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)

The molecular weight (MW) and dose dependency of several of the toxic effects and antitumor and antiviral activities of a new series of five maleic anhydride-divinyl ether copolymers (MVE) were established. Each polyanion preparation was relatively homogeneous and exhibited a narrow MW range, from 12,500 (MVE-1) to greater than 52,000 (MVE-5). All of the polyanions were effective as adjuvants to surgery against the metastatic Lewis lung carcinoma, and also exhibited marked antitumor activity against the P815 mastocytoma. MVE-1 retained antitumor activity while losing considerable antiviral activity. This polyanion also exhibited the least toxicity with regard to criteria such as sensitization to the lethal effects of endotoxin, inhibition of reticuloendothelial function, and depression of the microsomal mixed functional oxidase system. The MVE-4 (MW, 32,000) and MVE-5 (MW, 52,600) polyanions exhibited potent antitumor and antiviral activity, but also demonstrated dose-dependent toxic effects.
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PMID:Relationship of molecular weight to antiviral and antitumor activities and toxic effects of maleic anhydride-divinyl ether (MVE) polyanions. 10 18

The antimetastatic effect of cepharanthin with or without 5-fluorouracil (5-FU) was examined in an experimental model of lung metastasis induced by Lewis lung carcinoma (3LL) in C57BL/6crSlc mice. Injection of cepharanthin i.p. after removal of the implanted primary tumor inhibited the development of lung metastases. Combination therapy with cepharanthin plus 5-FU inhibited significantly the lung metastases. Lung metastases were inhibited by i.v. injection of peritoneal macrophages activated with cepharanthin. Cepharanthin depressed aniline hydroxylase and aminopyrine demethylase activities of the hepatic microsomal drug-metabolizing system in tumor-bearing mice. Moreover, the concentration of 5-FU in the tissues (lung, liver, kidney, spleen and blood) was increased significantly by coadministration of cepharanthin. A possible mechanism of the inhibition of lung metastases by treatment with cepharanthin may be that this drug acts through macrophage activation and depression of the hepatic microsomal drug-metabolizing system. These findings raise the possibility that combination therapy with cepharanthin plus 5-FU may have clinical value in the prevention of cancer metastasis.
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PMID:Inhibitory effect of a biscoclaurine alkaloid, cepharanthin, on lung metastasis of Lewis lung carcinoma. 188 Sep 98

Immunoreactive calcitonin (CT) secreted by DMS 53, a cell line derived from human small cell carcinoma of the lung, consists almost entirely of molecular species larger than the mature hormone (Mr 3,420). Messenger RNA isolated from DMS 53 cells and nude mouse tumors was translated in wheat germ systems, and the products were precipitated with CT-specific antisera. Analyses of the translation products by electrophoresis on 15% polyacrylamide-sodium dodecyl sulfate gels indicated synthesis of a Mr 16,500 preprohormone that was reduced to Mr 14,500 by cotranslation with microsomal membranes. Immunoprecipitation of CT from media from pulse-labeled cultures revealed two major products (Mr 16,500 and Mr 14,500) and up to three minor secreted polypeptides (Mr 9,400, 8,400, and 6,800). Intracellular CT from cell homogenates appeared almost entirely as a single major product (Mr 14,500) and possibly 3-4 minor components (Mr 16,500; 9,200, 8,400, and 6,800). No glycosylated forms of CT were demonstrable by lectin binding methods or labeling attempts with tritiated sugars. The presence of multiple CT species in DMS 53 cells suggests significant post-translational processing of the larger precursor molecules and the accumulation and secretion by small cell carcinoma of the lung of several intermediate immunoreactive forms via a glycosylation-independent secretory pathway.
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PMID:Biosynthesis of procalcitonin in small cell carcinoma of the lung. 300 May 86

Liver metastases due to the more common neoplastic diseases such as colorectal, breast, or bronchogenic carcinoma are a frequent occurrence and are associated with an ominous prognosis. Earlier detection followed by appropriate therapeutic interventions might have a decided effect on the subsequent course of disease. Controversy exists over the selection of tests with the greatest sensitivity, specificity, and potential utility. Preliminary evidence suggest that gamma-glutamyl transpeptidase and 5'-nucleotidase may be of particular significance. Four enzymes--gamma-glutamyl transpeptidase, 5'-nucleotidase, leucine aminopeptidase, and alkaline phosphatase plus carcinoembryonic antigen--were compared in the same blood samples from selected patients with breast and small cell carcinoma of the lung. Gamma-Glutamyl transpeptidase was the most sensitive test with 28/29 (97%) patients with hepatic metastases having elevated enzymatic activity in their sera. For patients with small cell carcinoma of the lung followed serially, gamma-glutamyl transpeptidase activity was increased an average of 5 months before liver metastases were detected by clinical means. Two factors are important in the interpretation of the results of gamma-glutamyl transpeptidase analysis: (1) Hepatic dysfunction due to diseases other than metastatic tumor involvement can cause a rise in enzyme levels as can (2) medications or ethanol which activate the hepatic microsomal drug metabolizing system. Of particular importance, however, is the fact that antitumor chemotherapy, even intensive and multiple agent, did not appear to effect the enzyme activity in the sera of patients with breast or small cell carcinoma of the lung. Gamma-glutamyl transpeptidase in combination with carcinoembryonic antigen may be of particular value in detecting liver metastases and in assessing subsequent response to therapy.
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PMID:Biological markers as an aid in the clinical management of patients with liver metastases. 612 62

This paper provides an overview of cancer chemotherapy with special reference to the pharmacokinetics of the nitrosoureas. At physiological PH, the chloroethylnitrosoureas can be decomposed into an isocyanate and 2-chloroethyl diazene hydroxide. Therefore, it is clear that they have both alkylation and carbamoylation actions. In addition to the spontaneous chemical dissociation, the nitrosoureas can be metabolized by liver microsomal enzymes to more polar hydroxylated products, and certain nitrosoureas can be denitrosated by these enzymes to the parent urea. Since the lipid-soluble nitrosoureas and some of the water-soluble nitrosoureas such as ACNU and MCNU demonstrated to cross the blood-brain barrier, they have been used in the treatment of primary brain tumors and tumors and tumors of metastatic origin. It has been demonstrated from the results of our study and other reports that the alkylation of DNA by ACNU progresses more slowly as compared with that of other alkylating agents. This is an important finding in relation to the appearance of delayed myelosuppression of the nitrosoureas and in the design of dose schedules of these agents. The major clinical emphasis has been directed towards the more active chloroethylnitrosoureas with reduced myelosuppression, and attempts are now made for this purpose. Unfortunately, the results of phase I and II trials of the newly developed nitrosoureas suggest that these agents produce delayed and cumulative bone marrow toxicity. Antitumor activity of the nitrosoureas is frequestly observed in chronic myelocytic leukemia, malignant lymphoma, brain tumors and small cell carcinoma of the lung, and less frequently in gastrointestinal carcinoma, multiple myeloma and malignant melanoma. In order to enhance clinical effects of the nitrosoureas, further investigation of the design in therapeutic schedules on the basis of their pharmacokinetic characteristics will be needed.
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PMID:[Cancer chemotherapy with special reference to pharmacokinetics of nitrosoureas]. 622 95

The antimetastatic effect of GIV-A (fucoidan) and/or 5-FU was examined in an experimental model of lung metastases induced by Lewis lung carcinoma in mice. Injection of GIV-A i.p. after removal of the implanted primary tumor inhibited the development of lung metastases. Combination treatment with GIV-A and 5-FU inhibited significantly the lung metastases. The number of peritoneal macrophages, total cells and macrophages in the lung increased in mice treated with GIV-A. Binding of the third component of complement (C3) cleavage products (C3b) to the C3 receptor on peritoneal macrophages after i.v. injection of GIV-A was enhanced, as shown by the fluorescent antibody technique. Lung metastases were inhibited by i.v. injection of peritoneal macrophages activated with GIV-A. GIV-A depressed aniline hydroxylase and aminopyrine demethylase activities of the hepatic microsomal drug-metabolizing system in tumor-bearing mice. Moreover, the concentration of 5-FU in the tissues (lung, liver, kidney, spleen and blood) was increased significantly by coadministration of GIV-A. The picryl chloride-induced delayed type hypersensitivity (PC-DTH) response in mice was depressed after the implantation of tumor and treatment with 5-FU. GIV-A restored the suppression of PC-DTH by 5-FU, but did not increase the PC-DTH of normal mice. GIV-A not only enhanced the degree of spleen cell-mediated sheep red blood cell (SRBC) hemolysis (quantitative hemolysis of SRBC), the indexes of the spleen and thymus and the number of spleen cells, but also restored the suppressive effect of 5-FU. In the group receiving GIV-A, the percentages of splenic Thy1.2-, L3T4- and asialo GM1-positive cells were significantly increased as compared with the tumor-bearing mice treated with saline. Furthermore, the L3T4+/Lyt2+ ratio showed a tendency to increase, and the Lyt2+/Thy1.2+ ratio was decreased. These results suggest that the antitumor effect of GIV-A may be correlated with the changing pattern of the Thy1.2-, L3T4- and asialo GM1-positive cells, C3 activation, macrophage activation and depression of the hepatic microsomal drug-metabolizing system. These findings raise the possibility that GIV-A may have clinical value in the prevention of cancer metastasis.
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PMID:Immunological analysis of inhibition of lung metastases by fucoidan (GIV-A) prepared from brown seaweed Sargassum thunbergii. 857 81

In furtherance of our structure-activity relationship studies on the antitumor activity of indolo[2,3-b]quinolines, novel cytotoxic derivatives bearing methyl groups at N-5, C-11, C-2 and/or C-9, as well as methoxy-groups at C-2 and/or C-9, were synthesized by the modified Graebe-Ullmann reaction. To elucidate the metabolic pathways of these compounds, zygomycete fungus Cunninghamella elegans ATCC 9245 (which is known to produce drug metabolites that are also formed in mammals) was used as a mimetic organism. Simultaneously, biotransformation of the same substrates was carried out with a microsomal fraction of rat liver. Three forms of microbial conversion were observed: hydroxylation of the aromatic ring or hydroxylation of the methyl group, and O-demethylation. The reaction proceeded regioselectively, and only positions C-2 and C-9 were affected in the indolo[2,3-b]quinoline system. The products formed were found to be identical with the metabolites generated by rat liver microsomes. The metabolites obtained displayed a cytotoxic activity in vitro against colon adenocarcinoma SW-707 and lung carcinoma A-549 (ID50 in the range 0.27-3.04 microM), which was as strong as that of the substrates. In the course of the further metabolic pathway study of indolo[2,3-b]quinolines we found that metabolites with a hydroxyl group in the aromatic system were transformed to non-cytotoxic polymeric products by multicopper oxidases: human ceruloplasmin or fungal laccase (used as mimetic enzyme), whereas metabolites with a hydroxymethyl group did not undergo such bioconversion. The last mentioned compounds can be regarded as a novel type of cytotoxic indolo[2,3-b]quinoline derivatives formed in metabolic processes.
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PMID:Microbial conversion of methyl- and methoxy- substituted derivatives of 5H-indolo[2,3-b]quinoline as a method of developing novel cytotoxic agents. 1065 30

RH1 (2,5-diaziridinyl-3-(hydroxylmethyl)-6-methyl-1,4-benzoquinone) has shown preferential activity against human tumour cell lines which express high levels of DTD (EC 1.6.99.2; NAD(P)H:quinone oxidoreductase, NQO1, DT-diaphorase) and is a candidate for clinical trials. EO9 (3-hydroxy-5-aziridinyl-1-methyl-2-[1H indole-4,7-dione]prop-beta-en-alpha-ol) is a known substrate for DTD but clinical trials were disappointing, as a result of rapid plasma clearance and reversible dose-limiting kidney toxicity. It is an obvious concern that RH1 does not exhibit the same limitations. We therefore describe the antitumour activity and pharmacology of RH1 in mice and compare its pharmacological characteristics to those of EO9. Significant antitumour activity (P = 0.01) was seen for RH1 (0.5 mg/kg, i.p.) against the high DTD-expressing H460 human lung carcinoma. Pharmacokinetic analysis of RH1 in mice showed a t1/2 of 23 min with an area under the curve of 43.0 ng hr mL(-1) resulting in a calculated clearance of 5.1 mL min(-1), 10-fold slower than EO9. RH1 was also more stable than EO9 in murine blood, where the breakdown was thought to be DTD-related. NADH-dependent microsomal metabolism of RH1 and EO9 in both liver and kidney was slow (<100 pmol/min/g tissue), reflecting the low microsomal DTD expression (<35 nmol/mg/min). Liver cytosol metabolism was rapid for both compounds (>4500 pmol/min/g tissue), although DTD levels were low (21.4+/-0.6 nmol/mg/min). DTD activity in the kidney cytosol was high (125+/-8.2 nmol/mg/min) and EO9 was rapidly metabolised (4396+/-1678 pmol/min/g), but the metabolic rate for RH1 was 7-fold slower (608+/-86 pmol/min/g), even though RH1 was shown to be an excellent substrate for DTD (Vmax = 800 micromol/min/mg and a Km of 11.8 microM). The two DTD substrates RH1 and EO9 are clearly metabolised differently, suggesting that RH1 may have different pharmacological properties to those of EO9 in the clinic.
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PMID:Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice. 1071 41

The effects of motorcycle exhaust particulate (MEP) on human cytochrome P-450 (P-450)-dependent monooxygenases were determined using human hepatoma cell line HepG2 and lung carcinoma cell line NCI-H322 treated with organic extracts of MEP from a two-stroke engine. Gas chromatography and mass spectrometry analysis of MEP extract revealed the presence of carcinogens benzo[a]pyrene, benz[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[g,h,i]perylene, chrysene, and indeno[1,2,3-c,d]pyrene in the chemical mixture. Treatment with MEP extract produced concentration- and time-dependent increases of monooxygenase activity in HepG2 cells. Treatment of the cells with 100 microg/ ml MEP extract for 24 h markedly increased benzo[a]pyrene hydroxylation, 7-ethoxycoumarin, and 7-ethoxyresorufin O-deethylation activities in microsomes. Immunoblot analysis of microsomal proteins using mouse monoclonal antibody 1-12-3 against P-450 1A1 revealed that MEP extract induced a P-450-immunorelated protein in the hepatoma cells. RNA blot analysis of cellular total RNA using a human P-450 1A1 3'-end cDNA probe showed that MEP extract increased the level of a hybridizable P-450 mRNA. These P-450 1A1 inductive effects of MEP extract were similar to those from treatment with 10 microM benzo[a]pyrene or 3-methylcholanthrene (3-MC) in HepG2 cells. Treatment of lung carcinoma NCI-H322 cells with 100 microg/ml MEP extract, 10 microM benzo[a]pyrene, or 3-MC resulted in induction of monooxygenase activity, protein, and mRNA of P-450 1A1, similar to the induction observed with the hepatoma cells. The present study demonstrates that MEP extract has the ability to induce human hepatic and pulmonary P-450 1A1 in the liver- and lung-derived cell lines, and the induction involves a pretranslational mechanism. Induction of the human hepatic and pulmonary P-450 1A1 in vitro may provide important information in the assessment of MEP metabolism and toxicity in humans.
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PMID:Induction of cytochrome P-450 1A1 in human hepatoma HepG2 and lung carcinoma NCI-H322 cells by motorcycle exhaust particulate. 1087 32

The present study has determined the effects of 6-nitrochrysene (6-NC) on human cytochrome P450-dependent monooxygenases in human hepatoma HepG2 cells. Treatment of HepG2 cells with 6-NC increased the activities of microsomal benzo[a]pyrene hydroxylase, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylases, cytosolic glutathione S-transferase and N-acetyltransferase, and S9 metabolic activation of 6-NC in the Ames mutagenicity test. Immunoblot and RNA blot analyses revealed that 6-NC induced CYP1A1 protein and mRNA levels in the hepatoma cells. Nuclear transcription assay demonstrated that 6-NC increased the transcription rate of CYP1A1 gene in HepG2 cells. Treatment of human lung carcinoma NCI-H322 cells with 6-NC increased benzo[a]pyrene hydroxylase activity and CYP1A1 protein and mRNA levels. These results demonstrate that 6-NC is an inducer of human CYP1A1 and the induction occurs at a transcriptional level in HepG2 cells. The ability of 6-NC to induce liver and lung CYP1A1 may be an important factor to consider in assessing 6-NC metabolism and toxicity in humans.
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PMID:Induction of cytochrome P450 1A1 in human hepatoma HepG2 cells by 6-nitrochrysene. 1103 35


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