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)

Since human colorectal tumors are insensitive to most chemotherapeutic agents, there is a need for the discovery of new drugs that would show activity against this disease. In an attempt to better appreciate the relevance of a widely used mouse colon tumor (colon adenocarcinoma Co38) as a screening model for human colorectal tumors, we compared the main phase I and phase II drug-metabolizing enzyme systems in both tumoral and nontumoral colon tissues. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C, 2E1, and 3A), epoxide hydrolase, and glutathione-S-transferases (GST-alpha, -mu, and -pi). The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: total cytochrome P-450, 1-chloro-2,4-dinitrobenzene-GST, selenium-independent glutathione peroxidase, 3,4-dichloronitrobenzene-GST, ethacrynic acid-GST, total glutathione, epoxide hydrolase, UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase. Results obtained by Western blot showed that mouse colon adenocarcinoma Co38 did not express any of the probed cytochromes P-450, whereas human colorectal tumors expressed only low levels of cytochrome P-450 3A. GST-alpha and GST-pi were detected in all tumoral and nontumoral tissues of both species. The neutral GST-mu was expressed in all murine tissues investigated and was found to be polymorphic in human tissues. For human peritumoral and tumoral colorectal tissues there was no significant difference between GST isoenzyme levels, whereas mouse colon adenocarcinoma Co38 had a lower expression of GST-mu and GST-pi, compared to normal mouse colon. Enzymatic activities for glutathione peroxidase, 3,4-dichloronitrobenzene-GST, and ethacrynic acid-GST confirmed the Western blot results for GST-alpha, GST-mu, and GST-pi, respectively. Total GSH levels were similar between murine and human tumors but were 3-fold higher in human tumors than in peritumoral tissues, whereas they were 7-fold lower in mouse colon tumor Co38, compared to normal mouse colon. Epoxide hydrolase was not expressed in either mouse colon adenocarcinoma Co38 or normal mouse colon tissues, whereas it was expressed in human colon peritumoral and tumoral tissues at similar levels. No significant difference was observed between human tumors and peritumoral tissues for UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase. For murine colon tissues, the conjugation pathways (UDP-glucuronosyltransferase and sulfotransferase) were lower in colon adenocarcinoma Co38, whereas the converse was observed for the corresponding hydrolytic enzymes (beta-glucuronidase and sulfatase).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparison of mouse and human colon tumors with regard to phase I and phase II drug-metabolizing enzyme systems. 142 2

The incidence and mortality rates from most cancers increase exponentially with age. It is likely that this aging phenomenon is partially due to specific changes that occur in the host resulting in an increased susceptibility to neoplasia. Our hypothesis is that one such host factor is a deficiency in GSH, based on the importance of this compound in the detoxification of a wide variety of exogenous and endogenous carcinogens and free radicals, as well as in the maintenance of immune function.
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PMID:The role of glutathione in aging and cancer. 142 93

This study was undertaken to elucidate the mechanism(s) of cross-resistance (4.9-fold) to mitomycin C (MMC) in a multi-drug-resistant cell line, P388/R-84. Intracellular accumulation of MMC by sensitive (P388/S) and P388/R-84 cells was comparable. Despite a 32% reduction in NADPH cytochrome P-450 reductase activity (responsible for MMC activation) in P388/R-84 cells, the rate of MMC bio-reduction by sensitive and resistant cells was similar. These results suggested that MMC resistance in P388/R-84 cell line must depend on factors other than impaired drug accumulation or bio-activation. Recent studies suggest that glutathione transferase (GST) dependent drug detoxification also contributes to cellular resistance of a variety of alkylating agents. Even though overexpression of GST has been noted in some MMC resistant tumor cells, it is not known if its level affects sensitivity to MMC. We have, therefore, determined the effect of ethacrynic acid (an inhibitor of GST activity) treatment on MMC cytotoxicity in P388/R-84 cells, which have about 2-fold higher GST activity than P388/S cells. The IC50 value for the inhibition of GST activity in vitro by ethacrynic acid (EA) was 16.5 microM (5 micrograms/ml). A depletion in intracellular GSH was also observed by treating P388/R-84 cells with EA alone or in combination with MMC. A non-toxic concentration of EA (1 microgram/ml; 3.3 microM) increased MMC cytotoxicity by 36% in P388/R-84 cells. MMC cytotoxicity was increased 2-fold by EA treatment in glutathione (GSH)-depleted P388/R-84 cells. These results suggest that GST mediated drug inactivation may represent another important mechanism of MMC resistance.
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PMID:Modulation of mitomycin C resistance by glutathione transferase inhibitor ethacrynic acid. 144 27

Previous metabolic studies in rats have suggested in vivo formation of the acrolein-glutathione (acrolein-GSH) adduct following administration of the highly reactive alpha, beta-unsaturated aldehyde acrolein. Early studies by several investigators demonstrated that similar compounds such as alpha, beta-unsaturated aldehyde-cysteine adducts have toxic (carcinostatic) activity against Ehrlich ascites tumor cells implanted in mice. The current studies investigated the in vivo toxicity associated with the acrolein-GSH adduct in the male Sprague-Dawley rat. The 1:1 acrolein-GSH adduct was synthesized and characterized by physical-chemical methods. Rats given the acrolein-GSH adduct intravenously at 0.5 or 1 mmol/kg developed nephrotoxicity characterized by glucosuria, proteinuria, elevation in serum urea nitrogen, and gross and histologic changes of the kidney. The toxicity was not affected by pretreatment of rats with pyrazole, an alcohol dehydrogenase inhibitor; disulfiram, an inhibitor of aldehyde dehydrogenases; or probenecid, a renal organic anion transport inhibitor. Administration of a similar but nonaldehydic glutathione conjugate, S-n-propylglutathione, did not result in nephrotoxicity in the rat. The nephrotoxicity induced by the acrolein-GSH adduct was inhibited by acivicin, a gamma-glutamyl-transpeptidase inhibitor. These results indicate that the acrolein-GSH adduct requires processing through the first step of the renal mercapturic acid synthesis pathway to be activated to a toxic species.
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PMID:Nephrotoxicity of the 1:1 acrolein-glutathione adduct in the rat. 147 Nov 52

Increased lipid peroxide levels were obtained 1 h after a 60-min 43 degrees C hyperthermia treatment of a solid murine C3H mammary adenocarcinoma, grown subcutaneously in the hind paws of mice. Previous work from our group revealed that this heat treatment depletes the intracellular glutathione (GSH) content in this tumor. To investigate GSH depletion as one tentative mechanism behind the increased lipid peroxide levels obtained, we also measured the formation of lipid peroxidation products after extensive DL-buthionine-S,R-sulfoximine (BSO)-induced GSH depletion. The lipid peroxide effect provoked by BSO was less than that of the 60-min hyperthermia treatment. We therefore propose that the increased lipid peroxide levels induced by heat treatment do not correlate primarily with the observed decrease in GSH levels. Furthermore, in thermotolerance-induced tumors, lipid peroxide levels after a second heat treatment were observed to increase concomitantly with the cessation of thermotolerance. Lipid peroxide levels were also studied in liver, lung, and heart. Following BSO treatments, and up to 2-fold increase was observed in these organs in non-tumor-bearing mice. It was also observed that the intrinsic lipid peroxide levels in these organs from tumor-bearing mice were approximately 1.5- to 4-fold higher in comparison with non-tumor-bearing mice, thus indicating a systemic effect of the tumor implant.
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PMID:Lipid peroxide levels in a murine adenocarcinoma exposed to hyperthermia: the role of glutathione depletion. 147 52

We examined the relationship between intracellular levels of glutathione (GSH), glutathione-S-transferase (GST) activity, and the kinetics of DNA cross-links induced by the bifunctional alkylating drugs melphalan (MLN), chlorambucil (CLB), and mechlorethamine (HN2) in a rat mammary carcinoma cell line (WT) and in a subline selected in vitro for primary resistance to MLN (MLNr, 16-fold resistance). MLNr cells exhibit a 2-fold increase in intracellular GSH concentration and an approximately 5-fold increase in GST activity as compared with the parent cells. They are cross-resistant to a variety of drugs, including CLB (6-fold) and HN2 (14-fold). Treatment of WT cells with 30 microM MLN or CLB induced a significant accumulation of DNA-DNA cross-links for up to 8 h, which decreased over a 24-h period. In MLNr cells, no significant cross-link formation was induced by either MLN of CLB at any time between 0 and 24 h. Doses of up to 100 microM MLN failed to induce cross-links in MLNr cells. Formation of cross-links was observed immediately after treatment with HN2 in both cell lines and was followed by a subsequent decrease during a 24-h incubation in drug-free medium. At an equimolar concentration (30 microM), the numbers of HN2-induced cross-links were significantly lower in MLNr cells than in WT cells. However, treatment of MLNr cells with 60 microM HN2 resulted in cross-link levels similar to those obtained using 30 microM HN2 in WT cells. The 35% decrease in MLN accumulation observed in MLNr cells could not entirely explain the absence of cross-links, since thin-layer chromatographic analysis demonstrated that both cell lines accumulate a significant amount of MLN and metabolize it to the same extent. Significant amounts of MLN were also detected in nuclei isolated from WT and MLNr cells that had been treated with 30 microM [14C]-MLN. Intracellular depletion of GSH by a nontoxic concentration of L-buthionine-(S, R)-sulfoximine (BSO, 100 microM; about 70% GSH depletion) significantly sensitized MLNr cells to MLN and increased cross-link formation. A nontoxic concentration (50 microM) of ethacrynic acid (EA, an inhibitor of GST showing some specificity for Yc/Yp subunits) also sensitized MLNr cells to MLN and increased cross-link formation. Our data demonstrate that both EA and BSO are effective modulators of nitrogen mustard cytotoxicity in tumor cells resistant to alkylating drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Nitrogen mustard-DNA interaction in melphalan-resistant mammary carcinoma cells with elevated intracellular glutathione and glutathione-S-transferase activity. 150 71

The role of DT-diaphorase (DTD, EC 1.6.99.2) in the bioreductive activation of mitomycin C was examined using purified rat hepatic DTD. The formation of adducts with reduced glutathione (GSH), binding of [3H]mitomycin C to DNA, and mitomycin C-induced DNA interstrand cross-linking were used as indicators of bioactivation. Mitomycin C was metabolized by DTD in a pH-dependent manner with increasing amounts of metabolism observed as the pH was decreased from 7.8 to 5.8. The major metabolite observed during DTD-mediated reduction of mitomycin C was 2,7-diaminomitosene. GSH adduct formation, binding of [3H]mitomycin C and mitomycin C-induced DNA interstrand cross-linking were observed during DTD-mediated metabolism. In agreement with the pH dependence of metabolism, increased bioactivation was observed at lower pH values. Temporal studies and experiments using authentic material showed that 2,7-diaminomitosene could be further metabolized by DTD resulting in the formation of mitosene adducts with GSH. DNA cross-linking during either chemical (sodium borohydride) or enzymatic (DTD) mediated reduction of mitomycin C could be observed at pH 7.4, but it increased as the pH was decreased to 5.8, showing the critical role of pH in the cross-linking process. These data provide unequivocal evidence that the obligate two-electron reductase DTD can bioactivate mitomycin C to reactive species which can form adducts with GSH and DNA and induce DNA cross-linking. The use of mitomycin C may be a viable approach to the therapy of tumors high in DTD activity, particularly when combined with strategies to lower tumor pH.
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PMID:Bioreductive activation of mitomycin C by DT-diaphorase. 151 Sep 75

We have used an extensively characterized human glioma cell line in an athymic mouse model to evaluate new therapeutic approaches for human supratentorial high grade gliomas. The tumor, D-54MG, is a subline of a human anaplastic glioma. Eight days after homozygous nu/nu BALB/c athymic mice received intracranial (IC) injections of a tumor homogenate, the whole brain was irradiated with either single fractions of 4, 8, 9, and 12 Gy or twice daily fractions, separated by least 6 hr, of 2.28 Gy x 2 or 7.53 Gy x 2. To evaluate whether or not glutathione depletion influenced animal survival, animals at each dose level received either intraperitoneal (IP) buthionine sulfoximine (BSO) alone or I.P. BSO plus BSO in the drinking water. There was a stepwise prolongation of animal survival with increasing doses of external beam radiation. Mean survival in 9 of the 10 control groups (8-12 animals per group) ranged from 14.1 to 18.8 days. Mean survival ranged from 15.3 to 22.5 days at 4 Gy, 25 to 30 days at 8 Gy, 22.3 to 29.7 days at 9 Gy, and 32.9 to 33.6 days at 12 Gy single dose irradiation. At 2.28 Gy x 2 split dose irradiation mean survival was 29.3 days, for 7.53 Gy x 2 mean survival was over 47 days. The data for single fraction irradiation fit a linear regression line (r = 0.908) of mean animal survival = (1.22 [dose in Gy] + 16.7) days. Tumor GSH levels were decreased with all BSO dosing regimens tested. The most aggressive regimen (I.P. BSO+oral BSO for 5 days), reduced tumor GSH to 6.2% of control. Increased survival in irradiated glutathione depleted mice versus mice receiving radiation alone was not seen.
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PMID:The radiation dose-response relationship in a human glioma xenograft and an evaluation of the influence of glutathione depletion by buthionine sulfoximine. 151 45

We have synthesized two 2-nitroimidazole derivatives and evaluated their hypoxic radiosensitization properties. The first, a 4-fluorobenzylamine conjugate of 2-nitroimidazole (PK-110), was designed so that it could also be labeled with the F-18 and used for positron emission tomographic imaging of hypoxia. The second, the L-phenylalanine methyl ester conjugate of 2-nitroimidazole (PK-130), was designed in an attempt to exploit amino acid transport channels to enhance drug transport into the tumor. The effects of these drugs (and SR-2508, for comparison) in vitro on the aerobic and hypoxic radiosensitivity of Chinese hamster V79 cells were evaluated using clonogenic assays. PK-130 and PK-110 at 0.1 and 1.0 mM were more efficient hypoxic cell radiosensitizers than obtained with 1.0 mM SR-2508. Marginal aerobic radiosensitization was observed for 1.0 mM treatment with PK-130 and PK-110, however, no aerobic radiosensitization was observed at 0.1 mM. Glutathione (GSH) depletion (less than 5% of control levels) by L-buthionine sulfoximine (BSO) further enhanced the SER for both PK-130 and PK-110 at 0.1 mM to 3.2 +/- 0.63 and 2.4 +/- 0.16, respectively. The results of this study encourage the in vivo tumor radiosensitization evaluation of PK-130 and PK-110.
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PMID:4-Fluorobenzylamine and phenylalanine methyl ester conjugates of 2-nitroimidazole: evaluation as hypoxic cell radiosensitizers. 153 Dec 20

Three human colon tumor (HCT) cell lines, designated C, Moser and 116, exhibiting a gradation of resistance to chlorozotocin, a glucose-linked chloroethylnitrosourea (1-, 2.9-, and 5.8-fold respectively) were examined to assess the determinants of drug sensitivity. Although the O6-alkylguanine-DNA transferase content was relatively higher in the most resistant 116 cells than in the sensitive cell line C, its level in Moser cells did not correlate with the intermediate chlorozotocin sensitivity. Glutathione content in these tumor cell lines did not show a parallelism with drug resistance. The ethidium bromide fluorescence assay was used to quantitate the kinetics of DNA interstrand cross-link formation and its removal after drug exposure. The peak levels of DNA interstrand cross-links induced in HCT cells correlated with their resistance to chlorozotocin with cross-link indices of 0.03, 0.10 and 0.20, respectively, for 116, Moser and C cell lines. All three cell lines demonstrated DNA cross-link repair to different extents. While the smaller number of cross-links formed in resistant 116 and Moser cells were eliminated in a rapid phase of repair, the lesions formed at a much greater frequency in C cells remained largely unrepaired. These results draw attention to the role of increased DNA cross-link repair as a mechanism of nitrosourea resistance in the HCT cells studied.
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PMID:Formation and disappearance of DNA interstrand cross-links in human colon tumor cell lines with different levels of resistance to chlorozotocin. 153 92


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