed. As a control, studies with the established hypoxic cell sensitizer Misonidazole showed that both tumours could be sensitized to radiation by that drug, in the case of Lewis lung carcinoma the use of the excision cell survival assay showed that this was due to hypoxic cell sensitization.
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PMID:Lack of radiosensitization in Lewis lung carcinoma and a murine plasmacytoma by MTDQ and MTDQ-DA. 320 85

Misonidazole, SR-2508, nitrofurazone and other nitroheterocycles stimulated release of 14CO2 from [1-14C]glucose but not from [6-14C]glucose when incubated with mouse Ehrlich ascites cells or human A549 lung carcinoma cells in vitro. This demonstrated that the nitro compounds activated the hexose monophosphate shunt and is evidence that an important pathway of nitro reduction in these cell lines is electron transfer from NADPH-dependent cytochrome c reductase to the nitro group. Shunt activity was stimulated under both aerobic and anaerobic conditions. For catalase-free Ehrlich cells, aerobic effects were greater than anaerobic, indicating that NADPH was used for reduction of H2O2, via GSH peroxidase and reductase, as well as for one-electron nitro reduction, under aerobic conditions. Several of the compounds tested stimulated 14CO2 release from [2-14C]glucose as well as from [1-14C]-glucose. This shows that the cellular requirement for NADPH, in the presence of nitro drug, was great enough to cause recycling of pentose phosphates. Recycling could decrease the availability of ribose-5-P needed for nucleic acid synthesis, which could partly explain the inhibition of DNA synthesis observed upon prolonged aerobic incubation of cells with nitro compounds. Comparison of the rate of disappearance of nitrofurazone from anaerobic A549 cell suspensions with the rate of 14CO2 release suggests that the drug reduction in this cell line was catalyzed almost entirely by NADPH-requiring enzymes.
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PMID:Nitroheterocycle metabolism in mammalian cells. Stimulation of the hexose monophosphate shunt. 642 13

A review of misonidazole pharmacokinetics in 83 consecutive patients treated for tumours other than glioma has shown that among patients not receiving enzyme-inducing agents the plasma elimination half life is lower in patients taking steroids. Such a difference is not seen if patients already taking enzyme inducers are given steroids. Five further patients with carcinoma of the lung, treated with radiation over a period of 3 weeks, have been studied in greater detail. Misonidazole, in oral dose of 1 gm-2, was given in conjunction with the first and last radiotherapy fractions, and dexamethasone, in a divided daily dose of 8 mg, was given throughout the radiation treatment, commencing after the first treatment. Misonidazole pharmacokinetics were studied at each administration. Following the dexamethasone treatment period there was a 25% reduction in misonidazole plasma elimination half life, a 24% reduction in plasma AUC0-00, and a 38% increase in 24 h urinary excretion (all changes being statistically significant--P less than 0.005). No changes were observed in the plasma AUC0-24 and urinary excretion of the major metabolite desmethylmisonidazole. Glomerular filtration rates in one patient, before and after treatment with dexamethasone, remained unchanged. These results suggest that the effect of dexamethasone on misonidazole kinetics is not related to an enhancement of demethylation.
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PMID:The role of dexamethasone in the modification of misonidazole pharmacokinetics. 662 54

The influence of the radiosensitizer misonidazole on the effectiveness of several alkylating agents and cis-platinum against advanced solid murine tumors was investigated. Tumor regrowth delay, frequency of tumor regressions, and animal life span were used to evaluate misonidazole in combination with cyclophosphamide, L-phenylalanine mustard, 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea, aziridinyl-benzoquinone, and cis-platinum. In the advanced M5076 ovarian carcinoma, misonidazole enhanced the activity of cyclophosphamide, L-phenylalanine mustard, 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea, and aziridinyl benzoquinone, but not cis-platinum. In early B16 melanoma, misonidazole plus cyclophosphamide was no more effective than cyclophosphamide alone. In advanced Lewis lung carcinoma, misonidazole enhanced the antitumor activity of cyclophosphamide but not 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea. Misonidazole, at 1000 mg/kg, increased the antitumor effectiveness of L-phenylalanine mustard and cyclophosphamide in M5076 tumors by factors of 2.2 and 1.8, but caused only a 1.2- and 1.3-fold increase in the myelotoxicity of these agents as determined by spleen colony assay of normal bone marrow. Misonidazole also increased the toxicity of cyclophosphamide and L-phenylalanine mustard in non-tumor-bearing mice but to a lesser degree than it enhanced antitumor activity. These results indicate that misonidazole is capable of enhancing the effects not only of ionizing radiation but of alkylating agents as well.
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PMID:Enhancement of antitumor activity of alkylating agents by the radiation sensitizer misonidazole. 747 Oct 58