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Biomedical subjects

C M Townsend

Publications and source records attributed to C M Townsend.

At least 253 records · Page 14Linked to original sources
PubMed1986

Effects of cyclosporin A and alpha-difluoromethylornithine on the growth of hamster pancreatic cancer in vitro.

The growth and survival of hamster H2T pancreatic ductal adenocarcinoma in vitro are known to be significantly reduced by inhibitors of polyamine biosynthesis. alpha-Difluoromethylornithine (alpha-DFMO) is a specific and irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in polyamine biosynthesis. alpha-DFMO treatment inhibits the growth of H2T pancreatic cancer cells and decreases H2T cell survival in vitro and in vivo. In the present study, the effects of cyclosporin A (CsA) were examined on growth, survival, and polyamine levels in H2T pancreatic ductal adenocarcinoma in vitro. CsA had inhibitory effects on H2T pancreatic cancer growth similar to those of alpha-DFMO; these effects were blocked by the addition of the polyamine putrescine. Polyamine levels were found to be significantly altered in cells treated with CsA and/or alpha-DFMO. The combination of CsA (8.3 X 10(-4) mM) and alpha-DFMO (0.5 mM or 1.0 mM) inhibited H2T cell survival to a greater extent than either agent alone. These results suggest that CsA in combination with other agents that inhibit polyamine synthesis may be useful for the treatment of pancreatic cancer.

Animals↗
PubMed1986

Bile inhibits release of cholecystokinin and neurotensin.

We have investigated the effect of bile on fat-stimulated release and basal plasma levels of cholecystokinin-33/39 (CCK) and neurotensin in six awake dogs prepared with chronic gastric and duodenal cannulas. Experimental bile diversion was achieved by catheterization of the common bile duct through the duodenal cannula; the gallbladder was undisturbed. Bile diversion significantly enhanced the release of both CCK and neurotensin that was stimulated by intraduodenal (ID) infusion of a triglyceride suspension (corn oil) (0.5 gm/kg-hr). The integrated release with ID triglyceride (ng [0 to 90 min]/ml) for CCK was control 5.58 +/- 0.83, bile diversion 14.47 +/- 2.81, bile excess 1.68 +/- 0.56, and for neurotensin was control 0.35 +/- 0.19, bile diversion 1.26 +/- 0.35, and bile excess 0.45 +/- 0.31. ID infusion of excessive bile (bile collected during bile diversion) significantly inhibited both the release and basal levels of CCK. Bile diversion alone did not modify plasma levels of CCK or neurotensin. We conclude that: endogenous bile exerts a negative feedback effect on release of CCK and neurotensin induced by triglyceride and on basal plasma levels of CCK; bile is unnecessary for the stimulation of endocrine cells in the intestinal mucosa by dietary fat; and measured basal levels of CCK and neurotensin represent a real amount of circulating peptide in the fasting state, that is, the basal levels are real and not artifactual.

Animals↗
PubMed1986

Gastrin stimulates growth of colon cancer.

Gastrin is trophic for normal gastric and colonic mucosa. We examined the potential trophic effects of chronic gastrin administration on the growth of mouse colon adenocarcinoma (MC-26). Thirty-three mice bearing transplantable MC-26 colon cancers were treated with varying doses (125, 250, or 500 micrograms/kg/day) of pentagastrin. Significant increases in tumor weight and DNA content were observed. Fundic mucosal weight and DNA content in these mice showed a dose-related trophic response. The weight of control fundic mucosa was 10 mg and rose to 20, 45, and 65 mg with increasing doses of gastrin. The DNA content of control fundic mucosa was 155 micrograms and rose to 220, 340, and 480 micrograms as the dose of gastrin was increased. Pentagastrin stimulated growth of the MC-26 colon cancer, but the threshold for gastrin-stimulated tumor growth was different from that of normal mucosal growth. The hyperplastic response of the fundic mucosa was increased by increasing gastrin doses; whereas, colon cancer hyperplasia was maximal at the lowest dose tested (125 micrograms/kg/day) and did not increase further with increasing doses of hormone. Mice bearing gastrin-stimulated tumors died at a significantly greater rate than did mice with untreated tumors (80% of control mice and none of the treated mice were alive at day 55). The effects of gastrin treatment on the growth of MC-26 colon cancer persist after treatment is discontinued; mice with tumors that were treated with gastrin for either 7 or 14 days and in which the treatment was stopped were all dead by 35 or 28 days, respectively, after the end of treatment.

Adenocarcinoma↗
PubMed1985

Effect of aging on pancreatic secretion in rats.

We have characterized the effects of aging on the pancreatic exocrine secretory response to the normal stimulatory hormones, secretin, and cholecystokinin. Young (6 month old) and aged (26 months old) male Sprague-Dawley rats were prepared with pancreatic fistulas and challenged with different doses of secretin (0.03, 0.06, and 0.12 nmol/kg) and cholecystokinin-8 (0.3, 0.6, and 1.2 nmol/kg) intravenously. The pancreatic secretion was measured for volume and bicarbonate and protein outputs. Our results show that in aged rats, the basal pancreatic secretion volume and protein and bicarbonate outputs were significantly reduced, and the pancreatic secretion volume and protein and bicarbonate responses to graded doses of secretin or cholecystokinin-8 were significantly reduced. This study demonstrates that pancreatic exocrine function in rats diminishes with age.

Aging↗
PubMed1985

Surgical adjuvant treatment of locally advanced breast cancer.

The reported incidence of local recurrence after mastectomy for locally advanced breast cancer (TNM Stage III and IV) is between 30% and 50%. The purpose of this study was to evaluate the effect of radiation therapy (XRT) followed by total mastectomy on the incidence of local recurrence in patients with locally advanced breast cancer. Fifty-three patients who presented with locally advanced breast cancer, without distant metastases, were treated with XRT (4500-5000 R) to the breast, chest wall, and regional lymph nodes. Five weeks after completion of XRT, total mastectomy was performed. There were no operative deaths. The complications that occurred in 22 patients after surgery were flap necrosis, wound infection, and seroma. Patients have been followed from 3 to 134 months. Twenty-five patients are alive (3-134 months), 12 free of disease; 28 patients have died with distant metastases (6-67 months). Isolated local recurrence occurred in only two patients. Four patients had local and distant recurrence (total local recurrence is 6/53). The remaining patients all developed distant metastases. We have devised a treatment strategy which significantly decreases the incidence of local recurrence in patients with locally advanced breast cancer. However, the rapid appearance of distant metastases emphasizes the need for systemically active therapy in patients with locally advanced breast cancer.

Breast Neoplasms↗
PubMed1985

The role of neurotensin in human gallbladder motility.

Gallbladder contraction in response to a fatty meal is thought to be caused by release of cholecystokinin (CCK). We have previously demonstrated a close correlation between circulating concentrations of CCK and contraction of the gallbladder in normal humans and in gallstone patients. Recent studies in animals, however, have shown that other potentially cholecystokinetic hormonal agents are released by a fatty meal, which suggests that other hormones may be involved in postprandial gallbladder contraction. Neurotensin, a 13-amino acid peptide, is released by fat; we have shown it to cause gallbladder contraction in dogs. In the present study, we measured release of neurotensin in seven normal adult volunteers. We determined the effects of infused neurotensin (4 pmol/kg-min) on gallbladder contractility, measured by ultrasonography in 10 adult volunteers, and we evaluated release of neurotensin in eight patients with gallstones. After ingestion of fat, we found significant release of neurotensin in normal volunteers from a mean basal concentration of 15.9 +/- 3.5 pg/ml to a maximum of 34.7 +/- 0.2 pg/ml. In the gallstone patients after fat ingestion, neurotensin rose from a basal of 16.8 +/- 3.1 pg/ml to a maximum of 53.4 +/- 28.1 pg/ml, which was a significantly greater release than in controls. Intravenous infusion of neurotensin produced dilatation of the gallbladder (from a mean basal volume of 13.7 +/- 2.3 cc to 20.0 +/- 1.8 cc). Neurotensin causes relaxation of the gallbladder in humans and, by contributing to stasis, may be involved in the formation of gallstones.

Adult↗
PubMed1985

Proglumide, a gastrin receptor antagonist, inhibits growth of colon cancer and enhances survival in mice.

Some tumors are responsive to hormone manipulation. Some gastric and colonic adenocarcinomas from both humans and animals have specific gastrin receptors. A transplantable mouse colon adenocarcinoma cell line (MC-26) contains gastrin receptors; growth of MC-26 colon cancer in vivo is stimulated by pentagastrin (PG). The purpose of this study was to determine whether a gastrin-receptor antagonist, proglumide (PGL), would inhibit growth of MC-26 colon cancer and prolong survival in tumor-bearing mice. Subcutaneous tumors were induced by injecting single-cell suspensions of MC-26 cells into 50 mice divided into 10/group. In Experiment 1, all mice received 1 X 10(5) tumor cells and treatment groups were divided as follows: Group A received intraperitoneal (IP) saline (0.2 ml tid beginning on day 1); B, IP, PGL (250 mg/kg tid) from day of tumor cell inoculation; and C, IP PGL (250 mg/kg tid) from day 7 after tumor implantation. In Experiment 2, mice were inoculated with half the number of tumor cells. Group I mice received saline and Group II received PGL in the same manner starting on day 1. Tumors were measured and all mice were sacrificed on day 23. In Experiment 1, mean tumor area in Group B (PGL-treated) was significantly smaller than Group A on days 11, 14, 17, and 21. Tumors of Group C were significantly smaller than controls on day 21. Survival of PGL-treated mice was significantly prolonged. In Experiment 2, mean tumor area, mean tumor weight, and tumor DNA and RNA content were significantly less in the PGL-treated group than control. It was concluded that growth of a gastrin-responsive colon cancer was inhibited and host survival was enhanced by treatment with a gastrin-receptor antagonist. Hormone manipulation may be a useful treatment for gastrointestinal cancers.

Adenocarcinoma↗
PubMed1985

Surgical management of tumors that produce gastrointestinal hormones.

Gastrointestinal hormones are produced by specialized endocrine cells found both in the pancreas and distributed throughout the gut. Tumors, both benign and malignant, produce excessive amounts of hormone and thereby cause characteristic syndromes. Surgical management must be primarily directed at tumor removal in order to effect cure of the syndrome, as well as to prevent complications of persistent tumor growth and, subsequently, metastasis.

Gastrointestinal Hormones↗
PubMed1985

Rapid and repeated blood sampling in the conscious laboratory rat: a new technique.

A method for obtaining repeated blood samples from conscious rats by translumbar vena cava puncture is presented. Studies performed at laparotomy enabled us to select a 5/8-in., 25-gauge needle as the ideal instrument for aspirating blood. The awake rat is held prone by an assistant and the needle inserted at the level of the first lumbar vertebra in the coronal plane at an angle of 45 degrees from the vertical. We performed the procedure 350 times in 30 rats (100-300 g) at weekly intervals for 8 wk. Each time, we have obtained 2 ml of blood. The time required for obtaining 30 samples is 15-20 min. There have been no complications and only three deaths (mortality rate, 0.9% per puncture); in all three instances the rats jerked free, lacerating the vena cava. The procedure has been performed in guinea pigs and hamsters, with equal ease, without morbidity or mortality. This new technique permits rapid, atraumatic, repeated samplings from awake animals with no morbidity and minimal mortality.

Animals↗
PubMed1985

Gastrin receptors in normal and malignant gastrointestinal mucosa: age-associated changes.

Synthetic human gastrin 17-I (MG) and an analogue, [Leu15]gastrin-17-I (LG), were radiolabeled with Na125I by Iodo-Gen, EnzymoBead, and chloramine-T methods, and the characteristics of the radiolabeled peptides were determined. When 125I-MG was iodinated by chloramine-T, its biological activity and its binding activity were almost abolished, whereas the biological activity of 125I-LG, iodinated by either of the methods, and of 125I-MG, iodinated by Iodo-Gen and EnzymoBeads, was not significantly affected. The kinetics, affinity, and specificity of binding of 125I-MG, iodinated by Iodo-Gen, to crude and purified membranes from rat fundic mucosa were examined and found to be similar to that for 125I-LG. Age-associated changes in the number and affinity of gastrin receptors (GR) on the crude membranes of gastrointestinal mucosa of rats was also examined. Significantly fewer GR were observed on the crude membranes of fundic mucosa of aged (24 mo old) compared with young (3- and 6-mo-old) rats. In addition, specific gastrin-binding sites (4.7 +/- 0.9 fmol/mg prot) with low affinity (Kd = 3.7 +/- 1.2 nM) were observed in the antrum of aged rats, the significance of which is not understood. There were, however, no differences in the number and characteristics of GR in other regions of the intestine of old and young rats. The presence of GR was additionally assessed in cell lines of gastrointestinal cancers from humans, mice, and hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1985

Distribution of neurotensin in the canine gastrointestinal tract.

The distribution of immunoreactive neurotensin in the canine gastrointestinal tract from the esophagus to the rectum, as well as in the pancreas, was determined by a specific neurotensin radioimmunoassay. Immunoreactive neurotensin was found throughout the gastrointestinal tract and in the pancreas. The highest concentrations of immunoreactive neurotensin were found in the mucosal extracts of the jejunum (422 +/- 68 ng/gm) and ileum (3025 +/- 289 ng/gm). Small but substantial amounts of immunoreactive neurotensin were found in the esophagus, fundus (includes fundus and corpus), antrum, duodenum, colon, and pancreas. The concentrations of neurotensin in the mucosal extracts of the jejunum and ileum increased in a graded fashion from the proximal jejunum to the distal ileum. The neurotensin concentration in extracts of the seromuscular layers of jejunum (73 +/- 14 ng/gm) and ileum (187 +/- 38 ng/gm) were statistically higher in comparison with other gut loci.

Animals↗
PubMed1985

Importance of the ileum in neurotensin released by fat.

Neurotensin is a potent stimulant of pancreatic exocrine secretion. Ileal mucosa is the storage site for about 90% of total neurotensin. Release occurs rapidly after a fatty meal and during perfusion of the duodenum and jejunum with fat but not during perfusion of the ileum with fat. To determine the origin of neurotensin released after fat stimulation, we studied the pattern of release of neurotensin before and after resection of the distal two thirds of the small bowel. Six dogs with gastric and duodenal fistulas were studied on different days. All dogs received infusions (in random order) of intraduodenal corn oil (Lipomul) (3 ml/kg/hr) and intravenous calcium chloride (0.36 mmol/kg intravenous bolus, followed by 0.36 mmol/kg/hr infusion) before and 6 weeks after resection of the distal two thirds of the small bowel with preservation of the ileocecal valve. Plasma levels of neurotensin were measured by specific radioimmunoassay. We found that release of neurotensin, in response to both intraduodenal Lipomul and intravenous calcium chloride stimulation, was abolished by resection of the distal small bowel. Before surgery, Lipomul-stimulated release of neurotensin rose to a peak concentration of 51 +/- 17 pg/ml at 30 minutes. After surgery there was no release (the levels were unchanged from basal). Before surgery, intravenous calcium chloride produced a peak release of neurotensin (52 +/- 15 pg/ml) 2 minutes after bolus injection. After surgery, neurotensin was not released by intravenous calcium. We conclude that the source of neurotensin released by perfusion of the proximal gut and by intravenous calcium infusion is the ileum. The release of neurotensin from the distal gut appears to be dependent on a signal from proximal to distal gut. The identity of the signal is unknown but is either a nerve reflex or a peptide agent.

Animals↗
PubMed1985

Effect of aging on gallbladder contraction and release of cholecystokinin-33 in humans.

The objective of this study was to examine the effect of aging on gallbladder contraction and cholecystokinin (CCK) release, as well as on the correlation between the two in humans who are free of gallbladder disease. Twenty-nine human volunteers were divided into a young group of 14 individuals (ages 22 to 42 years, median age 32 years) and an older group of 15 individuals (ages 60 to 84 years, median age 66 years). In the study each person in both groups was given corn oil (Lipomul), 1.5 ml/kg, by mouth after an overnight fast. Blood was collected for measurement of CCK-33 by radioimmunoassay before and at intervals after ingestion of Lipomul. Simultaneous measurements of gallbladder volume were obtained by real-time varian ultrasonography. Both fasting and fat-stimulated concentrations of CCK in plasma were significantly higher in the older individuals than in the younger volunteers. The 60-minute integrated measurement of CCK release was significantly increased in the older people as compared with the young. Both fasting and maximally contracted gallbladder volumes were equal in the older and younger groups. The rate of emptying of the gallbladder was equal in both age groups, but the gallbladders of older people appeared to show an earlier initiation of contraction. The highly significant correlation of gallbladder contraction with levels of CCK was similar in both age groups, but the sensitivity of the gallbladder to CCK in the older people was significantly decreased. In conclusion, both fasting and fat-stimulated plasma levels of CCK increase with aging. The sensitivity of the gallbladder muscle to stimulation by CCK is diminished with age, but this appears, teleologically, to be matched by the increased release of CCK, so the kinetics of gallbladder emptying are little different in the aged.

Adult↗
PubMed1984

Role of neurotensin in pancreatic secretion.

The objective of this study was to examine the effect of neurotensin (NT) on pancreatic exocrine secretion in awake dogs (n = 5) with chronic gastric and pancreatic fistulas. Intravenous (IV) infusion of NT (1 microgram/kg/hr) alone significantly stimulated pancreatic secretion of protein and bicarbonate without causing release of secretin or cholecystokinin-33 (CCK-33). IV NT potentiated the secretory response of pancreatic bicarbonate to the intraduodenal (ID) infusion of HCl alone and to ID infusions of the amino acids, phenylalanine and tryptophan (AA) alone, as well as to an ID mixture of AA plus HCl. IV NT acted in an additive manner with ID AA, ID HCl, or ID AA plus HCl in the stimulation of pancreatic protein output. The addition of IV NT to each luminal secretagogue (ID AA, ID HCl, or ID AA plus HCl) failed to elevate plasma concentrations of CCK-33 or secretin over those observed during ID infusion of each secretagogue alone. ID corn oil (Lipomul) stimulated the simultaneous release of CCK-33, NT, and secretin significantly; IV infusion of NT (0.5 microgram/kg/hr) resulted in plasma NT levels that were similar to levels observed after ID Lipomul. These studies provide evidence that endogenous NT, CCK, and secretin may interact in the physiologic regulation of pancreatic exocrine secretion.

Amino Acids↗
PubMed1983

Heterogeneous responses of an in vitro model of human stomach cancer to anticancer drugs.

Four permanent clones of a human adenocarcinoma of the stomach and the parent line from which they were isolated were used as an in vitro model system to evaluate the effects of 8 anticancer agents on cell survival. The drugs tested were actinomycin D (Act-D), Bleomycin (Bleo), adriamycin (adria), melphalan, chlorambucil, 5 Fluorouracil (5FU), 1,2:5,6-Dianhydrogalactitol (DAG), and 1-(2-chloroethyl)-3-(4-methyl cyclohexyl-1-nitrosourea) (MeCCNU). Although the cell lines had similar growth properties, morphologies and modal chromosome numbers, the clones expressed heterogeneous survival responses to each of six drugs tested. A comparison of the doses lethal to 90% of a clonal population (LD90) for each drug indicated large differences between the most sensitive and least sensitive clones. For chlorambucil there was a 160% difference between the LD90 values of the most and least sensitive clones. For MeCCNU the difference was 200%; for adria, 230%; Bleo, 280%; 5FU, 360%; and melphalan, 600%. Despite the heterogeneity in response among the clones to these agents, no particular clone was always the most sensitive or resistant. Of particular interest was the finding that these stomach cancer clones demonstrated uniform responses to both Act-D and DAG. Since the differential drug sensitivities expressed by heterogeneous tumor populations could be a cause of treatment failure in the patient, the demonstration of uniform sensitivities to Act-D and DAG are encouraging and suggest that other anticancer drugs which produce uniform cell killing may be identified and tested. Act-D and adria were the most effective of the drugs tested when compared on a dose for dose basis. Both agents killed more than 99.9% of the parent cell line with doses below 3 micrograms/ml (1-h treatments). The cells were least sensitive to 5FU, with only 30% of the cells killed at 100 micrograms/ml. The studies reported here indicate that this human stomach cancer model can provide valuable insight into the design of clinical protocols for treatment of gastric carcinoma in man.

Adenocarcinoma↗
PubMed1983

The role of surgery in the Zollinger-Ellison syndrome.

When the Zollinger-Ellison syndrome was first identified, total gastrectomy was proposed as the most effective treatment for the secretory manifestations of the syndrome. Recently, however, great enthusiasm has developed for medical treatment by means of H2-receptor antagonists. The authors have cared for 27 patients with the Zollinger-Ellison syndrome at The University of Texas Medical Branch in the past 12 years and have been pleased with the results of total gastrectomy, which was performed in 23 of the 27 patients (one patient refused operation and three patients had lesser gastric operations). Twenty-three patients underwent total gastrectomy with Roux-en-Y esophagojejunostomy. There were no operative deaths. Primary tumors were found in 17 patients, seven of whom also had metastatic tumors. No tumors were found in nine patients. Nine patients are dead; the actuarial survival rate for all patients was 75% at 5 years and 52% at 10 years. Eleven of the 27 patients had the multiple endocrine neoplasia I syndrome. Of the 18 survivors, only three have normal serum gastrin levels, and all three had extrapancreatic gastrinomas, one in peripancreatic lymph nodes, one in the liver, and one in a cystic tumor attached to the stomach. Nutritional results were good to excellent, with a mean postoperative weight loss of 14.7% (mean follow-up period was 45 months). The authors conclude that treatment of the hypersecretory problems of the Zollinger-Ellison syndrome by total gastrectomy is safe and dependable. Results compare well with those of long-term medical management, whose success is dependent upon serial favorable responses to a lifetime of repeated challenges.

Adolescent↗
PubMed1983

Inability of thoracic duct drainage to prevent hyperacute rejection.

Serum and lymph albumin and Ig levels were measured during 6 weeks of lymphocyte depletion by thoracic duct drainage (TDD) in 21 patients prior to renal allotransplantation. In ten of these patients, the amount of protein lost from all sources (blood sampling, dialysis, and lymph centrifugation) was measured. The total amount of albumin lost was significantly greater than the amount of IgG lost. However, serum IgG declined at a faster rate and to a greater extent than albumin. Hyperacute or acute humoral rejection occurred in 14 grafts in 10 patients prepared by TDD despite negative crossmatch tests. These data suggest that removal of lymphocytes by TDD, rather than protein loss alone, affects IgG levels. On the other hand, TDD and IgG depletion do not prevent hyperacute or acute humoral rejection. This is most likely due to the inability of currently employed crossmatch tests to predict accurately which patients will manifest antibody-mediated graft rejection.

Drainage↗