Biomedical subjects

G Batist

Publications and source records attributed to G Batist.

At least 73 records · Page 4Linked to original sources

PubMed1993

In vivo reversal of doxorubicin resistance by a new tiapamil analog Ro11-2933.

The effectiveness of a calcium antagonist analog Ro11-2933 to modulate doxorubicin (DOX) response in DOX-sensitive (WT) and -resistant (DOXr, 200-fold) cell lines was investigated and compared to verapamil (VP) in vitro and in vivo in rats bearing mammary carcinoma using equivalent nontoxic doses. In vitro exposure to a nontoxic concentration of Ro11-2933 (2 microM) normalizes the DOX accumulation defect observed in DOXr cells, increases DOX-induced DNA single-strand breaks and effectively sensitizes DOXr cells to DOX. Ten microM VP was required to obtain an effect equivalent to that seen with 2 microM Ro11-2933. Intravenous administration of DOX at 5 mg/kg to the rat bearing the DOXr tumors has no significant therapeutic effect on tumor growth (P > .5), whereas it was found effective in inhibiting the growth of WT tumors (P < .05). Ro11-2933 or VP administered alone has no significant effect on tumor growth as compared to a saline-treated group (P > .1). Combination of Ro11-2933 with DOX effectively inhibits DOXr tumor growth as compared to DOX alone. Combination of DOX with VP was found less effective than Ro11-2933 and the results were not statistically significant from DOX treatment alone (P > .5). Our data demonstrate that Ro11-2933 is well tolerated after i.v. administration and an effective modulator of DOX resistance in a solid tumor model.

Animals↗

PubMed1992

Eradication of hepatic metastases of carcinoma H-59 by combination chemoimmunotherapy with liposomal muramyl tripeptide, 5-fluorouracil, and leucovorin.

We have investigated the effect of a combined chemoimmunotherapy protocol with liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE), 5-fluorouracil (5-FU), and 5-formyltetrahydrofolate (leucovorin) on the growth of hepatic metastases using carcinoma H-59, a liver-homing subline of the Lewis lung carcinoma (P. Brodt, Cancer Res., 46: 2442-2448, 1986). C57BL/6 mice inoculated with the tumor cells via the intrasplenic route received three i.v. injections of liposomal MTP-PE, the first of which was administered 3 days prior to tumor cell inoculation. Chemotherapy with 5-FU and leucovorin at the maximal tolerated doses (30 mg/kg per injection) was initiated immediately after tumor inoculation and continued on alternate days for a total of 4 injections. The incidence of liver metastases in animals which received the combined therapy was compared to that in animals treated with chemotherapy or immunotherapy alone. We found that while the number of liver metastases was reduced in all of the treatment groups as compared to control untreated or placebo-treated animals, the combined effect of 5-FU leucovorin and liposomal MTP-PE was significantly better than that of chemotherapy or immunotherapy alone. This was reflected in a reduced incidence (70% as compared to 100% in all other groups) and in a significant reduction in the number and size of the liver nodules. Our results suggest that the efficacy of 5-FU and leucovorin in the treatment of hepatic metastases could be significantly augmented by the addition of the liposome-encapsulated immunoadjuvant MTP-PE.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1992

Neoadjuvant chemotherapy with cytosine arabinoside by continuous infusion and cisplatin for resectable squamous cell carcinoma of the esophagus.

The combination of cisplatin and cytosine arabinoside has been shown in experimental models to be synergistic. We conducted a pilot study of cytosine arabinoside and cisplatin in unresectable or metastatic cancer of the esophagus in five patients and found significant activity, also on visceral metastasis. Therefore, we decided to examine this combination in the neoadjuvant setting. Since January 1989, eight patients with squamous cell carcinoma esophageal cancer were treated with two cycles of cytosine arabinoside (50 mg/m2) by continuous infusion for 4 days and by cisplatin (100 mg/m2) on the 5th day. Their ages ranged from 54-79 years. One patient had Stage I, three had Stage II, and four had Stage III disease. Responses assessed by endoscopy and computed tomographic (CT) scan prior to surgery were three with partial response, three with minor response, and two with no response. Only six patients were surgically resectable after chemotherapy. Toxicity consisted of grade 3 (one patient) and grade 4 (two patients) neutropenia, grade 3 (three patients) anemia, and grade 3 (two patients) and grade 4 (three patients) thrombocytopenia. All patients had subjective improvement of dysphagia 4 weeks after chemotherapy. Median survival of the whole group was 7.5 months. We concluded that there was no evidence of synergy of these drugs given in this manner in esophageal carcinoma since the response rate was no different from that achieved with cisplatin alone.

Aged↗

PubMed1992

Nitrogen mustard-DNA interaction in melphalan-resistant mammary carcinoma cells with elevated intracellular glutathione and glutathione-S-transferase activity.

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)

Animals↗

PubMed1992

Drug resistance in cultured rat liver epithelial cells spontaneously and chemically transformed.

Cultured rat liver epithelial cells (RLE) transformed with repeated treatments of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) demonstrate many features of the common biochemical phenotype of multidrug resistance (MDR) seen in vivo in 'resistant hepatocytes'. The cells have increased glutathione-S-transferase placental subunit (GST-Yp), gamma-glutamyltranspeptidase (GGT), glutathione (GSH) and glutathione peroxidase and are resistant to MNNG. Phenotypically identical RLE cells spontaneously transformed by selective culture conditions showed low levels of GGT and GST and were not resistant to MNNG. Both chemical and spontaneous transformants are cross resistant to doxorubicin although resistance is consistently greater in chemical transformants. No direct correlation was found between the degree of resistance to doxorubicin and MDR gene expression in either of the chemically or spontaneously transformed RLE cells. These observations suggest that in chemical carcinogenesis, other mechanisms of drug detoxification are involved and that MDR expression is not a consistent feature.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Glutathione S-transferase in chemotherapy resistance and in carcinogenesis.

Cytosolic glutathione S-transferases are composed of two monomeric subunits. These monomers are the products of different gene families designated alpha, mu, and pi. Dimerization yields either homodimeric or heterodimeric holoenzymes within the same family. The members of this complex group of proteins have been linked to the detoxification of environmental chemicals and carcinogens, and have been shown to be overexpressed in normal and tumor cells following exposure to cytotoxic drugs. They also are overexpressed in carcinogen-induced rat liver preneoplastic nodules in rat liver. In all of these cases, the changes in expression of glutathione S-transferases are paralleled by increased resistance to cytotoxic chemicals. The degree of resistance is related to the substrate specificity of the isozyme. The relationship of the glutathione S-transferase genes to drug resistance has been directly demonstrated by gene transfer studies, where cDNAs encoding the various subunits of glutathione S-transferase have been transfected into a variety of cell types. This review discusses the results of numerous studies that associate resistance to alkylating agents with overexpression of protective detoxifying glutathione S-transferase enzymes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Radiation-induced damage to DNA in drug- and radiation-resistant sublines of a human breast cancer cell line.

An Adriamycin-resistant subline of a human breast cancer cell line, MCF-7 ADRR, has been shown to exhibit radioresistance associated with an increase in the size of the shoulder on the radiation survival curve. In the present study, damage to DNA of MCF-7 sublines WT and ADRR by 60Co gamma radiation was measured by filter elution techniques. The initial amount of DNA damage, measured by both alkaline and neutral filter elution, was lower in ADRR cells, suggesting that these cells are resistant to radiation-induced single- and double-strand DNA breaks. In the case of double-strand breaks the difference between WT and ADRR cells was significant only at the lower radiation doses studied (up to 100 Gy). In cells depleted of glutathione (GSH) by L-buthionine sulfoximine (BSO) treatment, ADRR cells were sensitized to radiation-induced DNA damage, while WT cells were unaffected. The rate of repair of single- and double-strand DNA breaks following radiation was the same for both sublines, and repair of radiation damage was not affected by BSO treatment in either cell line. The relative resistance of ADRR cells to initial DNA damage by radiation is the only difference so far detected at the molecular level which reflects radiation survival, and it is possible that other factors are involved in the resistance of ADRR cells to killing by radiation. Sensitization of ADRR cells to radiation-induced DNA damage by GSH depletion, although not likely to involve inhibition of GSH-dependent detoxification enzymes per se (irradiation was done at 4 degrees C), suggests that at the molecular level radioresponse in this subline is related to maintenance of GSH/GSSG redox equilibrium.

Breast Neoplasms↗

PubMed1991

Whey proteins in cancer prevention.

Epidemiological and experimental studies suggest that dietary milk products may exert an inhibitory effect on the development of several types of tumors. Some recent experiments in rodents indicate that the antitumor activity of the dairy products is in the protein fraction and more specifically in the whey protein component of milk. We and others have demonstrated that whey protein diets result in increased glutathione (GSH) concentration in a number of tissues, and that some of the beneficial effects of whey protein intake are abrogated by inhibition of GSH synthesis. Whey protein is particularly rich in substrates for GSH synthesis. We suggest that whey protein may be exerting its effect on carcinogenesis by enhancing GSH concentration.

Animals↗

PubMed1991

In vivo and in vitro mechanisms of drug resistance in a rat mammary carcinoma model.

Many in vitro tumor models have been examined to help understand the precise mechanisms responsible for drug resistance. The importance of these results in vivo remains uncertain. MatB 13762 is a rat mammary adenocarcinoma cell line that can be grown both in vitro and as a solid tumor in Fischer 344 rats, thus permitting the examination of tumor cell drug resistance under both conditions. Two cell lines have been selected in vitro for resistance to Adriamycin (AdrR) and melphalan (MlnR), respectively. Each subline has the following features: AdrR, increased mdr-1 messenger RNA, a high level of cross-resistance to vincristine and atypical low level resistance to melphalan and 1,3-bis(2-chloroethyl)-1-nitrosourea, decreased cellular glutathione content, and increased expression of Yc and Yp glutathione S-transferase isozymes; MlnR, low level drug resistance to melphalan and cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea, Adriamycin, and vincristine; increased cellular concentration of glutathione; elevated glutathione S-transferase activity; and greatly increased messenger RNA specific to the Yc and Yp glutathione-S-transferase subunits. Most of the biochemical and molecular features described above are present but significantly less prominent in tumors grown in vivo. This model provides the opportunity to examine the magnitude of expression and the clinical significance of in vitro resistance in an in vivo model.

Animals↗

PubMed1991

Glutathione depletion in human and in rat multi-drug resistant breast cancer cell lines.

The effects of GSH depletion in a human breast cancer cell line and a multi-drug resistant subline (ADRr) were determined in a number of experimental conditions. The ADRr cells contained lower GSH concentration which cannot be explained solely on the basis of differences in cell kinetics, and yet the rate-limiting synthetic enzyme gamma-glutamylcysteine synthetase was increased 2-fold. Inhibition of GSH synthesis by BSO resulted in more rapid and more pronounced GSH depletion in ADRr compared to the wild-type cells, suggesting that enhanced GSH utilization and efflux in the resistant cells account for the lowered basal concentration. In addition, the gamma-glutamyl moiety salvage enzyme gamma-glutamyltranspeptidase was reduced markedly in the ADRr cell line. Since these cells have overexpression of the efflux pump protein P-glycoprotein, we examined the effects on cellular GSH of inhibition of the pump's function by verapamil. We found that verapamil significantly depleted cellular GSH. In a rat mammary carcinoma cell line selected in Adriamycin for multi-drug resistance, a similar molecular phenotype has been described including diminished cellular GSH concentration. Verapamil treatment of these cells also resulted in significant depletion of cellular GSH. These results are consistent with the recent report that combined treatment of BSO and verapamil has an additive effect on cytotoxicity. It is likely that decreased basal GSH concentration is due to oxidation and conjugation of it in reactions catalyzed by the enhanced peroxidase and GST found in these cells.

Animals↗

PubMed1991

Effect of proliferative state on glutathione S-transferase isoenzyme expression in cultured rat liver epithelial cells.

A specific biochemical phenotype is expressed during chemical hepatocarcinogenesis, which includes increased activity of the various isoenzyme forms of glutathione S-transferase (GST) composed of class alpha (Ya/Yc), class mu (Yb) and class pi (Yp) gene products. In vitro cell lines of normal and chemically transformed rat liver epithelial cells provide an opportunity to examine the regulation of expression of GST isoenzymes. We have studied the effect of the state of proliferation in culture on both the enzymic activity and the isoenzyme-specific mRNA expression. In normal rat liver epithelial cells (WB-F344), basal expression of the Yp subunit decreases, and of the Yb subunit increases, in cells at confluence compared with those in logarithmic-phase growth. In a subline of WB-F344 cells that has been chemically treated in vitro (GN6), there was greater Yp expression; however, the effect of growth status on both subunits was the same as in the nontransformed WB-344 cells, and the Ya subunit was not expressed. Inhibition of RNA synthesis with actinomycin D was limited, demonstrating pronged half-lives of the GST mRNAs, and shows a slightly greater decrease in GST-Yp specific mRNA levels in the confluent cells. Also nuclear run-off experiments demonstrate identical transcription rate in confluent and pre-confluent cells. These data suggest that the increase in Yp steady-state RNA in preconfluent cells is due to increased stability of the GST-Yp mRNA. In tumor cells derived from GN6 cells, the regulatory effects of growth status on the Yb and Yp expressions were absent. However, in these cells Ya subunit was expressed and this was subject to the effects of cell proliferation. We conclude that the growth status of cells in culture exerts a significant regulatory control on the GST isoenzyme gene expression. The effects are probably mediated at independent regulatory sites in each gene. The state of transformation of rat liver epithelial cells may determine responsiveness to this effect.

Animals↗

PubMed1990

Phenotypic expression in spontaneously transformed cultured rat liver epithelial cells.

Five clonal cell strains of an early-passage normal rat liver epithelial cell line were transformed spontaneously using the protocol of "selective culture" condition. Twelve cell lines were established from the tumors produced after injecting these transformed cells into 1-day-old syngeneic rats. The phenotypic expressions of these spontaneously transformed tumor cell lines were studied and compared to those of cell lines obtained from tumors produced by rat liver epithelial cells transformed by N-methyl-N'-nitro-N-nitrosoguanidine. Like the chemically induced tumor cells, spontaneously transformed tumor cells exhibited phenotypic heterogeneity in the expression of isoenzymes, proto-oncogenes, growth factors and their receptors, and cellular responses to the effect of growth factors. However, unlike the chemically induced tumor cells, these spontaneously induced tumor cells did not express the "resistant phenotypes" characteristic of chemically induced or promoted tumors. Although all the spontaneously induced tumor cell lines expressed variable amounts of transforming growth factor-alpha mRNA, it was not functionally coordinated with the expression of its receptor, the epidermal growth factor receptor. Thus, spontaneously transformed rat liver epithelial cells demonstrate both similarity and diversity in their phenotypic expression when compared to their chemically induced counterpart. This model of spontaneous transformation of cultured rat liver epithelial cells may be useful for the mechanistic study of non-chemically induced carcinogenesis.

Animals↗

PubMed1990

A phase II trial of carboplatin (CBDCA) in small-cell and non-small-cell lung cancer with correlation to in vitro analysis of cytotoxicity.

A Phase II trial of carboplatin (CBDCA) was performed in 33 patients with advanced lung cancer, including 15 patients with inoperable Stage III non-small-cell (NSCLC) and 18 patients with relapsed small-cell (SCLC) lung cancer. Initial dosage was 320 mg/m2 infused over 24 h; in the absence of hematologic toxicity, subsequent doses were escalated to 400 mg/m2. Patients received a median of two cycles (range 1-13 for NSCLC and 1-5 for SCLC) of therapy. There were no complete or partial responses among the NSCLC patients. Among the SCLC patients, two had a partial response. In vitro analysis of the cytotoxicity of CBDCA and its parent compound cisplatin by two different methods for 20 NSCLC cell lines suggested that equivalent tumor cell kill is achieved by the two compounds, but this occurs at a log lower concentration of cisplatin than of CBDCA. The in vitro cytotoxicity against NSCLC of CBDCA at a concentration predicted to be in the range produced by the dose employed in this Phase II study correlated well with the resulting very modest in vivo benefit. In vitro, a continuous dose-response relationship exists for CBDCA, suggesting that if higher doses could be administered safely to patients, greater clinical benefit might occur. We conclude that single agent CBDCA in the dosage and schedule administered has less than 20% activity (95% confidence intervals 0-19%) in NSCLC and an 11% response rate in SCLC (95% confidence intervals 2-34%). Despite this outcome, in vitro data in human NSCLC cell lines suggest higher dosages should perhaps be evaluated before discounting a role for CBDCA in the management of NSCLC.

Adult↗

PubMed1990

Radiation response of drug-resistant variants of a human breast cancer cell line: the effect of glutathione depletion.

Two drug-resistant variants of the human breast cancer cell line MCF-7 have been shown previously to exhibit radiation resistance associated with an increase in the size of the shoulder on the radiation survival curve. In the present study, glutathione (GSH) depletion was achieved by exposure of cells to buthionine sulfoximine (BSO) with, in some cases, additional treatment with dimethyl fumarate. Levels of GSH in the adriamycin-resistant subline MCF-7 ADRR are initially lower than in the other two sublines and are depleted to a greater extent by exposure to BSO. Wild-type MCF-7 cells are not sensitized by GSH depletion when irradiated under aerated conditions but are sensitized under hypoxic conditions to an extent which is related to the level of GSH depletion. In contrast both the drug-resistant sublines (MCF-7 ADRR and the melphalan-resistant line MCF-7 MLNR) are radiosensitized by GSH depletion under both aerated and hypoxic conditions. It is hypothesized that in the case of the MCF-7 ADRR cell line, which expresses high levels of the GSH-associated redox enzyme systems, GSH-S-transferase and GSH-peroxidase (GSH-Px), radiosensitization results when GSH-Px is inhibited in GSH-depleted cells. The reasons for radiosensitization of aerated MCF-7 MLNR cells cannot be explained on this basis, however, and other factors are being examined.

Antineoplastic Agents↗

PubMed1990

Mechanisms of resistance to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) in sensitive and resistant human glioma cells.

Resistance to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU), an experimental antitumor compound, was investigated in the sensitive SK-MG-1 cells and the 20-fold more resistant SKI-1 human glioma cells [which are 3-fold more resistant to 1,3,bis(2-chloroethyl)-1-nitrosourea (BCNU)]. The transport of SarCNU was examined by utilizing tritiated sarcosinamide. Sarcosinamide uptake into SK-MG-1 cells is via the catecholamine carrier that accommodates epinephrine. Dixon plot analysis of SarCNU inhibition of sarcosinamide uptake reveals that SarCNU is also accommodated by this carrier. The uptake of 0.5 mM [3H]sarcosinamide was temperature dependent, with similar levels of intracellular sarcosinamide accumulating at steady state in both cell lines. The uptake of sarcosinamide in SKI-1 cells obeyed Michaelis-Menten kinetics over a 200-fold range of concentrations with a Km of 1.52 +/- 0.151 mM and Vmax of 0.659 +/- 0.066 nmol/10(6) cells/min. This represents a more than 5-fold decrease in the uptake affinity and a more than 4-fold increase in the transport capacity compared with SK-MG-1 cells (Km = 0.282 +/- 0.041 mM; Vmax = 0.154 +/- 0.024 nmol/10(6) cells/min). The initial rate of sarcosinamide uptake is similar in both cell lines. Dixon plot analysis confirmed that SarCNU is a competitive inhibitor of sarcosinamide transport in SKI-1 cells with a Ki of 17.5 mM, which is more than 5-fold greater than the Ki obtained in SK-MG-1 cells. The steady state accumulation of SarCNU is significantly reduced by 47% in SKI-1 cells compared with the SK-MG-1 cells (cell to medium ratios of 0.65 +/- 0.11 and 1.22 +/- 0.08, respectively) (p less than 0.005). The accumulation of BCNU was comparable in the two cell lines. Since the Vmax of sarcosinamide (SarCNU) uptake is increased in the SKI-1 cells, the decrease in intracellular SarCNU is not related to decreased drug influx via the catecholamine carrier in SKI-1 cells. The efflux of tritiated sarcosinamide was temperature dependent and similar in both cell lines, with 54 and 58% of sarcosinamide being freely exchangeable in SKI-1 and SK-MG-1 cells, respectively. SarCNU efflux may or may not be altered. Since the expression of mdr is higher in the sensitive cells, it is unlikely that increased efflux of SarCNU mediated by the P-glycoprotein is responsible for drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyltransferases↗

PubMed1989

Implications for therapy of drug-metabolizing enzymes in human colon cancer.

Human colonic tissue is exposed to a variety of toxic chemicals and potential carcinogens in the diet and the intestinal microenvironment. Colonic adenocarcinoma is commonly resistant to the cytotoxic effects of most chemotherapeutic drugs. We have examined drug metabolic and detoxification pathways in clinical specimens of colon carcinoma and normal adjacent mucosa from 17 patients. All elements of xenobiotic metabolism examined are present in these tissues, including cytochrome P-450-dependent enzymes, glutathione, and glutathione-utilizing enzymes. In comparison of tumor tissue to its respective normal mucosa specific alterations in the pathways affecting a number of chemotherapeutic agents were detected, including significantly higher glutathione, glutathione peroxidase, and anionic glutathione-S-transferase activity. These and other alterations found here could be the target of therapeutic maneuvers to enhance the efficacy of antineoplastic treatment of human colon cancer.

Adenocarcinoma↗

PubMed1989

Glutathione and glutathione S-transferases in clones of cultured rat liver epithelial cells that express varying activity of gamma-glutamyl transpeptidase.

In rat chemical hepatocarcinogenesis models, the hepatocytes in the preneoplastic/neoplastic nodules characteristically demonstrate common biochemical changes including significant and often marked elevation in the cellular glutathione (GSH) content and in the activities of the enzymes gamma-glutamyl transpeptidase (GGT) and glutathione S-transferase (GST). Such consistent and concomitant biochemical changes may signify a common regulatory mechanism in the expression of these enzymes. We have utilized a panel of clonally derived rat liver epithelial cell lines that express varying activities of GGT to study the quantitative correlation between these three cellular components of the phase II drug metabolizing enzyme system. The results indicate that in confluent cultures, cells with high GGT activities have significantly higher cellular GSH content, and a linear correlation exists between the glutathione content and the logarithm of the GGT activity. In contrast, the basal activities of GST and GGT were not coordinately regulated. However, most of the chemical carcinogen-treated cell lines, regardless of their GGT activity, expressed higher GST activity than the normal parental rat liver epithelial cells. The basal expressions of both the Yb and Yp subunits of GST were also not correlated with the relative expression of GGT. Since GGT may play an important role in supplying the cells with the basic constituents for the synthesis of GSH and since GSH is an important cellular molecule in the protection of cells from toxic electrophiles, enhancement of GGT activity in preneoplastic/neoplastic nodules of chemical carcinogen-treated rats may represent a necessary biochemical adaptation for the induction of the "resistant" phenotype of these hepatocytes.

Animals↗

PubMed1989

Biochemical characteristics of mouse mammary tissues, preneoplastic lesions and tumors.

A number of metabolizing systems are measured in normal, preneoplastic and neoplastic mouse mammary tissues derived under three different conditions. These biochemical functions are considered to be important in the activation and detoxification of carcinogens and other xenobiotics and have been linked to the process of rat liver hepatocarcinogenesis. The cytochrome P450-dependent enzyme aminopyrine N-demethylase, consistently depressed in hepatocarcinogenesis models in mouse and rat, does not show a significant change among normal, preneoplastic and neoplastic mammary tissues. Glutathione and the enzymes of glutathione metabolism and utilization (e.g. glutathione-S-transferases and gamma-glutamyl transferase), active in the detoxification of xenobiotics, show no significant differences in carcinogen-induced tumors or in their homologous preneoplasias compared to control tissue. There is no increase in the anionic glutathione-S-transferase, a principal marker in rat hepatocarcinogenesis. The only observed biochemical change was a significant decrease in gamma-glutamyl cysteine synthetase the glutathione synthetic enzyme, in the carcinogen-induced preneoplastic and neoplastic line compared to control. Also inorganic glutathione peroxidase was lower in the preneoplastic, but not in the neoplastic tissues.

Aminopyrine N-Demethylase↗