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Biomedical subjects

C M Townsend

Publications and source records attributed to C M Townsend.

At least 235 records · Page 13Linked to original sources
PubMed1987

Treatment of hamster pancreatic cancer with alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis.

Polyamines are essential for cell division and growth. Inhibition of polyamine biosynthesis by alpha-difluoromethylornithine (DFMO) on the growth of hamster H2T pancreatic cancer was investigated both in vitro and in vivo. Cell-doubling time (TD) and survival fraction were determined after a single treatment with DFMO (5 mM). We examined the ability of putrescine to reverse the growth-inhibitory effect of DFMO. The TD for cells treated with DFMO in vitro was 49.6 +/- 5.7 versus 25.4 +/- 2.6 hours for control. The addition of putrescine to DFMO-treated H2T cells showed a reversal of the growth-inhibitory effect of DFMO. Cytotoxicity in vitro increased with prolonged treatment; the survival fraction after 24 hours of treatment was 32%; after 48 hours, 19%; after 72 hours, 13%; and after 92 hours, 8%. We performed two separate animal experiments. In experiment I, H2T cells were injected into the cheek pouch of male Syrian golden hamsters; controls did not receive DFMO. Continuous treatment with 3% DFMO in the drinking water was begun 7 days before, on the day of, or 7 days after tumor cell injection. In experiment II, 4 groups were treated identically to those in experiment I. An additional group of 10 hamsters received 3% DFMO and no tumor, and another additional group of 10 hamsters were housed individually with 3% DFMO begun 7 days after tumor cell injection. Tumor size, body weight, water, and food intake were measured. DFMO treatment in vivo significantly inhibited tumor size and inhibited growth of pancreatic cancer by as much as 50% of control. Our results demonstrate a significant antiproliferative effect of DFMO on the growth of pancreatic adenocarcinoma both in vitro and in vivo.

Adenocarcinoma↗
PubMed1987

Calcitonin gene-related peptide: possible tumor marker for medullary thyroid cancer.

We have sought to determine whether medullary thyroid carcinoma (MTC) released calcitonin gene-related peptide (CGRP) in vivo. MTC cells were inoculated from tissue culture into eight Wag-Rij rats. One month later blood was drawn before and after the intravenous injection of calcium, and plasma levels of CGRP and calcitonin (CT) levels in that blood were determined by radioimmunoassay. The tumor was examined for content of CGRP and of CT by means of radioimmunoassay and immunocytochemistry. The tumor was divided and portions were passed to another eight rats. One month later, the studies were repeated. The tumor was passed two additional times (four passages in all). Controls consisted of non-tumor-bearing Wag-Rij rats. Basal levels of plasma CGRP in control rats (7 +/- 1 ng/ml) were unaffected by calcium stimulation. In tumor-bearing rats, the plasma CGRP level, which was initially slightly elevated (15 +/- 7 ng/ml), rose progressively with passages to 279 +/- 79 ng/ml in the third passage and fell to normal values at the end of passage four. Hypercalcemia had no effect on plasma CGRP levels in tumor-bearing rats but did stimulate the release of CT in both control and tumor-bearing rats, although it is not clear whether this release was from the tumor or from normal thyroid parafollicular cells in these tumor-bearing rats. We conclude that rat MTC synthesizes and releases CGRP but, unlike CT, CGRP appears unresponsive to calcium stimulation.

Animals↗
PubMed1986

Heterogeneous survival responses of human gastric cancer clones to alpha difluoromethylornithine in vitro.

The effects of alpha Difluoromethylornithine (DFMO)2 on survival of human gastric cancer clones were studied in vitro. The responses were dose and time dependent. Treatments which lasted for less than 12 h were cytotoxic at only the highest doses used. The greatest effects on survival were observed only when cells were treated for 48 and 72 h. The effects on the clones produced by such prolonged treatment durations were heterogeneous, with survival values differing by as much as 460%. By contrast, the clonal survival responses to short DFMO treatments (12 h) were very uniform (dose differential of only 19%); however, this uniformity in response could be achieved only by using non-pharmacological doses of DFMO. The heterogeneity in survival responses in the clones might be slightly associated with their levels of intracellular spermidine. Clones with the smallest amounts of intracellular spermidine at the start of treatment were most sensitive to DFMO. However, this association may not hold up with further testing in other gastric cancer clones or when studied in other cancer lines in vitro.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Cell cycle kinetics responses of human stomach cancer cells to reduction in polyamine levels by treatment with alpha difluoromethylornithine in vitro.

Treatment of human gastric cancer clones in vitro with low doses of DFMO (5 mM) produced elongation of the cell population doubling times and lowering of the saturation densities. By contrast, DFMO treatment of normal human skin fibroblasts altered only the saturation density. The lack of an effect of 5 mM DFMO on the doubling time of normal fibroblasts may be directly related to baseline intracellular putrescine levels, which were about 2.5 times higher than in the cancer cells. The same dose of DFMO caused a rapid decrease in intracellular polyamine levels in the tumor clones. The effects on the doubling time and saturation density were almost totally abolished by the addition of 50 microM putrescine to the growth medium during the first 24 h of treatment with DFMO. Exposure to 5 mM DFMO for 24 h caused the human gastric cancer cells to become blocked in G1 phase only, and this led to a reduction in the fraction of cells in S phase. The G1 block was reversible and this cohort of cells eventually passed through S phase and then through G2 and M. A higher 100 mM dose of DFMO and longer exposure times for both doses produced cell cycle changes and death of more than 90% of the cell population. These data suggest that cell kinetics changes observed under these experimental conditions may reflect polyamine-related alterations in the biochemical events of cell cycle progression kinetics; but may also be the result of DFMO-induced loss of cell viability.

Cell Cycle↗
PubMed1986

Superoxide dismutase and catalase: a possible role in established pancreatitis.

The mechanism of cerulein-induced acute pancreatitis may involve the production of free radicals in excess of the capacity of endogenous intracellular scavengers. These radicals destroy the cellular membranes, releasing digestive enzymes and cellular proteins into the interstitium. Thereafter, a cascade of events, including polymorphonuclear infiltration and complement activation, leads to pancreatic destruction. The present study demonstrates that superoxide dismutase and catalase reduce the ultrastructural and biochemical injury associated with cerulein-induced acute pancreatitis in rats. Pretreatment with superoxide dismutase and catalase 30 minutes before injury did not appear to be protective, presumably because the half-life of intravenous superoxide dismutase is only 6 minutes. This and similar studies suggest a potential clinical role for free radical scavengers in acute established pancreatitis.

Acute Disease↗
PubMed1986

Neurotensin stimulates pancreatic exocrine secretion in rats.

Neurotensin (NT) stimulates pancreatic exocrine secretion in dogs and humans. The purpose of this study was to examine the effect of exogenous neurotensin on pancreatic exocrine secretion in rats. Five Sprague-Dawley male rats were prepared with pancreatic, gastric and duodenal fistulas. Bile was shunted into the duodenum in order to collect pure pancreatic juice. 24 h later, neurotensin (0.05, 0.1, 0.2, 0.3, 1.0 nmol/kg) was infused intravenously in a random fashion. Pancreatic juice was collected every 10 min, and the volume was recorded and protein and bicarbonate were measured. Neurotensin stimulated, in a dose-related manner, the pancreatic secretion of water, protein and bicarbonate. Neurotensin may be involved in the physiologic control of pancreatic secretion in rats.

Animals↗
PubMed1986

Gastrinoma.

Although there are multiple etiologies of clinical hypergastrinemia, the most important cause is gastrinoma [Zollinger-Ellison (ZE) syndrome]. The most significant advance in the management of patients with the ZE syndrome has been the development of the ability to establish firmly the correct preoperative diagnosis by radioimmunoassay. We believe that all patients who have the ZE syndrome should undergo operation for two reasons: to identify and resect all tumor and because in patients in whom no tumor is found or in whom all tumor cannot be resected, the most reliable relief of hypersecretory symptoms for the life of the patient can be achieved by total gastrectomy.

Cimetidine↗
PubMed1986

Differential response to gamma radiation of human stomach cancer cells in vitro.

In vitro effects of radiation were studied in two permanent cell lines (AGS and SII) from two patients with adenocarcinoma of the stomach and three permanent sublines from each cell line. Radiation survival parameters for AGS and SII parent cell lines and sublines were determined after in vitro irradiation of their cells with 0.5 to 10 Gy of 60Co gamma rays. The AGS and SII cell lines had different growth properties, DNA contents and radiation survival curves. Surviving fractions of SII parent cells (76 chromosomes) after 2.0 and 10 Gy were 1.22 and 17.8 times greater, respectively, than values for AGS parent cells (47 chromosomes). Sensitivities (D0) were 1.08 and 1.45 Gy for AGS and SII parent lines, respectively. The D0 values for AGS parent cells and sublines were similar (1.01 to 1.08 Gy), but SII parent cells and sublines had D0 values of 1.45, 1.36, 1.37 and 1.12 Gy (for SII-A). Also, the SII parent cells had survival fractions after 2.0 and 10 Gy that were 1.3 and 11.3 times greater, respectively, than values for the SII-A cells. These data show differences in radiation responses among stomach cancer cell lines and sublines that may relate to DNA content, but there was no consistent correlation between radiation response and a particular cell characteristic.

Adenocarcinoma↗
PubMed1986

Diagnostic role of gastrointestinal hormones in patients with chronic pancreatitis.

Thirty-three patients with chronic pancreatitis were studied in an effort to correlate release of gastrointestinal hormones (GIH) with the degree of pancreatic insufficiency. A prospective examination was conducted of fat-stimulated release of pancreatic polypeptide (PP), cholecystokinin (CCK), and neurotensin. Seventy-two-hour fecal fat determination, endoscopic retrograde pancreatography (ERP), and the bentiromide-PABA test were used to correlate the clinical stage of disease. The ERP was classified as positive only if the changes were advanced (or "marked") according to the Cambridge Classification. Five patients were defined to have mild disease, 13 moderate, and 15 severe. Any patient with clinical evidence of chronic pancreatitis and ERP changes that were less than advanced and had normal fecal fat and bentiromide tests received a grade of mild. Patients with one abnormal test were graded moderate, and those with two or three abnormal results were graded severe. In the 33 patients, the integrated 60-minute release of pancreatic polypeptide (PP) was 37.4 +/- 6.1 ng-60 min/ml in those five patients with mild disease, 102.3 +/- 10.3 ng-60 min/ml in the 13 patients with moderate disease, and 7.6 +/- 2.2 ng-60 min/ml in the 15 patients with severe disease. The integrated 60-minute release of neurotensin was 3.8 +/- 0.4 ng-60 min/ml in mild disease, 2.0 +/- 0.3 ng-60 min/ml in moderate disease, and 0.2 +/- 0.1 ng-60 min/ml in severe disease. CCK release did not correlate with the severity of disease. Enhanced release of PP appeared to correlate well with moderate stage of chronic pancreatitis, and depressed PP release with severe disease. Stimulated levels of PP and neurotensin appear to be useful in the diagnosis and staging of chronic pancreatitis. It is concluded that measurement of fat-stimulated release of PP and neurotensin may be useful to assess severity of disease in patients with chronic pancreatitis.

Adult↗
PubMed1986

Presence of estradiol-binding proteins in gastrointestinal tract of male rats.

In the cytosol from pancreas, fundus, and antrum of rats, two classes of specific, estradiol (E2)-binding proteins (EBPs) were observed, with 5- to 10-fold differences in their binding affinities, and 10- to 20-fold differences in their binding capacities. EBPs, both type I [high affinity, dissociation constant (Kd) less than 1.0 nM] and type II (low affinity, Kd greater than 5 nM), in the fundus were found to be specific for estrogens. None of the corticoids, or androgenic and progestogenic steroids tested demonstrated any significant inhibition of binding of radiolabeled E2 to EBP at doses as high as 5 X 10(-6) to 5 X 10(-5) M. At high concentrations of E2 (greater than 2-5 nM), nonsaturable EBPs were additionally observed in the pancreatic cytosol. In the intestine, however, EBP was not detected at E2 concentrations of less than 2 5 nM. Similarly, progesterone-binding proteins were nonmeasurable in either pancreas or gastrointestinal tissues at less than 5 nM concentrations of the ligand, indicating questionable physiological significance of the latter binding sites. The two classes of EBPs in the pancreas and stomach of rats, measured at near physiological E2 concentrations of less than 2 nM, however, may play a significant role in gastric and pancreatic functions, since sex steroids have been documented to have specific effects on structure and function of pancreas and stomach.

Animals↗
PubMed1986

Insulin receptor proliferation: a mechanism for tumor-associated hypoglycemia.

A 30-yr-old man was found to have intractable hypoglycemia associated with colon carcinoma metastatic to the liver. Analysis of glucose requirements before death revealed a level of glucose turnover in excess of 12.9 mg/kg X min, consistent with maximally stimulated whole body glucose utilization. This high level of glucose turnover was present at a time when plasma immunoreactive insulin was very low. Insulin binding was measured in freshly isolated circulating mononuclear cells before death and in plasma membranes prepared from several tissues obtained at autopsy. A 3- to 5-fold increase in insulin receptor number was found in the mononuclear cells and liver and muscle plasma membranes. In contrast, skin fibroblasts maintained in tissue culture demonstrated no increase in insulin binding, thus suggesting that the increase in insulin receptors in freshly isolated tissues was acquired rather than intrinsic. Antibodies directed against the insulin receptor were not present. The patient's serum concentration of insulin-like growth factor I was low, but the serum level of nonsuppressible insulin-like protein was elevated. Serum bioassayable insulin-like activity was decreased. Based on tumor bulk at autopsy and in vitro analysis of glucose transport by his tumor cells maintained in monolayer tissue culture, it was estimated that his tumor could directly account for less than one third of the whole body glucose requirement. These data suggest that the increased tissue utilization of glucose in this hypoglycemic patient was caused by proliferation of insulin receptors in liver and muscle induced by his nonislet cell tumor through an unknown humoral mechanism(s).

Adenocarcinoma↗
PubMed1986

Loss in cell killing effectiveness of anticancer drugs in human gastric cancer clones due to recovery from potentially lethal damage in vitro.

The ability of human gastric cancer clones to recover from potentially lethal damage was studied. Recovery was greatest following treatments with bleomycin or Adriamycin; the recovery ratios (i.e., survival) increased almost 8-fold during a posttreatment incubation period. Recovery was also possible following treatments with actinomycin D, 1,2:5,6-dianhydrogalactitol, and diaziquone; however, the recovery ratios never increased above 2. No recovery was observed following treatment with 5-fluorouracil. Recovery from potentially lethal damage may be related to the heterogeneity in survival responses observed following treatment with some anticancer drugs. Bleomycin and Adriamycin treatments result in large heterogeneous survival fractions among these human stomach cancer clones, and the potentially lethal damage recovery ratios were larger (and variable). However, actinomycin D, diaziquone, and 1,2:5,6-dianhydrogalacticol produce very uniform killing effects in these cells and the recovery ratios are very much smaller and less variable. Finally the large amount of recovery observed after bleomycin or Adriamycin treatments resulted in the loss of cell killing effectiveness of the agents. Because the survival fractions increased during the recovery period, the net effect on cell killing was reduced to an amount normally obtained with doses that were up to six times smaller.

Antineoplastic Agents↗
PubMed1986

Role of gastrin and gastrin receptors on the growth of a transplantable mouse colon carcinoma (MC-26) in BALB/c mice.

We recently reported trophic response of transplantable mouse colon cancer cells (MC-26) to pentagastrin, in vivo, and demonstrated gastrin receptors on MC-26 cells, in vitro. In the present study, growth of MC-26 cells in mice, in response to pentagastrin, was studied in relation to binding kinetics and capacity of gastrin receptor. Gastrin receptor levels on mouse fundic and colonic membranes and on MC-26 cellular membranes were determined before MC-26 cell inoculation and designated as Day 0 levels. Four groups of mice were next inoculated with MC-26 cells and given injections of either pentagastrin (treated) or normal saline (control) for 10 or 15 days. At the end of the treatment periods, body, tumor, fundic, and colon weights were noted and gastrin receptor measured. tumor and fundic weights increased significantly within 15 days of pentagastrin treatment, compared to control values. In control (non-pentagastrin treated) mice, the binding affinity of gastrin receptor on tumor membranes was significantly decreased and associated with the complete loss of high-affinity gastrin receptor (Kd = less than 0.5 nM) by Day 15 of tumor growth. On the other hand, both the binding affinity and gastrin receptor levels of tumor membranes were maintained at Day 0 values by pentagastrin treatment. Endogenous gastrin was therefore ineffective in maintaining high-affinity gastrin receptor on control tumors. A significant number of low-affinity gastrin-binding sites (Kd = less than 2 nM) appeared in control tumors by Day 15, which could reflect rapid dedifferentiation or conformational changes of gastrin receptor in the absence of high levels of normal regulatory hormones. These studies demonstrate that the trophic effects of gastrin on MC-26 cells are probably mediated by its regulation and maintenance of the binding affinity and capacity of gastrin receptor on the cancer cells, in vivo.

Animals↗