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Biomedical subjects

D G Scarpelli

Publications and source records attributed to D G Scarpelli.

At least 19 recordsLinked to original sources
PubMed1992

K-ras mutation is an early event in pancreatic duct carcinogenesis in the Syrian golden hamster.

K-ras oncogene mutation has been shown to be a frequent event in pancreatic ductal adenocarcinomas induced by the carcinogen N-nitroso-bis(2-oxopropyl)amine in the hamster. The present study examines the mutational status of the K-ras oncogene in lesions that precede the appearance of invasive ductal adenocarcinomas. Syrian golden hamsters (80-100 g) received 12 weekly doses of 15 mg/kg N-nitroso-bis(2-oxopropyl)amine and were serially sacrificed at 8, 12, 14, 16, or 24 weeks following the initiation of treatment. Ten microns-thick sections of formalin-fixed paraffin-embedded pancreas were examined for hyperplasia, papillary hyperplasia, carcinoma in situ, and invasive and metastatic ductal carcinoma. Marked lesions of interest were scraped from the slide, subjected to polymerase chain reaction-mediated amplification of the first exon of the K-ras gene, and probed by oligonucleotide-specific hybridization for mutations at codon either 12 or 13. Of 186 samples assayed, K-ras codon 12 mutations were detected in 26% of hyperplasias, 46% of papillary hyperplasias, 76% of carcinoma in situ, 80% of adenocarcinomas, and 43% of lymph node metastases. Codon 12 mutations were exclusively G to A changes at the second position. Codon 13 mutations were only detected in 9 of 168 samples. These results suggest that K-ras activation is an early event in N-nitroso-bis(2-oxopropyl)amine-induced pancreatic carcinogenesis in the hamster.

Adenocarcinoma↗
PubMed1992

Stimulation of DNA synthesis in pancreatic duct cells by gastrointestinal hormones: interaction with other growth factors.

Pancreatic duct cells of the Syrian hamster were grown as monolayers on thin layers of type I collagen coated onto microporous membranes. The effects of a number of potential trophic factors were tested by their ability to increase [3H]thymidine incorporation into cellular DNA. To measure the effect of growth factors, cells were subjected to a period of growth factor depletion to induce a state of partial quiescence in DNA synthesis. Cells responded with a significant increase in thymidine incorporation after the addition of epidermal growth factor (EGF) alone or a growth factor mixture containing EGF plus insulin, transferrin, selenium, linoleic acid, bovine pituitary extract, triiodothyronine, and dexamethasone. When the serum substitute, Nu Serum IV (5%, vol/vol), was added to this mixture, addition of several gastrointestinal (GI) hormones including secretin, vasoactive intestinal polypeptide (VIP), bombesin, and gastrin caused significant increases in thymidine incorporation at concentrations of 0.01-1 microM. At 1 microM, these hormones stimulated DNA synthesis relative to their respective control in the order secretin (178%) greater than bombesin (153%) greater than VIP (138%) greater than gastrin (126%). Cholecystokinin octapeptide, a known trophic factor for pancreatic acinar cells, did not cause significant increases in thymidine incorporation in cultured duct cells. These results suggest that pancreatic duct cells possess receptors for a number of GI hormones and respond to the trophic effects of hormones known to stimulate pancreatic growth in vivo.

Animals↗
PubMed1991

Prognostic implications of proliferative activity and DNA aneuploidy in Astler-Coller Dukes stage C colonic adenocarcinomas.

Paraffin-embedded surgical specimens from 69 patients who underwent resections of otherwise untreated Dukes stage C adenocarcinoma of the colon were examined for proliferative activity, DNA aneuploidy, DNA index, and proportion of aneuploid cells by flow cytometry. Results were correlated to clinical characteristics of the patients and to overall survival times. DNA aneuploid tumors were identified in 60 cases (87%), diploid tumors in 9 cases (13%). The mean S-phase fraction for all cases was 17.6%, with a standard deviation (SD) of 7.8. In univariate statistical analysis, younger patient age, lower tumor proliferative activity, DNA index less than or equal to 1.2, and presence of only 1-4 lymph nodes with tumor involvement were found to be significant predictors of improved patient survival. In multivariate Cox regression analysis, low tumor proliferative activity, younger patient age, and location of the tumor in the right or transverse colon were found to be significant independent predictors of increased patient survival. When tumor proliferative activity was stratified into statistically defined subgroups, patients with tumors of low proliferative activity (S-phase less than mean - 0.5 SD) had significantly longer survival than patients with tumors of moderate proliferative activity (S-phase value greater than mean - 0.5 SD and less than mean +0.5 SD) or high proliferative activity (S-phase greater than mean +0.5 SD). These results suggest that tumor proliferative activity in Dukes C colon carcinoma may be an important biological factor in determining patient prognosis.

Adenocarcinoma↗
PubMed1991

Enhancement of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine-induced tumorigenesis in Sprague-Dawley rats by orotic acid.

The effect of orotic acid (OA) on the carcinogenicity of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) in rats was evaluated. A group of 5 week old Sprague-Dawley male rats were placed on a synthetic 20% protein diet containing 1% OA. A second group was placed on a regular, OA-free diet of similar composition. Approximately 2 weeks later, animals from both groups grown to 100 g were treated with 400 mg/kg HPOP delivered continuously for 14 days via 2002 Alzet osmotic pumps implanted s.c. Rats fed the OA diet were kept under this diet for 13 weeks following initiation of HPOP treatment and subsequently were placed on the regular diet for another 12 weeks, at which time they were killed. In the absence of OA, HPOP-treated rats developed adenomas in the kidney and lungs at incidences of 5 and 33% respectively, while pancreas and liver were unaffected. On the other hand, rats fed the OA diet and treated with HPOP developed renal mesenchymal tumors and pulmonary adenomas at incidences of 70 and 65% respectively. In addition, HPOP induced cystic lesions in the pancreas of animals fed the OA diet. The enhancement of the tumorigenic effectiveness of HPOP was at least partly ascribed to the effect of OA treatment on the rate by which carcinogen-induced alkylation of DNA was repaired in various tissues. Accumulation of N7-methylguanine in kidney, lung and pancreas of rats fed the OA diet was 1.6, 1.9 and 2.4 times higher than in respective organs of animals fed the regular diet. Similarly, concentrations of the premutagenic O6-methylguanine (O6-MeG) were 3.0, 3.1 and 2 times greater in the kidney, lung and pancreas of rats fed the OA diet than in the respective organs of those fed the regular diet. Feeding an OA diet to HPOP-treated rats did not have an effect on either the resistance of the liver to this carcinogen or on the level of O6-MeG accumulation in the DNA of this tissue.

Animals↗
PubMed1990

Characterization of differentiated Syrian golden hamster pancreatic duct cells maintained in extended monolayer culture.

Epithelial cells isolated from fragments of hamster pancreas interlobular ducts were freed of fibroblast contamination by plating them on air-dried collagen, maintaining them in serum-free Dulbecco's modified Eagle's (DME):F12 medium supplemented with growth factors, and selecting fibroblast-free aggregates of duct cells with cloning cylinders. Duct epithelial cells plated on rat type I collagen gel and maintained in DME:F12 supplemented with Nu Serum IV, bovine pituitary extract, epidermal growth factor, 3,3',5-triiodothyronine, dexamethasone, and insulin, transferrin, selenium, and linoleic acid conjugated to bovine serum albumin (ITS+), showed optimal growth as monolayers with a doubling time of about 20 h and were propagated for as long as 26 wk. Early passage cells consisted of cuboidal cells with microvilli on their apical surface, complex basolateral membranes, numerous elongated mitochondria, and both free and membrane-bound ribosomes. Cells grown as monolayers for 3 mo. were more flattened and contained fewer apical microvilli, mitochondria, and profiles of rough surfaced endoplasmic reticulum; in addition, there were numerous autophagic vacuoles. Functional characteristics of differentiated pancreatic duct cells which were maintained during extended monolayer culture included intracellular levels of carbonic anhydrase and their capacity to generate cyclic AMP (cAMP) after stimulation by 1 X 10(-6) M secretin. From 5 to 7 wk in culture, levels of carbonic anhydrase remained stable but after 25 to 26 wk decreased by 1.9-fold. At 5 to 7 wk of culture, cyclic AMP increased 8.7-fold over basal levels after secretin stimulation. Although pancreatic duct cells cultured for 25 to 26 wk showed lower basal levels of cAMP, they were still capable of generating significant levels of cAMP after exposure to secretin with a 7.0-fold increase, indicating that secretin receptors and the adenyl cyclase system were both present and functional. These experiments document that pancreatic duct monolayer cultures can be maintained in a differentiated state for up to 6 mo. and suggest that this culture system may be useful for in vitro physiologic and pathologic studies.

Animals↗
PubMed1990

Coexpression of glutamine synthetase and carbamoylphosphate synthase I genes in pancreatic hepatocytes of rat.

In the mammalian liver the distribution of ammonia-detoxifying enzymes, glutamine synthetase (GS) and carbamoylphosphate synthase I (ammonia) (CPS-I), is mutually exclusive in that these enzymes are expressed in two distinct populations of hepatocytes that are zonally demarcated in the liver acinus. In the present study we examined the distribution of GS and CPS-I in pancreatic hepatocytes to ascertain if the expression of these two genes in these hepatocytes is also mutually exclusive. Multiple foci of hepatocytes showing no clear acinar organization develop in the adult rat pancreas as a result of a change in the differentiation commitment after dietary copper deficiency. Unlike liver, GS and CPS-I are detected by immunofluorescence in all pancreatic hepatocytes. In situ hybridization revealed that all pancreatic hepatocytes contain GS and CPS-I mRNAs. The sizes of these two mRNAs in pancreas with hepatocytes are similar to those of the liver. The concomitant expression of GS and CPS-I genes in pancreatic hepatocytes may be attributed, in part, to the absence of portal blood supply to the pancreas vis-à-vis the lack of hormonal/metabolic gradients as well as to possible matrix homogeneity in the pancreas.

Animals↗
PubMed1990

Activation of K-ras in transplantable pancreatic ductal adenocarcinomas of Syrian golden hamsters.

High mol. wt genomic DNA was prepared from normal hamster pancreas and the solid and ascites variants of two different hamster transplantable carcinomas, one induced by N-nitrosobis(2-oxopropyl)amine and the other spontaneously occurring. This DNA was transfected into NIH/3T3 cells and resulted in cells that were capable of forming tumors when injected into nude mice. Analysis of the nude mouse tumors by Southern blotting revealed the presence of a band specific for hamster K-ras. Polymerase chain reaction (PCR)-mediated amplification of the K-ras codon 12-13 region of genomic DNA prepared from the transplantable tumors produced a 117 bp fragment which was analyzed by both allele-specific oligonucleotide hybridization and direct DNA sequencing. Oligonucleotide hybridization with probes specific for changes in the first or second position of codons 12 or 13 detected a G to A transversion in the second position of codon 12 in the chemically induced transplantable tumor, and a G to A change in the second position of codon 13 in the spontaneously occurring transplantable carcinomas. The result obtained for the chemically induced tumor was confirmed by direct dideoxy sequencing of the PCR-amplified product. These findings are the first to show a specific oncogene activation in an experimental pancreatic tumor model and also parallel the results recently reported for K-ras mutations in human pancreatic carcinoma.

Animals↗
PubMed1990

Metabolism and activation of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine by isolated hepatocytes and pancreatic cells of the Syrian hamster.

The metabolism of the pancreatic carcinogen N-nitroso-bis(2-oxopropyl)amine (BOP) was studied using primary hepatocytes and acinar and duct cells isolated from Syrian hamsters. Metabolic activation of BOP was verified by detecting its conversion to CO2 covalently bound metabolites and soluble products containing the alpha-carbon of the nitrosamine. At concentrations below 0.2 mM, BOP was completely activated by hepatocytes within 60 min. At high substrate concentration (1 mM) or high cell density (5 x 10(6) cells/ml), reduction of BOP to N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine and N-nitrosobis(2-hydroxypropyl)amine contributed significantly to the metabolic profile. The conditions which favored metabolic activation of BOP were used to compare metabolism by hepatocytes and pancreatic cells. Under such conditions, the ratio of activation products formed by hepatocytes versus those formed by acinar cells was 14.5:1; the corresponding ratio for covalently bound metabolites was 19:1. Hepatocytes activated BOP 106 times more rapidly than duct cells as determined from yields of activation products or 152 times more rapidly as determined from labeling of cellular macromolecules. Acinar cells showed a higher capacity for metabolic activation than duct cells. The ratio for the yield of activation products from acinar versus duct cells was 4.3:1; the corresponding ratio for covalent binding was 5.8:1. The relatively low capacity of pancreatic cells for activation of BOP compared to hepatocytes is in agreement with the low levels of DNA binding in the pancreas compared to other organs after administration of BOP to the hamster in vivo. The observation that the ratio for total covalent binding of BOP in hepatocytes versus acinar cells was higher than that seen previously for the liver versus the pancreas in vivo is consistent with the hypothesis that alkylating agents derived from BOP reach the pancreas after formation in other organs. The liver would be the prime source for such alkylating agents.

Animals↗
PubMed1990

Transdifferentiation of ductular cells into hepatocytes in regenerating hamster pancreas.

The transdifferentiation of regenerating pancreatic cells into hepatocytes in the Syrian golden hamster and Fischer rat is an example of the surprising plasticity of cells in the adult animal. While earlier experiments suggested that these might be derived from acinar cells, unequivocal evidence of this in both models has not been forthcoming. In this paper, we document that pancreatic ductular epithelium in the hamster is the cell of origin and that presumptive hepatocytes can be identified morphologically as early as the 3rd day after the induction of regeneration. The patterns of development of various organelles as characterized by their acquisition of liver-specific protein markers parallels those that have been reported by others during the differentiation of embryonic and postnatal hepatocytes. Colloidal gold-labeled antibody staining of carbamoyl phosphate synthetase, a liver-specific mitochondrial enzyme, and catalase, a peroxisomal enzyme, first appeared 60 hours and 4.5 days postregeneration, respectively. At these times, the morphologic features of the hepatocyte phenotype in the pancreas were ambiguous. Morphometric analysis showed that for both enzymes, the number of gold particles/organelle increased to a maximum by the 9th week. In contrast, urate oxidase, a liver-specific peroxisomal enzyme, was not identified by ultrastructural immunochemistry until the 14th day after regeneration and remained at low levels through the 9th week.

Animals↗
PubMed1989

DNA alkylation in the hamster induced by two pancreatic carcinogens.

N-Nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) alkylate DNA and other macromolecules in the liver, kidney, pancreas, and lungs when injected s.c. in the Syrian hamster. Two of the most abundant DNA adducts found were the N7-methylguanine and O6-methylguanine, which in the liver accounted for about 60% of total DNA alkylation. A third adduct which was invariably found in liver and kidneys, but could not always be detected in pancreas and lungs, was identified as N7-(2-hydroxypropyl)guanine. Quantitation of N7-methylguanine by its UV spectrum and radioactivity, following administration of single-labeled [1-14C]BOP or HPOP, showed that the specific activity of this adduct was one half that of the nitrosamine. This excludes participation of the gamma carbons of these nitrosamines in methylation reactions and indicates that intermediates in which scrambling of the alpha and gamma carbons is possible are not involved in yielding the ultimate methylating agent. Finally, a comparison of the alkylation levels caused by equivalent doses of BOP and HPOP showed that BOP targeted DNA and other cytoplasmic components of kidney, lungs, and pancreas more extensively than HPOP. Ratios of N7-methylguanine in BOP versus HPOP treated hamsters, at doses less than 40 mg/kg body weight, were 3.1 in the kidney, 7.0 in the pancreas, 3.9 in the lung, and only 3.5 in the liver. These ratios are in accordance with the greater carcinogenic potency of BOP compared to HPOP and also the different organotropic properties of the two carcinogens.

Alkylation↗
PubMed1989

Toxicology of the pancreas.

The pancreas of mammals is capable of biotransforming drugs and other chemicals and subject to toxic injury by the resultant reactive metabolites. In the case of experimental animals, especially rodents, numerous chemical toxicants have been identified for the exocrine pancreas and, to a lesser degree, the endocrine component. These include alcohol, alloxan, azaserine, dimethylbenzo[a]anthracene, ethionine, 4-hydroxyaminoquinoline-1-oxide, beta-oxidized derivatives of dipropylnitrosamine, oleic acid, and streptozotocin. Depending on the toxicant, the cellular effects span the gamut from acute injury and death, to hyperplasia, metaplasia, and malignant transformation. In contrast to the well-established toxic effects of chronic alcohol abuse on the human pancreas, its susceptibility to toxic injury by therapeutic drugs has become clinically apparent more recently. A drug should be considered as toxic only when it induces acute pancreatitis documented by clinical findings and laboratory tests; the condition improves when the drug is discontinued and worsens when the patient is challenged by readministration of the drug. At present, only 8 therapeutic drugs have fulfilled these criteria and are classified as toxic for pancreas. These are, azathioprine, estrogens, furosemide, methyldopa, pentamidine, procainamide, sulfonamides, and thiazide diuretics. Controlled exposure to cultured component cells of pancreas may be of potential value in identifying such drugs, documenting their toxicity, and allowing for biochemical and toxicologic investigation of the mechanisms involved.

Animals↗
PubMed1989

Carcinogenicity of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, N-nitrosobis(2-hydroxypropyl)amine and cis-N-nitroso-2,6-dimethylmorpholine administered continuously in the Syrian hamster, and the effect of dietary protein on N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine carcinogenesis.

The effect of continuous week-long administration of the three pancreatic carcinogens N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP), N-nitrosobis(2-hydroxypropyl)amine (BHP), and cis-N-nitroso-2,6-dimethylmorpholine (cis-NNDM), by a s.c. implanted osmotic pump, was examined in Syrian hamsters. HPOP at total doses of 220-250 mg/kg body weight induced ductal adenocarcinomas in the pancreas (41%), and cholangiomas (18%) and cholangiocarcinomas (18%) in the liver, 25 weeks following the initiation of treatment. Higher doses of HPOP resulted in severe hepatic injury and increased mortality (LD50 = 280 mg/kg). Cis-NNDM and BHP were less toxic than HPOP and induced pancreatic lesions at doses of 950 mg/kg. These data document that a week-long schedule of continuous administration of HPOP for the induction of pancreatic cancer compares favorably with those involving weekly injections. Application of this model to study the effect of dietary protein in HPOP-induced carcinogenicity showed that the number of cystic, intermediate and tubular complexes in the pancreas was significantly higher in animals fed a 20% as compared to an 8% protein diet 2 weeks prior to HPOP administration. Furthermore, the incidence of pancreatic adenocarcinomas and in situ carcinomas was only 13% in the hamsters fed the low-protein diet as compared to 46% in those fed the high-protein diet.

Adenocarcinoma↗
PubMed1989

Role of periductal and ductular epithelial cells of the adult rat pancreas in pancreatic hepatocyte lineage. A change in the differentiation commitment.

Development of pancreatic hepatocytes in adult rats maintained on copper deficient diet containing 0.6% trien (CuDT) has been reported recently. To elucidate the histogenesis of hepatocytes a sequential study was undertaken using morphologic, histochemical, immunochemical, in situ hybridization, and Northern blot analysis. Male F-344 rats weighing 80 to 90 g were fed CuDT for 8 weeks and returned to normal rat chow. Beginning from 4 weeks of copper depletion, there was a progressive loss of acinar cells and by 8 weeks more than 90% of the acinar tissue was lost. During this period, there was an increase in the number of adipocytes in the interstitium, and in the number of interstitial and ductular cells. Morphologic observations were confirmed by immunoblot and Northern blot analysis, in which the amount of pancreatic proteins and their mRNAs decreased between 5 and 8 weeks. During this period, a progressive increase in the level of albumin mRNA was observed. In situ hybridization, performed at 7 weeks of copper deficiency, showed localization of albumin mRNA over interstitial and ductular cells. Pancreatic hepatocytes were identified immediately after the rats were returned to a normal diet and gradually increased in number. The hepatocytes occupied almost 60% of the pancreatic volume by 8 weeks. During the early recovery phase, hepatocytes were identified in ductules as well as in the interstitium. Based on these studies, it is concluded that both the ductular cells and interstitial cells, which resemble oval cells of liver, are capable of transforming into pancreatic hepatocytes and these cells may be considered stem-cell equivalent.

Animals↗
PubMed1989

Histopathologic and flow cytometric analysis of adenomatous colonic polyps.

We evaluated the histopathology, DNA content, and proliferative activity of colonic polyps independently. Paraffin-embedded specimens were used as source material. In each case, additional sections were cut at 3 microns and stained with hematoxylin-eosin and trichrome for histopathologic analysis. For DNA analysis and measurement of proliferative activity, the polyp parts were dissected and the nonpolypoid tissue was discarded. The study was limited to those specimens that were received in our department in the years 1972 and 1977. Of the 104 polyps that were submitted for flow cytometric analysis, 36 could not be analyzed owing to excessive debris or insufficient nuclei. DNA aneuploidy was identified in 32% of the cases, with a higher value noted in larger polyps and in severely dysplastic polyps, but these values were not statistically significant. Multiple adenomas from the same patient often showed different DNA histograms. When analyzed according to the percentage of cells in S phase, no significant difference was found in proliferative activity of polyps according to DNA content or size of the polyps. These results suggest that the diagnostic significance of aneuploidy and proliferative activity in polyps must be interpreted with caution.

Adenoma↗
PubMed1988

Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation.

Study of transdifferentiation provides an excellent opportunity to investigate various factors and mechanisms involved in repression of activated genes and derepression of inactivated genes. Here we describe a highly reproducible in vivo model, in which hepatocytes are induced in the pancreas of adult rats that were maintained on copper-deficient diet containing a relatively non-toxic copper-chelating agent, triethylenetetramine tetrahydrochloride (0.6% w/w) for 7-9 weeks and then returned to normal rat chow. This dietary manipulation resulted in almost complete loss of pancreatic acinar cells at the end of copper-depletion regimen, and in the development of multiple foci of hepatocytes during recovery phase. In some animals, liver cells occupied more than 60% of pancreatic volume within 6-8 weeks of recovery. Northern blot analysis of total RNA obtained from the pancreas of these rats revealed the expression of albumin mRNA. Albumin was demonstrated in these pancreatic hepatocytes by immunofluorescence. The advantages of this model over the previously described models are: a) low mortality (10%), b) depletion of acinar cells, and c) development of multiple foci of hepatocytes in 100% of rats.

Animals↗
PubMed1988

Lack of expression of glutathione-S-transferase P, gamma-glutamyl transpeptidase, and alpha-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators.

Many structurally unrelated nonmutagenic peroxisome proliferators induce altered areas, neoplastic nodules, and hepatocellular carcinomas in rats. Unlike the lesions induced by genotoxic hepatocarcinogens, these lesions do not stain positively for the phenotypic markers gamma-glutamyl transpeptidase (GGT) and glutathione-S-transferase P (GST-P). To ascertain whether the absence of immunocytochemically detectable GST-P and GGT proteins in peroxisome proliferator-induced neoplastic lesions is due to the absence of specific mRNAs, we analyzed the total RNA isolated from hepatocellular carcinomas induced by three different peroxisome proliferators (ciprofibrate, Wy-14643, and BR-931) and the genotoxic carcinogens, 2-acetylaminofluorene and aflatoxin B1 (AFB), for the presence of GST-P, GGT, and alpha-fetoprotein (AFP) mRNAs. Northern and dot blot analysis of total RNA isolated from liver tumors induced by three different peroxisome proliferators revealed no detectable GST-P, GGT, and AFP mRNAs. GST-P mRNA was also not detected in a transplantable hepatocellular carcinoma established from a liver tumor induced by ciprofibrate. In contrast, GST-P mRNA levels were high in primary liver tumors induced by both 2-acetylaminofluorene and AFB and the two transplantable hepatocellular carcinomas established from such tumors. By immunoblot method, GST-P protein was found to be abundant in both primary and transplantable liver tumors induced by genotoxic carcinogens but not in those derived from peroxisome proliferator treatment. The GGT and AFP mRNAs were also not found in all 18 liver tumors induced by peroxisome proliferators that were analyzed and also in the ciprofibrate-derived transplantable liver tumor. The expression of GGT and AFP genes in liver tumors induced by 2-acetylaminofluorene and AFB was variable. These studies with peroxisome proliferators show that the GST-P and GGT gene derepression is not essential for the hepatocarcinogenesis or successful tumor transplantation. Further characterization of the molecular basis for the differential expression, particularly of the GST-P gene in liver tumors, may help identification of the critical event(s) in hepatocarcinogenesis by genotoxic carcinogens and nongenotoxic peroxisome proliferators.

Animals↗