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Biomedical subjects

C M Townsend

Publications and source records attributed to C M Townsend.

At least 199 records · Page 11Linked to original sources
PubMed1989

The effects of 2-deoxy-D-glucose and alpha-difluoromethylornithine on the growth of pancreatic cancer in vivo.

The glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), inhibits growth of some cancers. alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in polyamine biosynthesis. We and others have previously shown that DFMO inhibits cancer growth in a number of models. The present study was designed to investigate the effects of 2-DG alone and combined with DFMO on the growth of H2T hamster pancreatic ductal adenocarcinoma. Twenty-eight male Syrian golden hamsters were inoculated with 500,000 H2T cells, and then randomized into four groups of seven each: group 1 served as control; group 2 received DFMO (3% in drinking water); group 3 received 2-DG (500 mg/kg/day) intraperitoneally; group 4 received a combination of 2-DG and DFMO. Treatment began 5 days after tumor cell inoculation and continued for 28 days. At the end of the treatment period, the area of the H2T tumor was reduced 31% by DFMO compared with a 22% reduction caused by 2-DG. Tumor weight was significantly reduced (31%) by DFMO but not by 2-DG. Tumor contents of DNA, RNA, and protein were also reduced by DFMO but not 2-DG. Tumor concentration of the polyamines, putrescine and spermidine, were reduced by DFMO, but 2-DG did not alter levels of polyamines. The combination of DFMO and 2-DG caused a significantly greater reduction in tumor weight and putrescine content compared with DFMO alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

DNA synthetic activity in tumor-bearing mice.

The rate of DNA synthesis in normal tissues exhibits circadian rhythmicity. However, there have been conflicting reports of the effects of tumor burden on the circadian rhythm of DNA synthesis in non-cancer tissues. We have developed a mouse colon cancer (MC-26) that exhibits different growth under different photoperiods. The purpose of this study was to analyze DNA synthetic activity in tissues removed from tumor-bearing and tumor-free mice maintained under two different photoperiods. Two groups each of approximately 80 male Balb/c mice were acclimated to one of two light-dark cycles, 12L:12D or 6L:18D. Half of each group were injected with 5.0 x 10(4) MC-26 cells. Twenty-two days later, all mice were killed in subgroups at 4-6 hr intervals over one 24-hr period. Colons and tumors were removed for measurement of DNA synthesis. Results were analyzed by means of one-way analysis of variance (ANOVA) in order to determine whether DNA synthesis varied significantly within groups over the 24-hr period. The DNA synthetic activity, as measured by uptake of tritiated thymidine, exhibited significant temporal variation in the colons of control (tumor-free) mice under both the 12L:12D and 6L:18D photoperiods. The colons of tumor-bearing mice failed to exhibit a fluctuation under a 12L:12D photoperiod but did show a significant 24-hr rhythm under the 6L:18D photoperiod. The subcutaneously growing cancers did not exhibit a circadian variation in DNA synthetic activity under either photoperiod. Both photoperiod and the presence of cancer appear to affect the DNA synthetic activity observed in mice bearing the MC-26 colon cancer.

Animals↗
PubMed1989

Twenty-four-hour variations in ornithine decarboxylase and acid phosphatase in mice.

Polyamines are essential for cell growth and differentiation. Ornithine decarboxylase (ODC) is the rate-limiting enzyme in polyamine biosynthesis. Acid phosphatases (AP) are lysosomal enzymes that are important in normal intracellular metabolism. Twenty-four-hour variations in these enzymes may be important in understanding the temporal responses of different tissues to various stimuli. The purpose of this study was to examine a variety of tissues for fluctuations in the levels of ODC and AP over a 24-hr period. Significant circadian variations in the amount of ODC activity were observed in all tissues examined. Activity of AP varied with time of day in the liver, kidney, and heart. The highest and lowest measurements of ODC activity were as follows: liver, 81.5 +/- 7.0, 47.9 +/- 4.4; colon, 11.7 +/- 1.2, 3.1 +/- 0.7; stomach 3.1 +/- 0.4, 0.9 +/- 0.1; kidney, 420.9 +/- 0.9, 67.5 +/- 0.8; and heart, 4.7 +/- 1.0, 2.5 +/- 0.2. The highest and lowest measurements of AP activity were as follows: liver 3.8 +/- 0.1, 2.8 +/- 0.1; kidney, 3.4 +/- 0.1, 1.9 +/- 0.1; and heart, 2.6 +/- 0.1, 2.0 +/- 0.1. These findings suggest that rhythmic fluctuations in polyamine biosynthesis and lysosomal enzymes may influence other metabolic pathways differentially throughout 24 hr.

Acid Phosphatase↗
PubMed1989

Involvement of cholecystokinin receptors in the adverse effect of glucocorticoids on diet-induced necrotizing pancreatitis.

The mechanism that explains the association between corticoids and acute pancreatitis is unknown. Our hypothesis was that chronic glucocorticoid treatment could adversely affect the course of hemorrhagic pancreatitis by acting through cholecystokinin (CCK) receptors. Acute necrotizing pancreatitis was induced by feeding young female mice a choline-deficient, ethionine-supplemented (CDE) diet for 60 hours. Treatment with hydrocortisone (10 mg/kg/day) was begun 1 week before pancreatitis. At the onset of the CDE diet, a group of hydrocortisone-treated mice were also given the CCK receptor antagonist CR-1409 (5 mg/kg three times a day). Control mice received injections of saline solution. A follow-up of 336 hours was conducted for survival analysis. Hydrocortisone given alone did not produce pancreatitis. Hydrocortisone, however, did increase the pancreatic necrosis caused by the CDE diet (from 40% to 70%) and significantly reduce survival (from 40% to 9%). CR-1409 completely abolished the adverse effects of hydrocortisone on pancreatitis. We measured amylase release by dispersed pancreatic acini from mice chronically treated with hydrocortisone in response to CCK-8. Treatment with hydrocortisone increased both the sensitivity and the responsiveness of the pancreas to CCK-8. We conclude that glucocorticoids alone may not induce acute pancreatitis, but they can increase the risk of a more severe form of pancreatitis developing. The glucocorticoid effect appears to be attributable to a CCK receptor-mediated sensitization of the pancreas to endogenous CCK. Thus, CCK-receptor blockade may improve survival in necrotizing pancreatitis associated with chronic glucocorticoid treatments.

Amylases↗
PubMed1989

Effects of gastrointestinal peptides on gastrointestinal cancer growth.

The trophic effect of gut hormones may have important clinical applications for treatment of gut and pancreatic cancers. We now have developed methods by which we can quantitate gut hormone receptors in normal and neoplastic gut mucosa and pancreas. Analysis of gut and pancreatic tumors for gut hormone receptors may thus allow us to select patients with these cancers who would respond to treatment with hormones, antihormones, or hormone ablation in a manner similar to current strategies that are employed successfully for treatment of patients with breast cancer.

Animals↗
PubMed1988

Inhibition of human gastric adenocarcinoma xenograft growth in nude mice by alpha-difluoromethylornithine.

We studied the effect of inhibition of polyamine biosynthesis by alpha-difluoromethylornithine on the growth of a human gastric adenocarcinoma (CLEES) xenotransplanted in nude mice. CLEES is a well-differentiated gastric adenocarcinoma of the intestinal type. The doubling time has ranged from 7 to 10 days through 11 passages. Electron microscopic and immunohistochemical studies comparing the original tumor and xenotransplants showed similar structure and similar amounts of carcinoembryonic antigen. Polyamine biosynthesis is required for cell division. alpha-Difluoromethylornithine inhibits ornithine decarboxylase, the rate-limiting enzyme in polyamine biosynthesis. In this study, 48 athymic mice were used in two experiments. In the first experiment, two groups of 12 mice each were inoculated with CLEES tumor cells and received either tap water or a 3% alpha-difluoromethylornithine solution as drinking water. Tumor size was measured twice weekly. Tumor size was significantly decreased from controls by the fourth week of treatment and at all points of analysis thereafter for 7 wk. In the second experiment, alpha-difluoromethylornithine significantly reduced tumor concentrations of the polyamines putrescine and spermidine. In addition, the tumor content of DNA was significantly reduced in treated mice (0.64 +/- 0.16 mg) compared to controls (4.76 +/- 0.92 mg). Our data suggest that inhibition of polyamine biosynthesis may be a useful component of multidrug chemotherapy for human gastric adenocarcinoma. Establishment of tumor lines such as this gastric adenocarcinoma will facilitate further studies on the biological behavior of human gastric cancer and its response to chemotherapeutic manipulation in vivo.

Adenocarcinoma↗
PubMed1988

Treatment-induced changes in sensitivity in a multiclonal human tumor mixture model in vitro.

An in vitro model has been devised so that mixtures of human tumor cells can be grown together for studies related to drug-induced or -selected changes in sensitivity. In the studies reported here, two human astrocytoma clones, one sensitive and one resistant to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), were carefully matched for doubling times, cell cycle phase distributions, and colony-forming efficiencies. The clones were mixed and grown together, and after only three weekly treatments with MeCCNU (10 micrograms/ml for 1 h each week) the sensitive cells in the mixture were killed, leaving behind a population that was almost 100% resistant to further exposures to MeCCNU. The loss of the sensitive cells from the mixture each week was easily detected by visual observation of flow microfluorometry histograms since the clones had different DNA indices. Repeated weekly exposures of the unmixed resistant clone (AST 1-1) to MeCCNU caused very little accumulated cell kill. Similar exposures of the unmixed sensitive clone (AST 3-4) produced a linear decrease in survival over the first three weekly treatments with 10 micrograms MeCCNU/ml, but after that time these cells became progressively more resistant to MeCCNU. It is unlikely that the change to resistance in the AST 3-4 clone occurred because of contamination with the resistant AST 1-1 cells, because their DNA index remained stable. These data show that repeated treatments with a single agent can cause a tumor cell population to become more resistant. It remains to be tested whether this resistance was the result of cellular interactions, drug-induced changes in sensitivity, or selection for resistant cells already present in the populations. This mixture model may be useful in studies on how cellular interactions influence growth and drug sensitivity in tumor and normal cell populations.

Astrocytoma↗
PubMed1988

Effects of bombesin on growth of human small cell lung carcinoma in vivo.

Bombesin-like peptides are found in many different human tumors and are thought to function as an autocrine growth factor for small cell lung cancer in humans. In this study, a human small cell lung carcinoma (NCI-H69) was s.c. implanted bilaterally into the flanks of 12 nude mice. The mice were randomized and divided into two groups and given either bombesin (20 micrograms/kg) or saline i.p. 3 times a day. Tumor areas were measured twice weekly for 6 wk. At sacrifice, the tumors and normal pancreas were excised, weighed, and assayed for DNA, RNA, and protein content. Significant stimulation of tumor growth was observed at weeks 4, 5, and 6. Tumor weight at sacrifice was significantly elevated (77%) above the control, as was DNA content (78%). Bombesin significantly increased the weight (42%), DNA (48%), and protein (61%) contents of the normal mouse pancreas. We conclude that bombesin may act as an autocrine growth factor, or indirectly through the release of other growth factors, on human small cell lung carcinoma.

Animals↗
PubMed1988

Calmodulin antagonist trifluoperazine inhibits polyamine biosynthesis and liver regeneration.

Polyamines are essential for cell growth and differentiation. Trifluoperazine (TFP) is a potent, competitive inhibitor of the calcium-calmodulin complex. TFP, when given to rats after partial hepatectomy, causes a significant decrease in DNA synthesis. The purpose of this study was to examine the effects of TFP on polyamine biosynthesis and on liver regeneration after partial hepatectomy. TFP (60 mg/kg, bodyweight) or saline control was administered to 80 male Sprague-Dawley rats 2 h before, 2 h after, or at the time of hepatectomy. Polyamines (putrescine, spermidine and spermine) were measured at the time of hepatectomy, and at 6, 24, 48, and 72 h after hepatectomy. TFP, when it was administered either 2 h before or at time of hepatectomy, blocked increases in putrescine that are seen normally at 6 h after hepatectomy. When TFP was given at the time of partial hepatectomy, putrescine was increased at 24 h, and then returned to normal levels at 72 h. Spermidine was inhibited at 24 h, but not at 48 and 72 h. Spermine was not significantly altered at any time. The administration of TFP 2 h after hepatectomy did not significantly alter concentrations of polyamines. The weight of regenerating liver was decreased by TFP at 48 h (23 per cent) and 72 h (22 per cent) after hepatectomy. These findings provide evidence that the calcium-calmodulin complex is required for the synthesis of liver polyamines before liver regeneration can proceed.

Animals↗
PubMed1988

Differential sensitivity of pancreatic and colon cancer to cyclosporine and alpha-difluoromethylornithine in vivo.

We have previously reported that the in vitro growth of MC-26 mouse colon cancer and H2T hamster pancreatic cancer cells are inhibited by cyclosporine (CsA) and alpha-difluoromethylornithine (DFMO). The present study was designed to investigate the effects of these two drugs on the two experimental tumors (MC-26 and H2T) growing in vivo. Forty-eight male Balb/c mice or Syrian golden hamsters were inoculated with MC-26 (250,000) or H2T (500,000) cells, respectively, and then were randomized into four groups of 12 each: group I was control; group II received CsA; group III received DFMO; group IV received a combination of CsA and DFMO. MC-26 tumors were significantly more sensitive than H2T tumors to the effects of CsA and DFMO. MC-26 tumor growth and tumor weight, as well as the tumor content of DNA, RNA, and protein were all significantly more reduced by CsA and DFMO than were the H2T tumors. Our present study shows that both CsA and DFMO are potent inhibitors of MC-26 colon carcinoma growth in vivo, though DFMO is more than twice as effective as CsA. DFMO also produced greater reductions in the tumor content of DNA, RNA, and protein than did CsA. DFMO significantly decreased the concentrations of polyamines in both H2T and MC-26 tumors; the MC-26 tumors were affected to a greater degree.

Adenocarcinoma↗
PubMed1988

Changes in drug sensitivity of a human astrocytoma clone previously treated with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea in vitro.

We have shown in earlier studies that repeated weekly exposures of a human astrocytoma clone (AST 3-4) to MeCCNU (10 micrograms/ml for 1 h per week) produced a linear decrease in survival over the first 3 weekly treatments. But, after that time these cells became progressively more resistant to the 10 micrograms/ml concentration of the agent. In the studies reported here we show that these previously treated cells were also less responsive to other doses ranging from 1 to 30 micrograms MeCCNU/ml. This change in sensitivity to MeCCNU was accompanied by collateral changes in response to other agents: resistance to BCNU and Galactitol, increased sensitivity to Adriamycin, and no change to ionizing radiation. These experiments suggest that once repeated treatments with a single agent cause a tumor cell population to become more resistant, sensitivity to other agents may also change unpredictably.

Astrocytoma↗
PubMed1988

Effect of aging on gastric acid secretion, serum gastrin, and antral gastrin content in rats.

The purpose of this study was to characterize the effects of aging on gastric acid secretion and on serum and antral concentrations of gastrin in rats. Young and old Fischer 344 rats were prepared with gastric fistulas. Twenty-four hours after surgery, graded doses of human synthetic gastrin-17 (SHG-17) (2, 5, 10, 20, and 40 micrograms/kg) were given intravenously in random order. Gastric secretions were collected for gastric acid measurement before and at 15-min intervals after each dose of gastrin. In a separate study, blood was collected and the stomachs were removed for antral gastrin extraction from fed young and old rats. Serum and antral gastrin was measured by radioimmunoassay. The basal and gastrin-stimulated acid secretions were significantly decreased in aged rats compared to the young rats. The basal acid output was 0.4 +/- 0.2 microeq/15 min in the aged rats and 1.5 +/- 0.5 microeq/15 min in the young. The maximal acid output stimulated by gastrin was 11.1 +/- 1.8 microeq/15 min in the aged rats and 24.2 +/- 2.8 microeq/15 min in the young. Both serum and antral concentrations of gastrin were significantly decreased in aged rats. Serum gastrin concentration was 114.8 +/- 7.4 pg/ml in the aged rats and 192.0 +/- 14.4 pg/ml in the young. Antral gastrin concentration was 3.9 +/- 0.5 micrograms/g tissue in the aged rats, which was significantly less than the concentration in the young (6.5 +/- 0.4 micrograms/g tissue). Antral gastrin content did not change with aging.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1988

Peptide YY and gallbladder contraction. Studies in vivo and in vitro.

The purpose of this study was to examine the effect of peptide YY on contraction of the gallbladder in vivo and in vitro and on contraction of the sphincter of Oddi in vitro. In conscious dogs that were prepared with strain-gauge force transducers implanted in the gallbladder wall, peptide YY (400 ng/kg, bolus; 800 pmol/kg.h, infusion) did not affect the resting contractile pattern of the gallbladder, nor did it inhibit cholecystokinin-octapeptide (CCK-8)-stimulated gallbladder contraction. In contrast, the cholecystokinin antagonist proglumide (5, 10, 20, 40, or 80 mg/kg), given in vivo, inhibited CCK-8-stimulated gallbladder contraction in a dose-related manner. The highest dose of proglumide (80 mg/kg) completely abolished contraction of the gallbladder stimulated by CCK-8. In vitro studies showed that peptide YY (0.25, 0.5, or 1 microgram/ml) did not affect the resting tension of rabbit gallbladder strips, and it did not inhibit CCK-8-stimulated contraction of gallbladder strips. Proglumide (0.4, 0.8, 1.6, or 3.2 mg/ml) inhibited CCK-8-stimulated tension of gallbladder strips in a dose-related manner. Peptide YY and CCK-8 had no effect on the motility of the canine sphincter of Oddi in vitro, whereas acetylcholine caused contraction and adrenergic agonists caused relaxation. These results suggest that peptide YY and pancreatone (a peptidelike substance, extracted from ileal and colonic mucosa, that inhibits CCK-8-stimulated gallbladder contraction in vivo) do not appear to be identical.

Ampulla of Vater↗
PubMed1988

The isolation and characterization of estrogen binding proteins in the pancreas of male and female hamsters.

Specific estradiol binding proteins (EBP) that have been described in the pancreatic tissues of a number of species are thought to be important in maintaining the structural and functional integrity of the pancreas. However, possible sex-related differences in the presence and characteristics of EBP have not been examined. In the present study, we have analyzed the pancreatic tissues of male and female Syrian golden hamsters for the presence of EBP and progesterone binding protein (PBP), and further characterized these sites. Our results indicate the presence of only one class of EBP with a high capacity (greater than 500 fmol/mg protein) and low affinity (Kd greater than 1.0 nM) in the pancreatic cytosol of female hamsters. On the other hand, there appeared to be two distinct classes of EBP in the male pancreas. One class of EBP in the male pancreas had a high binding affinity (Kd = less than 0.05 nM) and low capacity (less than 10 fmol/mg protein); we have arbitrarily called these Type I EBP. The second class of EBP in the male pancreas which resembled EBP in the female pancreas had a high capacity (greater than 100 fmol/mg protein) and a low binding affinity (Kd = greater than 1.0 nM); we have called these Type II EBP. The sucrose-density gradient profile of EBP for male and female hamster pancreas demonstrated the presence of both an 8S binding protein and a 4S binding protein in the male pancreas; the female pancreas had only a 4S binding protein. PBP were not detected in pancreas of either male or female hamsters. We conclude that significant sex-related differences are present in the EBP populations of the hamster pancreas.

Animals↗
PubMed1988

Age-related changes in gallbladder contractility and gallbladder cholecystokinin receptor population in the guinea pig.

We have examined the effects of aging on guinea pig biliary motility both in vitro and in vivo. The first experiment compared contractile tension of gallbladder strips from young adult (6-12 months old) and 3-year-old guinea pigs in vitro. Contraction of gallbladder strips from the young guinea pigs was twice as forceful and was more sensitive to octapeptide of cholecystokinin (CCK-8) stimulation than the gallbladder strips from the older guinea pigs. The two groups were also studied in vivo by measuring changes in the intraluminal pressure of the gallbladder in response to exogenously administered doses of CCK-8. Young adult guinea pigs were more sensitive to CCK-8 at the lower doses tested and demonstrated gallbladder contractions that were more forceful than that of the old guinea pigs. CCK receptors were measured on gallbladder muscularis membranes from young adult and old guinea pigs. The number of receptors on gallbladder membranes decreased with age: 65.0 +/- 17.7 fmoles/mg protein on membranes from 1 year old; 7.9 +/- 2.0 fmoles/mg protein on membranes from 3 years old. The binding affinity of CCK receptors on gallbladder muscularis membranes for binding to CCK-8 was not significantly different in the two age groups studied. We conclude that age-related decreases in gallbladder responses to CCK-8 may be due to decreased concentrations of CCK receptors on gallbladder muscle cells.

Aging↗
PubMed1988

Growth factors and intestinal neoplasms.

Signals that control normal and neoplastic epithelial proliferation are not completely understood. We have reviewed the importance of the possible roles of the following control mechanisms: polyamine biosynthesis, intraluminal nutrients, gastrointestinal hormones and growth factors, bowel resection, carcinogens, and oncogenes. The mechanisms by which these agents act and the precise roles they play in normal and abnormal proliferation of intestinal mucosa have not yet been clearly defined. Peptide hormones and growth factors exert their mitogenic effects by first interacting with specific receptors in the cell membrane. Oncogenes induce production of growth factors or replace growth factors and, by themselves, stimulate growth. We believe that no single agent is likely to be responsible; rather, multiple agents are involved in stimulation of growth of normal and neoplastic intestinal epithelial cells. A clear understanding of the factors responsible for regulation of normal and abnormal intestinal cell growth will greatly facilitate the development of therapeutic strategies for the prevention and treatment of gastrointestinal cancers.

Animals↗