Effects of cancer disease on the metabolism of anticancer agents.
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Animals↗
Biomedical subjects
P Ghezzi
Publications and source records attributed to P Ghezzi.
Depression of liver drug metabolism and increase in plasma fibrinogen by interleukin 1 and tumor necrosis factor: a comparison with lymphotoxin and interferon.
Different recombinant cytokines were studied for their effects on mouse liver in vivo: interleukin 1-alpha and -beta, tumor necrosis factor, lymphotoxin, interferon-alpha A/D and gamma depressed liver cytochrome P450-dependent drug metabolism (measured by ethoxycoumarin deethylase activity) 24 h after treatment, at doses in the microgram range, while IL-2 had no effect on this enzymatic system. Interleukin 1 (both alpha and beta), tumor necrosis factor and lymphotoxin also increased plasma fibrinogen, a marker of liver acute phase inflammatory response. Interferon-gamma and tumor necrosis factor had an additive effect in depressing liver drug metabolism. When tested in vitro on isolated hepatocytes, only interleukin 1 depressed P450-dependent drug metabolism, while all the other cytokines were inactive, thus suggesting that their effect on the liver in vivo is not a direct effect but is mediated by other mediators.
7-Alkoxycoumarin O-Dealkylase↗
Depression of liver drug metabolism in sarcoma-bearing mice. Evidence for a circulating factor and dissociation from lipolytic activity.
Mice bearing the S-180 sarcoma displayed a depression of liver catalase and cytochrome P-450-dependent enzymes (ethoxycoumarin deethylase, ED) from day 6 following tumor implantation. Injection of serum obtained from tumor-bearing mice into normal mice caused depression of liver ED suggesting that a circulating factor was involved. Tumor-bearing mice did not show any significant change in serum triglycerides and food intake. By contrast, injection of endotoxin, interleukin-1 (IL-1) or tumor necrosis factor (TNF) caused not only a depression in liver ED but also a marked increase in serum triglycerides. To study the possible analogies between cancer-associated circulating factor and monokines, we studied the effect of dexamethasone (a known inhibitor of monokine synthesis) on liver ED activity in tumor-bearing mice. Dexamethasone (DEX) treatment increased (up to 60%) liver ED activity in tumor-bearing mice. We conclude that: (i) a circulating factor is involved in cancer-associated ED depression; (ii) that this mediator is not necessarily identical to TNF or IL-1 and (iii) that DEX reverses the depression of liver ED in cancer, possibly by inhibiting the synthesis, or the effects, of this factor.
7-Alkoxycoumarin O-Dealkylase↗
Recombinant tumor necrosis factor reduces hepatic drug metabolism in vivo in the rat.
To verify the potential in vivo inhibitory effect on liver function of tumor necrosis factor (TNF), also known as cachectin, antipyrine and diazepam were chosen to probe the hepatic mixed-function oxidase system. A single dose of TNF (30 micrograms/kg) to rats significantly reduced the plasma clearance of antipyrine and diazepam by about 30% and 25%, respectively; this resulted in concomitant prolongation of the elimination half-life (t1/2) of the two drugs, although of borderline significance for the benzodiazepine. This was probably due to a decrease in hepatic cytochrome P-450 activities that are responsible for antipyrine and diazepam metabolism in TNF-treated rats. This could be of clinical relevance if a similar effect occurs in humans after therapeutically effective doses of this biological response modifier.
Animals↗
Dexamethasone modulation of LPS, IL-1, and TNF stimulated serum amyloid A synthesis in mice.
Three secretory products of the macrophage, interleukin 1 (IL-1), tumor necrosis factor/cachectin (TNF) and hepatocyte stimulating factor/interleukin 6 (IL-6) modulate liver protein synthesis during the acute phase response. Induction of serum amyloid A (SAA) synthesis is one of the most notable acute phase changes in liver proteins, with maximal SAA concentrations varying over a thousand-fold range in proportion to the amount of tissue injury and cell necrosis. Exogenous IL-1 and TNF induce SAA synthesis in vivo and in vitro, while exogenous IL-6 is a far less potent stimulus of in vivo SAA gene expression. Dexamethasone (DEX), a potent inhibitor of macrophage IL-1, TNF and IL-6 synthesis, was utilized to analyze the endogenous mediators of SAA synthesis in mice injected with lipopolysaccharide (LPS). DEX, although itself exhibiting the capacity to stimulate SAA synthesis to a limited extent, significantly reduced LPS induced SAA production. However, DEX did not reduce, but rather potentiated, IL-1 and TNF stimulated SAA production, indicating that these monokines do not require macrophage products to mediate their in vivo SAA inducer activity. SAA synthesis was observed in adrenalectomized mice, following administration of LPS, IL-1 and TNF, indicating that SAA induction by monokines is not secondary to corticosteroid release.
Animals↗
Enhancement of in vivo immune response by tumor necrosis factor.
Interleukin 1 (IL-1) has been shown to regulate several immunologic functions. Since tumor necrosis factor (TNF) shares many biologic properties with IL-1, we have investigated here the role of TNF in the modulation of the immune response. We have thus tested low doses of human recombinant TNF-alpha (hu rTNF-alpha) for its capacity to enhance the in vivo antibody responses evaluated at the cellular level in the hemolytic plaque assay. It was found that hu rTNF-alpha, like human IL-1 beta, is able to enhance the immune response to a T cell-dependent antigen (sheep red blood cells). Interestingly, at variance with human recombinant IL-1 beta, hu rTNF-alpha was not able to enhance the in vivo antibody response to a T cell-independent antigen (type III pneumococcal polysaccharide). These results suggest that low levels of TNF may have a role in the modulation of the immune response in vivo and shed new light on the biologic significance of this mediator.
Animals↗
Chemotactic factor and P15E-related chemotaxis inhibitor in human melanoma cell lines with different macrophage content and tumorigenicity in nude mice.
The present study was designed to characterize the production of chemoattractants by human melanoma lines with high (M4Be, M3Da, NTerDa) or low tumorigenic (Doc8, M1Do) potential when heterotransplanted in nude mice. Supernatants from the Doc8 and M1Do cell lines were strongly chemotactic in vitro for mononuclear phagocytes. Chemotactic activity was destroyed by proteolytic enzymes, and upon gel filtration on Sephadex G75, it eluted in the cytochrome c region corresponding to an apparent m.w. of 12,000. Upon chromatofocusing, the Sephadex-separated tumor-derived chemotactic factor (TDCF) showed an isoelectric point of 5.5 to 6. Cell lines with high tumorigenic potential contained low or no detectable chemotactic activity. When culture supernatants of cell lines with modest (M3Da) or no (M4Be) chemotactic activity were exposed to immobilized monoclonal antibodies directed against the retroviral transmembrane protein P15E, appreciable chemotactic activity was detectable (M4Be) or preexisting levels increased (M3Da). The material eluted from Sepharose-bound anti-P15E antibodies inhibited the migration of monocytes in response to chemoattractants. These findings demonstrate the coexistence in some human melanoma cell line supernatants of factors (TDCF and P15E-related inhibitor) with opposite influence on monocyte chemotaxis. That tumor cell products play a pivotal role in regulating the extravasation of monocytes into neoplastic tissues is suggested by the close correlation observed between macrophage levels in melanomas grown in nude mice and levels of chemotactic activity detectable in culture supernatants.
Animals↗
Defective production of reactive oxygen intermediates by tumor-associated macrophages exposed to phorbol ester.
Macrophages were isolated from poorly immunogenic metastatic sarcomas (mFS6 and MN/MCA1) of C57BL/6 origin. Tumor-associated macrophages (TAM) showed little release of superoxide when exposed to phorbol myristate acetate. When exposed to a phagocytic stimulus (zymosan), TAM released appreciable amounts of superoxide. TAM had a lower number of specific binding sites for phorbol esters than resident or caseinate-elicited peritoneal macrophages, but had normal NADPH-cytochrome C reductase. The tumor environment, possibly through previously demonstrated products of neoplastic cells, may influence the functional status of in situ macrophages and, thus, impair host anti-tumor and anti-microbial defense mechanisms.
Animals↗
Time-dependent differential effects of natural and recombinant murine interferon-gamma on ornithine decarboxylase activity of tumor cells.
Incubation of quiescent tumor cells with fetal calf serum induced ornithine decarboxylase (ODCase) activity concomitantly with mitogenic stimulation. Pretreatment of cells with highly purified natural or recombinant murine interferon-gamma (MuIFN-gamma) for 5 h caused a dose-dependent increase of ODCase activity induced by fetal calf serum (FCS). Pretreatment of target cells with IFN-gamma for 5 h in absence of FCS stimulation did not induce ODCase activity. When pretreatment of cells with natural or recombinant MuIFN-gamma was prolonged for 18 h both ODCase activity and DNA synthesis induced by FCS were suppressed. By contrast when a mixture of MuIFN-alpha and -beta was used, ODCase activity was significantly suppressed after 5 h pretreatment compared to untreated controls. These results suggest that IFN-gamma exerts a differential effect on mitogen-stimulated events depending on the dose and the time of addition.
Animals↗
Recombinant tumor necrosis factor/cachectin and interleukin 1 pretreatment decreases lung oxidized glutathione accumulation, lung injury, and mortality in rats exposed to hyperoxia.
Single, preexposure, parenteral injection with both recombinant tumor necrosis factor/cachectin (TNF/C) and interleukin-1 (IL-1) prolonged the survival of rats (144 +/- 9 h) in continuous hyperoxia (greater than 99% O2 at 1 atm) when compared with rats injected with boiled TNF/C and boiled IL-1 (61 +/- 2 h), TNF/C alone (61 +/- 2 h), IL-1 alone (62 +/- 2 h), or saline (64 +/- 3 h). After exposure to hyperoxia for 52 h, pleural effusion volume, pulmonary artery pressure, total pulmonary resistance, and lung morphologic damage were decreased in those rats given TNF/C and IL-1 as compared with saline-injected rats. In parallel, ratios of reduced (GSH) to oxidized (GSSG) glutathione were greater (P less than 0.05) in lungs of TNF/C + IL-1-injected rats (91 +/- 20) than of saline-injected rats (30 +/- 4) that had been exposed to hyperoxia for 52 h. No differences were found in superoxide dismutase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, or catalase activities in lungs of TNF/C + IL-1- or saline-treated, hyperoxia-exposed rats. Our results indicate that pretreatment with TNF/C and IL-1 favorably altered lung glutathione redox status, decreased lung injury, and enhanced survival of rats exposed to hyperoxia.
Animals↗
Recombinant tumor necrosis factor depresses cytochrome P450-dependent microsomal drug metabolism in mice.
The effect of recombinant tumor necrosis factor on liver cytochrome P450 and related drug metabolism enzymes was investigated. Treatment of mice with tumor necrosis factor caused a marked depression of cytochrome P450 and some drug metabolizing enzymes (ethoxycoumarin deethylase and arylhydrocarbon hydroxylase) in the liver and many other organs. This effect was maximal 24-48 h after treatment and was dependent on the dose of tumor necrosis factor administered. Depression of liver drug metabolizing enzymes was also observed in the endotoxin-resistant C3H/HeJ strain of mice, thus ruling out that this effect may be due to minor endotoxin contamination of recombinant tumor necrosis factor. These data indicate that depression of liver drug metabolism might be an important side effect of tumor necrosis factor, and suggest a role for this macrophage product as an endogenous regulator of liver metabolism.
7-Alkoxycoumarin O-Dealkylase↗
Biochemical characterization of the hepatic effects in mice and rats of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a hepatic neoplasm promoter.
The biochemical effects on the liver of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), a phenobarbital-like enzyme inducer, were studied in the mouse and rat. In mice a single dose of TCPOBOP (3 mg/kg, ip) caused marked and long-lasting (at least 7 days) induction of liver cytochrome P-450, 7-ethoxycoumarin-O-deethylase, and epoxide hydrolase. TCPOBOP had much less effect in rats than in mice, even at a higher dose (30 mg/kg) TCPOBOP also induced DNA synthesis in mice and rats but ornithine decarboxylase activity only in mice. In addition, in mice but not in rats, TCPOBOP increased microsomal membrane fluidity, as detected by fluorescence polarization measurements.
7-Alkoxycoumarin O-Dealkylase↗
Role of reactive oxygen intermediates in the hepatotoxicity of endotoxin.
Administration of endotoxin (2.5 micrograms/mouse, iv) to Corynebacterium parvum-pretreated (14 days earlier, 1 mg/mouse, i.v.) mice caused a rapid (90 min) decrease in liver cytochrome P450-dependent drug metabolism and an elevation of serum transaminase. The time course of the priming effect of C. parvum suggested that macrophages might be responsible for this sensitization to endotoxin. The antioxidant N-acetylcysteine (500 mg/kg) effectively protected against this depression of liver drug metabolism, thus supporting the hypothesis that liver macrophage-generated free radicals might mediate this hepatotoxic effect of endotoxin.
7-Alkoxycoumarin O-Dealkylase↗
Induction of xanthine oxidase and heme oxygenase and depression of liver drug metabolism by interferon: a study with different recombinant interferons.
Induction of xanthine oxidase in mouse liver by interferon (IFN) was studied with three different recombinant human leukocyte IFN molecules: IFLrA, IFLrD and the hybrid IFLrA/D(Bgl II). The ability of different IFN species to induce xanthine oxidase correlated with their ability to depress liver cytochrome P-450-dependent drug metabolism, supporting the hypothesis that reactive oxygen metabolites generated by xanthine oxidase might be responsible for this impairment of liver function by IFN. The antioxidant N-acetylcysteine protected in vivo against the depression of liver drug metabolism by IFLrA/D. IFLrA/D was also found to induce liver microsomal heme oxygenase, an effect that was probably secondary to the observed depression of cytochrome P-450.
Animals↗
Dissociation between induction of ornithine decarboxylase and oxidative burst by phorbol esters in a macrophage cell line.
In order to investigate the correlation between stimulation of superoxide generation and induction of ornithine decarboxylase (ODC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) we have used the macrophage cell line J774.16 and a clone derived from this line that, by contrast with the parental line, is unable to generate superoxides in response to TPA. No difference was observed between the normal and the defective cells, with respect to ODC induction by TPA over a wide range of TPA concentrations (0.2-5.0 micrograms/ml). Similar results were obtained comparing resident and caseinate-elicited mouse peritoneal macrophages. Although resident macrophages did not generate superoxides in response to TPA, they did not differ from superoxide-generating, caseinate-elicited macrophages with respect to ODC induction. These data suggest a dissociation between the stimulation of the oxidative burst by TPA and a growth factor-like effect such as ODC induction.
Animals↗
Role of interleukin-1 in the depression of liver drug metabolism by endotoxin.
Endotoxin-resistant C3H/HeJ mice were used to test the hypothesis that a macrophage product, possibly interleukin-1, might mediate the depression of liver cytochrome P-450-dependent drug metabolism in endotoxin-treated mice. Depression of liver drug metabolism by endotoxin was observed in normal mice (C3H/HeN) but not in C3H/HeJ mice. Serum transfer experiments demonstrated that a serum factor was responsible for the depression of liver drug metabolism. Experiments of passive transfer of peritoneal macrophages showed that this endotoxin-induced factor might be a macrophage product. In vitro experiments showed that endotoxin-stimulated monocytes produced a factor that depressed cytochrome P-450-dependent metabolism in cultured hepatocytes. Homogeneous human monocyte and recombinant interleukin-1 also depressed liver drug metabolism both in vivo and in vitro, suggesting that this macrophage product might be involved in the regulation of liver function by the immune system.
7-Alkoxycoumarin O-Dealkylase↗
Tumor-derived chemotactic factor(s) from human ovarian carcinoma: evidence for a role in the regulation of macrophage content of neoplastic tissues.
Supernatants from freshly disaggregated human ovarian carcinomas maintained in vitro for 24 hr, from primary ovarian carcinoma cultures (4-6 days in culture) and from established ovarian cancer cell lines were examined for chemotactic activity on blood monocytes in blind-well chemotaxis chambers. Tumor-cell culture supernatants induced migration of peripheral blood monocytes across polycarbonate filters with considerable heterogeneity among different tumors. Induction of migration occurred only in the presence of a gradient between the lower and upper compartments of the chamber. Chemotactic activity was characterized by means of supernatants from primary ovarian carcinoma cultures. Chemotactic factor(s) was (were) produced in serum-free conditions and the production was inhibited by emetine but not by mitomycin C. The activity was destroyed by exposure to proteolytic enzymes and by heating at 100 degrees C but was unaffected by RNase, DNase, lipase and exposure to extreme pH values or heating at 56 degrees C. Upon fractionation on Sephadex G 75, the activity eluted as a single peak in the cytochrome C region, corresponding to an apparent molecular weight of about 12 kd. The percentage of macrophages was assessed in 25 freshly disaggregated tumor specimens. Ovarian carcinomas were heterogeneous in their macrophage content with values ranging from 4 to 36%. A significant (r = 0.62; p = 0.00097), though far from absolute, correlation was found between chemotactic activity of culture supernatants and percentage of tumor-associated macrophages. Tumor-derived chemotactic factor(s) could be one of the mechanisms involved in the regulation of the macrophage content of human ovarian carcinomas.
Carcinoma↗
Prostacyclin synthesis induced in vascular cells by interleukin-1.
Supernatants from cultures of human monocytes that had been stimulated with endotoxin or silica induced the synthesis of prostacyclin in endothelial and smooth muscle cells. The lymphokine mediating these effects on the cells of the blood vessel wall was identified as interleukin-1; interferons and interleukin-2 were inactive. Interleukin-1-induced prostacyclin synthesis represents a new aspect of the interaction between the immune system (as well as other tissues) and the vessel wall and may serve as a basis for the development of new strategies in antithrombotic therapy.
Blood Vessels↗