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Biomedical subjects

O Black

Publications and source records attributed to O Black.

At least 19 recordsLinked to original sources
PubMed1986

Combined effects of alpha-difluoromethylornithine and doxorubicin against pancreatic cancer cell lines in culture.

Pancreatic adenocarcinoma presents a clinical and experimental challenge because of its relative resistance to conventional modes of therapy. The present study explores a novel, biologically based approach to enhancing its chemosensitivity and to overcoming its chemoresistance in a panel of pancreatic adenocarcinoma cell lines (two human lines: PANC-1 and COLO-357; and two hamster lines: WD PaCa and PD PaCa). Difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase (ODC) that produces antiproliferative effects by polyamine depletion, was combined with the cytotoxic agent doxorubicin (DOX) in vitro. The inhibitory effects of DFMO were cytostatic and roughly additive to those of DOX. Although the response to the combination varied as a function of the cell lines studied and the response to DFMO as a single agent, all cell lines studied showed some increased inhibition with the combination. The most striking enhancement was seen in our most DOX-resistant cell line, WD PaCa, and also in PANC-1, a relatively sensitive cell line. Thus, the combination of DFMO and DOX shows promise as an experimental approach to the problem of drug resistance and the limited chemosensitivity of pancreatic cancer.

Adenocarcinoma↗
PubMed1984

Glutathione S-transferase activity in rat pancreas.

The biotransformation capability of pancreatic tissue was studied. Michaelis-Menten kinetics were determined for glutathione S-transferase in pancreatic tissue supernatants from control, phenobarbital (PB), and 3-methylcholanthrene (3MCA)-pretreated Sprague-Dawley male rats. The enzyme activity was measured spectrophotometrically with use of 1-chloro-2,4-dinitrobenzene as substrate. Pancreatic activity was about half the hepatic activity, and, further, the activity was not affected by pretreatment with PB or 3MCA as was the liver.

Animals↗
PubMed1984

Inhibition of growth of human or hamster pancreatic cancer cell lines by alpha-difluoromethylornithine alone and combined with cis-diamminedichloroplatinum(II).

A major problem in the therapy of pancreatic adenocarcinoma is its inherent resistance to most chemotherapeutic agents. Previously, we have reported that the four pancreatic cancer cell lines studied here have elevated levels of ornithine decarboxylase, a growth-regulating enzyme, and further that the degree of elevation tends to parallel the degree of chemoresistance. On the basis of these prior findings, we investigated the effects of alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, alone and in combination with cis-diamminedichloroplatinum(II) (cisplatin), to which two of the four cell lines display relative resistance. The cell lines studied were: two of human origin, PANC-1 and COLO-357; and two of hamster origin, WD PaCa and PD PaCa. Colony formation (clonogenic) assays were used to evaluate drug effects. Cells were exposed continuously to DFMO in medium. For the combined treatments, cells were exposed to cisplatin for 1 hr, washed, and then plated in DFMO-containing medium. The inhibitory effects of DFMO were predominantly cytostatic, were reversible by putrescine, and were roughly additive when combined with cisplatin. Our panel of cell lines responded heterogeneously to DFMO, with PANC-1 and WD PaCa showing the most sensitivity. The combination of DFMO and cisplatin appears to be a promising experimental approach to overcoming drug resistance in pancreatic cancer.

Animals↗
PubMed1983

Characterization of benzopyrene metabolism in rat pancreas.

The present studies characterized the pancreatic metabolic system which biodegrades benzo[a]pyrene (BP), in male Sprague-Dawley rats pretreated with 20 mg/kg 3-methylcholanthrene (3MC), 75 mg/kg phenobarbital (PB) or solvent as control. Type of cytochrome involved was examined by measuring the reaction in the presence of 7,8-benzoflavone (BF), an inhibitor of the cytochrome P-448-related enzyme activity. The data indicated that the enzyme activity was induced by pretreatment with PB but not with 3MC. These pretreatment protocols resulted in changes both in Km and Vmax. Studies with BF suggested that pancreatic tissue may not contain more than one class of hemoprotein. These studies pointed out species differences between the rat and guinea pig, and confirmed the pancreatic capability to metabolize procarcinogens and to further degrade carcinogenic metabolites.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Ornithine decarboxylase enzyme activity in human and hamster pancreatic tumor cell lines.

We measured ornithine decarboxylase (ODC) enzyme activity, protein and DNA levels in 4 pancreatic cancer cell lines, 2 derived from human tumors (COLO-357 and PANC-1) and 2 derived from hamster tumors (WDPaCa and PDPaCa). We measured the parameters in confluent stage conditions and in log-growth phase. We report that the enzyme levels in all cell lines are elevated with respect to normal pancreatic tissue. Half-life studies of ODC in the PDPaCa cell line indicate a 3-fold increase in half-life.

Animals↗
PubMed1981

Metabolism of 3-methylcholanthrene in rat pancreas.

In vitro and in vivo studies revealed that pancreases of Long-Evans male rats metabolized 3-methylcholanthrene (3MC) principally at the 1- and 2-carbon positions. The pancreatic metabolizing capability was not induced by pretreatment with either benzo(a)pyrene (BP) or phenobarbital (PB). During the period of observation from 5 to 48 hr, the maximum tissue content of radioactivity observed in the in vivo studies occurred at 16 hr after injection of 3MC in both liver and pancreas. Pancreatic tissue retained about four times more carcinogen per gram of tissue than liver tissues at all time periods.

Animals↗
PubMed1981

Metabolism of a carcinogen (7,12-dimethylbenzanthracene) in the pancreas of the Long-Evans rat.

Because of the high incidence of pancreatic cancer in the United States and because of the correlation of pancreatic cancer to environmental exposure, we have undertaken experiments to measure the metabolism of the carcinogen 7,12-dimethylbenzanthracene in the pancreas of the Long-Evans male rat. This study examined the in vitro metabolism of the carcinogen and found the production of aqueous products in pancreas to be similar to that in liver, however, the pancreatic capability was not induced to greater metabolism by pretreatment with either phenobarbital or 3-methylcholanthrene. High pressure liquid chromatographic analysis of the in vitro products of pancreatic metabolism demonstrated a relatively greater abundance of 5,6-epoxy-7-hydroxymethyl-12-methylbenzanthracene than the liver and a relatively less abundance of 7-hydroxymethyl-12-methylbenzanthracene and 7-methyl-12-hydroxymethylbenzanthracene than the liver. Carcinogen levels were measured in pancreas, liver, bile and blood at 2, 5, 10, 16, 22 and 36 hours after injection.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Pancreatic metabolism of benzo(a)pyrene in vitro and in vivo in the Long-Evans rat.

The in vitro metabolism of benzo(a)pyrene was compared between pancreas and liver with and without pretreatment. There was no significant difference in metabolic pathways between the two tissues. Evidence for induction of the metabolism was evident following 3-methyl-cholanthrene pretreatment. Temporal studies demonstrated rapid elimination of BP from the tissues within the first 5 hours with possible recirculation of metabolites 22 hours after injection of the carcinogen. There was significant binding of BP to DNA in pancreas and liver at 5 hours.

Animals↗
PubMed1978

Origin of tubular complexes developing during induction of pancreatic adenocarcinoma by 7,12-dimethylbenz(a)anthracene.

Implantation of 7,12-dimethylbenz(a)anthracene (DMBA) into the pancreas of rats has been shown to induce adenocarcinoma. Complexes of tubules, which have the appearance of proliferated intralobular ducts, frequently appear during tumor development. These complexes were studied by light and electron microscopy to determine their method of formation. In addition, a tubular complex was reconstructed from serial sections to determine its three-dimensional configuration. Although tubular complexes have been thought by others to result from ductal proliferation, the following observation indicate that they originate from zymogen-granule-containing cells: a) there is a continuum of transitional stages between acini and tubules, b) most tubules decrease in size and are replaced by connective tissue (evidence of regression rather than proliferation), c) few mitotic figures are seen in tubular complexes, d) the tubules comprise many cells which have an abundance of rough endoplasmic reticulum, an organelle which is sparce in ducts, and e) the three-dimensional arrangement of tubules appears identical to the branching, anastomosing arrangement of zymogen-granule-containing cells of the normal rat pancreas. Control animals in which only sutures were placed in the pancreas showed minimal reaction. It is concluded that "acini" become recognized as tubules when loss of zymogen granules accompanies tumor induction by DMBA. Transformation of these cells could be erroneously interpreted as transformation from proliferating ducts.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

Histofluorescence of 3-methylcholanthrene metabolites in the rat pancreas.

Pancreases of Long-Evans rats were treated in vitro and in vivo with 3-methylcholanthrene and examined by histofluorescence techniques. For in vitro studies, tissue sections were dipped in 3-methylcholanthrene and incubated in vitro. These sections revealed that acinar and ductal epithelium had equal fluorescence which suggested equal metabolic capability. For in vivo experiments, 3-methylcholanthrene was injected intraperitoneally and the rats were killed 60 min later. Two additional rats were provided with biliary cannulae to divert bile from the pancreatobiliary ducts. Frozen sections, 16 mu in thickness, were prepared and examined under the fluorescence microscope. The sections revealed that fluorescence was concentrated in the epithelium and lumen of ducts. Animals with diversion of bile from the pancreatobiliary ducts had similar intensity and distribution of fluorescence. The in vivo studies showed that ductal epithelium was exposed to greater concentrations of carcinogen than nonductal epithelium. These observations provide a link between epidemiological studies that show an increased incidence of pancreatic adenocarcinoma in populations exposed to environmental carcinogens and morphological studies that show the ductal cell to be the most likely cell of origin.

Animals↗
PubMed1977

Pancreatic acinar cell metabolism and function.

This review outlines progress made during the past 11 years in research related to pancreatic acinar cell metabolism and function. We have reviewed information gained at the cellular level concerning structural and functional relationships, and effects of fasting and feeding, as well as the action of gastrointestinal hormones and cholinergic agonists on acinar cells. In toto, this information outlines a significant role for gastrointestinal hormones as mediators of secretion, synthesis, and control of trophism. This information provides a basis for more sophisticated inquiries as to the mechanisms of injury of alcohol and drugs. The information may prove helpful in developing diagnostic modalities for pancreatic disease, as well as understanding the processes involved in neoplastic transformation.

Amino Acids↗
PubMed1976

Fine structure of pancreatic adenocarcinoma induced in rats by 7,12-dimethylbenz(a)anthracene.

We induced pancreatic adenocarcinomas in Long-Evans rats by placing crystals, 2-3 mg, of 7,12-dimethylbenz[a]anthracene (DMBA) in a 2- to 3-mm incision in the "head" of the pancreas approximately 1 cm from the duodenum. The incisions were closed with one or two silk sutures. The animals were killed 4-10 months after DMBA implantation, and nodules were removed and routinely prepared for light and/or electron microscopic study. Histologic organization varied from normal, through areas of tubule-like structures, to sheets of pleomorphic tumor cells. Electron microscopic study of tumor cells revealed large electron-lucent nuclei that frequently had irregular outlines and prominent nucleoli. The predominant feature of the cytoplasm was abundant rough endoplasmic reticulum. Zymogen granules were rare. Adjacent cells sometimes were jointed by an apical junctional complex to form a lumen into which projected irregular microvilli. A basal lamina sometimes occurred at the bases of the tumor cells. The fine structural similarity of these tumor cells to acinar cells was noted.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1975

Experimental induction of pancreatic adenocarcinoma in rats.

Adenocarcinomas of the pancreas were experimentally induced in rats after the implantation of 7,12-dimethylbenz[alpha]anthracene (DMBA). Rats were anesthetized with Nembutal, the pancreas was exposed, and a 2- to 3-mm incision was made in the "head" of the pancreas approximately 1 cm from the duodenum. Crystalline DMBA (2-3 mg) was implanted and the incision was closed with silk suture. Eight % of animals developed tumors in the pancreas from 119 to 363 days after implantation (mean, 194 days). Ten animals developed tumors in less than 180 days. The adenocarcinomas were invasive, metastasized, and had pronounced ductal cell characteristics. The light-microscopic morphology of these pancreatic tumors was presented.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1973

Protein synthesis in pancreas of fasted pigeons.

The regulation of protein synthesis in the pigeon has been studied by comparing the capability of cell-free amino acid incorporating systems of membrane-bound and membrane-free polysomes prepared from fasted and fed birds. New methods were developed for isolating polysomes since techniques used for other tissues did not provide quantitative recovery of polysomal RNA. The sucrose gradient profile of polysomes from pigeon pancreas showed a predominance of trisome species. Although initiation factors are present on polysomes, it was found that polysomes in cell-free systems would not initiate protein synthesis without exogenous initiation factors. This suggested the presence of an inhibitor or regulator of protein synthesis. These studies show that fasting resulted in: (a) decreased amounts of polysomes; (b) disaggregation of polysomes to monosomes; (c) decreased capability of polysomes to synthesize nascent peptides and to initiate additional synthesis, apparently not related to concentration of initiation factors.

Amino Acids↗