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Biomedical subjects

G Belvedere

Publications and source records attributed to G Belvedere.

At least 19 recordsLinked to original sources
PubMed1996

In vitro and in vivo characterisation of low-resistant mouse reticulosarcoma (M5076) sublines obtained after pulse and continuous exposure to cisplatin.

In order to simulate drug resistance observed in the clinic, two cisplatin-resistant cell lines were produced from a murine ovarian reticulosarcoma, M5076 (M5), by pulse (M5/CDDP) and continuous (M5/CDDPc) treatment with cis-diamminedichloroplatinum(II)(CDDP). These cell lines showed a similar stable low level of resistance (approximately 3-fold) to CDDP and cross-resistance to carboplatin, iproplatin and the new alkylating agent tallimustine, but not to L-PAM (L-phenylalanine mustard) and BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea). Collateral sensitivity to two inhibitors of topoisomerase II, VP16 (etoposide) and doxorubicin (Dox), but cross-resistance to the topoisomerase I inhibitor, camptothecin, were observed. The two cell lines were also sensitive to 5-fluorouracil. No increase in the level of glutathione or activity of glutathione S-transferase could be observed in resistant cells compared with the parental M5 cells. Total DNA platination immediately after treatment was similar in the parental and resistant cell lines. Repair of total DNA platination, measured after 24 h of recovery, was undetectable in M5 and M5/CDDP cells, but was 33% in M5/ CDDPc cells. Initial DNA-interstrand cross-links (DNA-ISC) were six times higher in M5 than in M5/CDDP cells, but 24 h after treatment, both lines had completely repaired this damage. M5/ CDDPc cells did not show formation of DNA-ISC at any time after treatment. The two resistant cell lines were tumorigenic when implanted in mice and resistant to CDDP treatment in vivo. The CDDP resistant tumours were not cross-resistant in vivo to L-PAM, BCNU and Dox, which had been active in vitro, nor to tallimustine, which had been cross-resistant in vitro. Mechanisms of resistance in M5/CDDP and M5-CDDPc seem to be based on a lower formation of DNA-ISC combined, for the latter cell line, with a higher repair capacity for total DNA platination.

Animals↗
PubMed1994

L1210 cells selected for resistance to methoxymorpholinyl doxorubicin appear specifically resistant to this class of morpholinyl derivatives.

We investigated the mechanism of resistance in murine L1210 leukaemia cells selected after treatment with FCE 23762 methoxymorpholinyl doxorubicin: (MMRDX), a methoxymorpholinyl derivative of doxorubicin active in vitro and in vivo on multidrug-resistant (mdr) cells, currently undergoing phase I clinical trials. The resistant subline obtained after repeated in vitro treatments, L1210/MMRDX, is resistant in vitro and in vivo to all tested methoxymorpholinyl derivatives and to cyanomorpholinyl doxorubicin, but shows resistance to morpholinyl derivatives only in vivo or following their activation with rat S9-liver fractions in vitro. L1210/MMRDX cells are sensitive to classic mdr- and altered topoisomerase (AT)-mdr-associated drugs. These cells do not appear to overexpress the mdr1 gene, nor do they exhibit impaired intracellular drug accumulation and efflux or altered levels of glutathione and glutathione S-transferase. The extent of DNA single-strand break formation and, after microsomal activation, of DNA interstrand cross-links after treatment with MMRDX was similar in the parent and the resistant subline. The mechanism of resistance in L1210/MMRDX cells remains to be identified but may prove a novel one, highly specific for this class of mdr-active anthracyclines.

Animals↗
PubMed1993

Studies on low-level MDR cells.

Acquired or spontaneous resistance is a major clinical problem in the treatment of cancer. Low levels of MDR gene expression or P-glycoprotein have been correlated with a high level of drug resistance in vitro and a poor response to chemotherapy in some tumors. A strong correlation between MDR mRNA, P-glycoprotein levels and degree of drug resistance has not been found in several resistant model tumor cell lines. In some cell lines at low and high level of resistance different mechanisms seem to be involved.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

DNA damage and cytotoxicity of mitoxantrone and doxorubicin in doxorubicin-sensitive and -resistant human colon carcinoma cells.

The effects of mitoxantrone (Mx) and doxorubicin (Dx) on cytotoxicity and DNA damage as assayed by alkaline elution were studied in two human colon adenocarcinoma cell lines sensitive (LoVo) and resistant (LoVo/Dx) to doxorubicin. Mx was more cytotoxic than Dx to LoVo cells and was partially cross-resistant in LoVo/Dx. In LoVo cells, Mx produced about 5 times more DNA single-strand breaks (DNA-SSB) than Dx, but both drugs caused an equal number of DNA double-strand breaks (DNA-DSB). In LoVo/Dx cells, the number of DNA-DSB was very low for both Dx and Mx, but DNA-SSB were about 20 times higher for Mx. In LoVo cells, the number of DNA-DSB and protein-associated SSB were similar at equitoxic concentrations. For LoVo/Dx, the partial cross-resistance of Mx might be explained by the much higher number of DNA-SSB produced by this drug.

Colonic Neoplasms↗
PubMed1989

Comparison of intracellular drug retention, DNA damage and cytotoxicity of derivatives of doxorubicin and daunorubicin in a human colon adenocarcinoma cell line (LoVo).

Formation of DNA single strand breaks (SSB) was assayed by alkaline elution in LoVo cells treated with doxorubicin, daunorubicin and six derivatives of these drugs modified either in the chromophore or the sugar. Seven compounds showed a biphasic relationship (initial increase and then a decrease) for the formation of DNA-SSB over the concentration range 0.05-10 micrograms/ml. At a drug concentration in the range causing an increase of DNA damage very fast repair of DNA-SSB was observed for 4'-deoxydoxorubicin and 4-demethoxydaunorubicin; the kinetics of DNA-SSB investigated after drug removal at a drug concentration reducing DNA-SSB showed a time dependent increase of DNA damage for both drugs although with different patterns. 4'-Deoxydoxorubicin reduced the effect of radiations on the rate of elution of DNA in a way resembling the formation of DNA interstrand cross links (ISC) at concentrations at which DNA-SSB were reduced. DNA-ISC were not produced by chemical reactions occurring during sample processing for alkaline elution and this derivative was not metabolized by LoVo cells. The IC50 of the anthracyclines were on a several log range, though for most of the derivatives the cytotoxicity curve showed a plateau at growth inhibition of about 15-30% at increasing intracellular drug levels. A relationship between DNA damage and cytotoxicity was observed only in a very small range of DNA-SSB. It is likely that the different effects of these anthracyclines on the formation of DNA-SSB depend on a qualitatively different interaction between drug-DNA and topoisomerase II when the drug concentration is raised.

Adenocarcinoma↗
PubMed1984

Erythrocyte-dependent metabolic activation of styrene and induction of sister chromatid exchange in cultured human lymphocytes.

Human erythrocytes can oxidize styrene to styrene-7,8-oxide in the absence of the co-factors required for metabolic reactions catalysed by the microsomal cytochrome P-450 system. This probably explains the increased incidence of sister chromatid exchanges (SCEs) that was detected in whole blood lymphocyte cultures from 11 male donors after treatment in vitro (48 h) with styrene (2 mM). Styrene-7,8-oxide (0.15 mM) also induced SCEs in these cultures. Styrene (0.5-4.0 mM) increased the incidence of SCEs only slightly in cultures of isolated lymphocytes (2 X 10(4) erythrocytes/ml), but had a clear dose-dependent effect in whole blood cultures (2-4 X 10(8) erythrocytes/ml). When erythrocytes were added to purified cultures, SCE incidence increased after treatment with styrene (2 mM). Cyclophosphamide elevated the incidence of SCEs almost equally efficiently in whole blood and in isolated lymphocytes. It is suggested that styrene induces SCEs after transformation to styrene-7,8-oxide by oxyhemoglobin in erythrocytes, whereas cyclophosphamide is activated by the lymphocytes themselves.

Biotransformation↗
PubMed1984

Effect of blood on styrene oxidation in perfused rat liver.

The oxidation of styrene to styrene oxide was studied in the isolated perfused rat liver in the presence and absence of blood at styrene concentrations of 2.5 and 50 mM. Erythrocytes contained in whole blood increased the levels of styrene glycol about 5 times after a short perfusion time with both concentrations. This increase was observed up to 1 h with 2.5 mM styrene. At both styrene concentrations styrene oxide was not detectable, either in the presence or absence of blood indicating that the liver was able completely to detoxify the styrene oxide produced by the mixed-function oxidases (MFO) and the oxyhemoglobin in the erythrocytes.

Animals↗
PubMed1984

Activation of styrene to styrene oxide in hepatocytes and subcellular fractions of rat liver.

The oxidation of styrene to styrene oxide and the hydration of this metabolite to styrene glycol was investigated in hepatocytes, 9000 x g supernatant (S9) and the microsomal fraction from rat liver. Similar amounts of free styrene oxide were found in microsomes, hepatocytes and S9. However, on the basis of the formation of styrene glycol and the depletion of glutathione (GSH), it appeared that hepatocytes were the most active system in the metabolism of styrene, followed by S9 and microsomes.

Animals↗
PubMed1984

Kinetics of caffeine metabolism in control and 3-methylcholanthrene induced rat liver microsomes.

The kinetics of formation of primary metabolites of caffeine (paraxanthine, theophylline, theobromine and 1,3,7-trimethyluric acid) was studied in control (CO) and 3-methylcholanthrene-induced (MC) rat liver microsomes. Vmax was similar but Km was 16 times lower for total caffeine metabolism in CO and MC microsomes, respectively. Similar behavior was observed in the formation of each metabolite. Single metabolites showed different degrees of induction at non-saturating concentrations of caffeine. Kinetics was non-linear in CO microsomes.

Animals↗
PubMed1983

Styrene oxidation to styrene oxide in human erythrocytes is catalyzed by oxyhemoglobin.

Oxygenated human erythrocytes catalyzed the oxidation of styrene to styrene oxide. This reaction was inhibited by CO but not by superoxide dismutase, catalase and scavengers of hydroxyl radicals. In partially deoxygenated erythrocytes styrene oxidation showed a linear relationship with the molar fraction of oxyhemoglobin. These data indicate that oxyhemoglobin and not free oxygen radicals are involved in styrene oxidation.

Carbon Monoxide↗
PubMed1983

Styrene oxidation to styrene oxide by hydroxyl radicals produced during reaction of xanthine with xanthine oxidase in the presence of Fe3+.

Styrene was oxidized to styrene oxide during reaction of xanthine (X) with xanthine oxidase (XO) in the presence of Fe3+. This reaction showed a dose-dependent requirement of iron and was inhibited by superoxide dismutase (SOD) and catalase, indicating that both the superoxide anion and H2O2 were essential. Styrene oxide production was inhibited by hydroxyl radical scavengers indicating that this reactive oxygen intermediate could be the proximal oxidant involved in styrene oxidation to styrene oxide.

Chemical Phenomena↗
PubMed1983

Styrene oxidation to styrene oxide coupled with arachidonic acid oxidation by soybean lipoxygenase.

Styrene was co-oxidated to styrene oxide during soybean lipoxygenase catalyzed formation of arachidonic acid lipid peroxides. Styrene oxidation showed linear dependence on the amount of enzyme and on arachidonic acid concentration, and saturation kinetics with styrene concentration. Styrene oxide formation was dependent on the lipid substrate used and was inhibited by antioxidants. Lipid peroxides appear to be able to support styrene oxidation when produced from rat liver microsomes.

Animals↗
PubMed1982

Ferrodoxin reductase catalyzes styrene oxidation to styrene oxide.

The flavoprotein ferredoxin reductase catalyzed the oxidation of styrene to styrene oxide in the presence of NADPH. This reaction was inhibited by the addition of catalase and superoxide dismutase. The addition of the nonheme iron protein ferredoxin partially inhibited styrene oxidation. H2O2 was also able to catalyze this reaction when added to the enzyme in the absence of NADPH.

Epoxy Compounds↗
PubMed1981

Induction of mixed-function oxidase by chronic treatment with 2,3,7,8-tetrachloro-dibenzo-p-dioxin in female rats.

The effect of a 45-week treatment with different doses of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) (0.01, 0.10 and 1.00 microgram/kg/week) was evaluated in female rat liver by determining cytochrome P-450 and b5 content and the activities of the enzymes cytochrome c reductase, aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase (7-ECD); TCDD content in the liver was also measured. Cytochrome b5 and cytochrome c reductase were unaffected at any of the dose levels and cytochrome P-450 was significantly induced only at the highest TCDD dose, but marked induction of AHH and 7-ECD was apparent when the animals were treated with 0.01 microgram/kg/week; a clear dose-response relationship was present in the induction at the 2 lower doses (0.01 and 0.10 microgram/kg/week). The amount of TCDD found in liver tissue (1050, 4740 and 30 700 ppt, respectively, for 0.01, 0.10 an 1.00 microgram/kg/week) indicated a relatively higher accumulation of this compound at lower doses.

Animals↗