Growth in Rats Gut: First Published As 10.1136/Gut.36.1.137 on 1 January 1995

Gut 1995; 36: 137-141 137

Profound duodenogastric reflux causes pancreatic growth in rats Gut: first published as 10.1136/gut.36.1.137 on 1 January 1995. Downloaded from T Gasslander, H Mukaida, M K Herrington, R A Hinder, T E Adrian

Abstract model was used to investigate the short term Although duodenogastric reflux is a effects of pronounced duodenogastric reflux on physiological event, excessive reflux may pancreatic growth in the rat, and to evaluate the be a pathogenetic factor in several diseases role of CCK in this process. ofthe foregut, including cancer. Long term profound duodenogastric reflux produces pancreatic and gastric tumours in rats. Methods The trophic effect of surgically induced Male Wistar rats weighing 175-200 g (Sasco duodenogastric reflux on the pancreas was Inc, Omaha, Nebraska, USA), were used in investigated and the mechanisms involved the study. They were housed individually and were examined. Rats with profound reflux fed standard pelleted rat chow with free access from a split gastroenterostomy were com- to water. pared with sham operated and unoperated controls after two and six weeks. In the six week experiment, one reflux and one DESIGN OF THE STUDY sham group were given the cholecystokinin (CCK) receptor antagonist devazepide Experiment I (25 nmollkg/h). Duodenogastric reflux To investigate possible growth effects of duo- caused a significant increase in pancreatic denogastric reflux on the pancreas, a group of weight, DNA, and plasma CCK and gastrin rats with a split gastrojejunostomy (n= 10) concentrations at both two and six weeks. were compared with sham operated rats (n=8) Devazepide substantially reduced the and unoperated controls (n=8), two weeks pancreatic weight increase after six weeks after surgery. but did not abolish it completely. CCK and gastrin were not affected by devazepide. These results suggest that CCK is largely Experiment II

responsible for the pancreatic growth The effects of duodenogastric reflux were http://gut.bmj.com/ induced by reflux but another factor may studied six weeks after surgery. Seventeen also be involved. The trophic effect of animals had a split gastrojejunostomy per- duodenogastric reflux may contribute to formed and eight of these also received the the increased incidence of pancreatic specific CCK receptor antagonist devazepide cancer reported after gastric surgery. (also called MK329, Merck Sharp & Dohme).20 (Gut 1995; 36: 137-141) These were compared with sham operated rats

with and without devazepide (n=6 and n=7, on October 1, 2021 by guest. Protected copyright. Keywords: duodenogastric reflux, pancreatic growth. respectively) and unoperated controls (n=5).

The regulation of pancreatic growth and tumour development is not fully understood. Several peptide hormones, and cholecystokinin (CCK) in particular, are known, however, to be trophic to the pancreas in experimental animal models.' 2 The release of some of these growth factors is influenced by surgical manipulation of the gastrointestinal Departments of tract, such as bowel resection, cholecys- Biomedical Sciences tectomy, and pancreatico-biliary diversion.3-9 and Surgery, Creighton University, Furthermore, some regulatory peptides Omaha, Nebraska, stimulate the growth of pancreatic cancer in USA experimental animal models.10S1 Long term T Gasslander reflux in H Mukaida (56 weeks) duodenogastric (DGR) M K Herrington rats, induced by split gastrojejunostomy, has R A Hinder recently been shown to induce pancreatic T E Adrian hyperplasia and adenomatous nodules without Correspondence to: using carcinogens.i6 The underlying patho- Dr T Gasslander, mechanism is not under- Departrnent of Surgery, physiological fully University Hospital, stood. In humans, several epidemiological S-581 85 Linkoping, studies have suggested that previous gastric Sweden. surgery is a risk factor for cancer.17-i9 Accepted for publication pancreatic Figure 1: The split gastrojejunostomy. See Methods section 29 April 1994 In the present study, the split gastrojejunostomy for details ofprocedure. 138 Gasslander, Mukaida, Herrington, Hinder, Adrian

SURGICAL PROCEDURES nective tissue, fat, and lymph nodes; and A split gastrojejunostomy (Fig 1) was per- weighed. It was minced with scissors and formed through an upper midline incision divided into aliquots for measurement of under general anaesthesia (ketamine DNA, total protein, and 3H-thymidine uptake. hydrochloride 100 mg/ml:xylazine 100 mg/ml, The whole duodenum and the first 10 cm of 10:1, 0.1 ml/100 mg body weight). The the efferent loop of jejunum distal to the Gut: first published as 10.1136/gut.36.1.137 on 1 January 1995. Downloaded from proximal jejunum was divided approximately anastomosis were separately excised, 2 cm distal to the ligament of Treitz and the measured, and weighed. The mucosa was afferent loop was anastomosed to the greater scraped off, weighed, and divided into aliquots curvature of the stomach 2-3 mm distal to the for measurement of DNA, total protein, squamocolumnar junction using one layer of 3H-thymidine uptake, and CCK. The aliquots interrupted 7-0 Prolene sutures. The efferent of tissue were stored in - 80°C until analysis. jejunal loop was anastomosed to the stomach The blood was immediately centrifuged at 4°C 10 mm distal to the afferent loop with the same in tubes containing 2 mg EDTA and 400 KIU technique. A sham operation was performed Aprotinin/ml blood, and the plasma was stored by transecting the proximal jejunum at the at - 800C for subsequent measurement of same point, anastomosing the bowel ends, and CCK and gastrin by radioimmunoassay. attaching the anastomosis to the stomach serosa. The surgery was performed after overnight fasting and the animals were BIOCHEMICAL ASSAYS deprived of water for 24 hours and of food for 3H-thymidine uptake was determined in a 48 hours after the procedure. beta counter after tissue solubilisation in The CCK receptor antagonist devazepide TS-1 (Research Products Int Corp, Mount was administered continuously (25 nmol/kg/h) Prospect, IL) and the addition of a scintilla- by means of a subcutaneously implanted tion cocktail (Safety Solv, Research Products osmotic mini pump (Alzet model no 2002, Int Corp). DNA was determined fluorimetri- Alza, Palo Alto, CA). The devazepide was cally on a crude tissue homogenate by the dissolved in 70% dimethyl sulphoxide and the method described by Labarca and Paigen22 mini pump was changed every 14th day under using bisbenzimidazole (Hoechst 33258) ether inhalation anaesthesia. Animals without as reagent. Protein was determined spectro- the antagonist, except for the unoperated photometrically by means of the Bio Rad controls, had a silicone tube (placebo) of the Protein Assay (Bio-Rad Chemical Division, same dimensions as the minipump implanted Richmond, CA). and changed in the same manner. Previous experiments have shown no effect of infusion of the carrier vehicle on pancreatic growth.2' RADIOIMMUNOASSAY CCK and gastrin were extracted from plasma http://gut.bmj.com/ using reverse phase Sep-Pak C18 cartridges TISSUE AND BLOOD COLLECTION (Waters Associates, Milford, MA) as previ- After an overnight fast the animals were ously described.23 24 CCK was extracted from weighed, given an intraperitoneal injection of small bowel muscosa by boiling in 0 5 M acetic 3H-thymidine (I[methyl-3H] thymidine 25 acid for 10 minutes. The extracts were freeze Ci/mmol, Amersham Corp, Arlington, IL; dried and stored at -200C. The peptides were 1 mCi/kg), and killed one hour after the later analysed by means of a specific, sensitive on October 1, 2021 by guest. Protected copyright. injection. They were anaesthetised in the same radioimmunoassay previously described in manner as for surgery (see above), the thorax detail.23 24 The CCK assay uses an antibody was opened, and blood was collected from the (CCK-2) raised to pure, unconjugated, right ventricle of the heart. The animals were porcine CCK-33 with Bolton and Hunter, thereby killed by exsanguination. The pancreas reagent-labelled sulphated CCK-8 as the was excised; carefully dissected free from con- tracer. Synthetic CCK-33 was used as a

2 weeks 6 weeks A B mg. * *** mg ¢ 700- -** 700- .0 .0 0) 600- 0 600- 0 0 > 500- 500- CD 4- 0 400- 400- Figure 2: Pancreatic wet .' weight/1 00 g body weight 4) 300- ¢ 300- in rats two weeks (A) 0i and six weeks (B) after ID split gastrojejunostomy 0L) 200- .0) 200- (DGR). Sham operation 100 : 100- (Sham) implies small CD CL bowel transection. CL O- Control=unoperated 0 01-1 7>,~,,J1,z.",,"{,,,, controls. MK=devazepide, DGR Sham Control DGR DGR Sham Sham 25 nmol/kg/h.*=p<0-05, + + ***=p<000I. MK MK Profound duodenogastric reflux causes pancreatic growth in rats 139

Total pancreatic DNA content (mg/i 00 g body weight, mean (SEM)) in rats two and six Devazepide reduced the pancreatic weight weeks after split gastrojejunostomy (DGR). Sham operation (Sham) implies small bowel transection. Control= unoperated controls. MK= devazepide, 25 nmol/kg/h increase significantly (p<005) after six weeks in the duodenogastric reflux group to a level Time DGR DGR+MK Sham Sham+MK Control that was not significantly different from that of 2wk 1-72 (022) 1.11 (0-12) 1-12 (0-12) the sham operated rats (Fig 2). There was no

6 wk 2-63 (0-16)* 2-09 (0-17)t 1-82 (0-13) 1-26 (0-14) 1-73 (0 20) difference in pancreatic wet weight between Gut: first published as 10.1136/gut.36.1.137 on 1 January 1995. Downloaded from the sham operated animals and the unoperated *=p<0o05 v sham, t=p<005 v sham+MK. controls at either two or six weeks. No significant difference was found in duodenal or standard. The assay measures all forms of jejunal mucosal weights between the duo- sulphated CCK but shows no significant cross denogastric reflux group and the sham or reaction with the gastrins. control groups at either time point (data not shown).

STATISTICAL ANALYSIS Statistical analysis was carried out using one PANCREATIC DNA AND PROTEIN CONTENT way analysis of variance (ANOVA) with the After six weeks, there was a significant increase Bonferroni post test for multiple com- in pancreatic DNA (mg/100 g body weight) in parisons. the duodenogastric reflux animals compared with the sham operated animals (p<005) (Table). The difference in pancreatic DNA Results after two weeks did not reach statistical signifi- Overall mortality among all duodenogastric cance. The total pancreatic protein content reflux rats was 13% (four of 31) with no was not significantly changed after either two deaths among the sham operated animals. or six weeks (data not shown). There was no significant difference in post- operative weight change between any of the groups. No dilatation or other macroscopic 3H-THYMIDINE UPTAKE change was found on the stomach or small No difference in 3H-thymidine uptake in bowel. pancreatic tissue or small bowel mucosa was observed between the groups at either two or six weeks (data not shown). TISSUE WET WEIGHTS The pancreatic wet weight was significantly increased in the duodenogastric reflux animals CCK AND GASTRIN CONCENTRATIONS after two weeks and was further increased after After both two and six weeks of duodeno-

six weeks compared with sham (Fig 2). gastric reflux, plasma CCK and gastrin con- http://gut.bmj.com/

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0- L uui Snam .ontrol DGR D+MK Sham Sham Control + MK 2 weeks 6 weeks r- *-** * - * - r - 80 80 I-* 0 0 T E * Figure 3: Plasma E 60 - CL 60- TF T1- cholecystokinin (CCK, upper panel) and plasma 0._C: ._CO gastrin (lowerpanel) in a, 0, 40- rats two weeks (left) and mCO 40 six weeks (right) after split 0) CO gastrojejunostomy (DGR). E E Ca Sham operation (Sham) cn w0 implies small bowel CDCu 20- 20 fl transection. Control= unoperated controls. MK=devazepide, 0- -1 25 nmol/kg/h. *=p<0.05, Snam Control DGR D+MK Sham Sham Control **=p<0.0I, + ***=p<000I. MK 140 Gasslander, Mukaida, Herrington, Hinder, Adrian

2 weeks shown that CCK is the major growth promot- ing factor in that experimental model.8 35. E CCKinduo(denal mucosa The split gastrojejunostomy used in the 0 CCK in jejurnal mucosa present study is a surgical model creating a 30 * . -----::I condition not very different from that seen in

Q 25 humans following gastrojejunal anastomosis. Gut: first published as 10.1136/gut.36.1.137 on 1 January 1995. Downloaded from Split gastrojejunostomy produces obligatory Figure 4: Cholecystokinin E 20 (CCK) in duodenal and duodenogastric reflux and is, thus, a suitable jejunal mucosa in rats tz 15 model for studies of different effects of duo- two weeks after split U H I~ denogastric reflux. The procedure is well gastrojejunostomy (DGR). 10 Sham operation (Sham) tolerated by the rats, as shown by a weight implies small bowel 5. increase in parallel with sham operated rats transection. and unoperated controls. We found no dilata- Control= unoperated 0- Sham Control tion of the upper gastrointestinal tract and no controls. * =p<005. macroscopic signs of growth of the small intestine as reported by Taylor et al.16 Their finding centrations were increased approximately could be either a long term effect not seen threefold (Fig 3). Devaizepide did not affect the within the first six weeks or due to differences plasma levels of eitheir of these peptides. The in the surgical techniques used. In our study, CCK content in the jejjunal mucosa was signifi- duodenogastric reflux induced pancreatic cantly decreased after two weeks in the duo- growth, mainly hyperplasia, and a threefold denogastric reflux ggroup compared with increase in plasma CCK concentrations. The controls (Fig 4), but there was no significant increased pancreatic DNA synthesis, however, difference at six weeks (data not shown). CCK must occur within the first two weeks since the in the duodenal mucc)sa was not changed by 3H-thymidine uptake was unchanged at both the procedure at any tiime point studied. time points, despite an increase in DNA content. This is similar to our experience with the pancreaticobiliary diversion model.37 Discussion In a previous study, it was suggested that the Duodenogastric reflu3x is a normal physio- source of increased plasma CCK was the logical phenomenon2!5 which can become hyperplastic duodenum and that the main excessive, particularly after gastric surgery in mechanism was stasis of food within the duo- which normal pyloric function is lost. Exces- denal loop.1631 In the short term, however, sive duodenogastric rneflux can give rise to a we did not see duodenal hyperplasia. clinical syndrome wit] h upper abdominal dis- Furthermore, the decreased CCK content in comfort.25 26 It has be(en implicated as a major the jejunal mucosa at two weeks (and a similar

factor in the pathogene.sis of a variety of benign but not significant tendency found after six http://gut.bmj.com/ and malignant foregut diseases, especially in weeks), together with the unchanged duodenal the oesophagus and 1the stomach.27-30 Long mucosal weight and mucosal CCK content term profound duodenogastric reflux in rats, caused by the split gastrojejunostomy in our induced by a split gastirojejunostomy, has been study, suggests an increased turnover of the shown to result in adexnomatous nodules in the peptide in the efferent jejunal loop. A possible pancreas.'6 The autho: rs found increased CCK explanation for this effect of reflux on CCK is and gastrin concentrat:ions associated with the an inactivation of trypsin when passing on October 1, 2021 by guest. Protected copyright. split gastrojejunostom,y after four weeks.31 As through the acid milieu in the stomach and, epidemiological studies in man have suggested thus, inhibition of the CCK releasing feedback previous gastric surgeiry, especially Billroth II mechanism in the efferent jejunal loop. gastrojejunostomy, as a risk factor for pan- Furthermore, it is known that gastric surgery, creatic cancer,17-19 further study of the mecha- with bypass of the pylorus, usually induces nisms by which gastric surgery, and associated rapid gastric emptying. Since CCK slows duodenogastric reflux, may induce pancreatic gastric emptying and intestinal transit,38 the hyperplasia is of interest. increased plasma CCK could represent an Pancreatic growth hias been seen with bowel adaptive response. Studies in humans with resection in rats3 and iwith cholecystectomy in previous gastric surgery have shown increased hamsters.4 CCK has been suggested as the postprandial levels of CCK,39 40 and we have main growth factor responsible but the mecha- found increased CCK concentrations post- nism by which CCK is increased is not estab- prandially in patients with primary duo- lished. A tenfold increase in the plasma CCK denogastric reflux.41 concentration in rats irs seen after pancreatico- As the CCK receptor antagonist did not biliary diversion from the upper small intes- completely abolish the pancreatic growth tine.7-9 The release of CCK is normally response to the procedure, it is probable that inhibited by increasing amounts of the pan- some other factor (or factors) in addition to creatic enzyme trypsiin in the upper small CCK are involved. This could also reflect an intestine32-35 but after pancreaticobiliary diver- inadequate dose of devazepide but the dose sion, with the proxima11 small intestine void of used was the same as has previously been trypsin, the feedback mechanism is compro- shown to antagonise effects on the pancreas mised. Pancreaticobilliary diversion induces of supra-physiological doses of exogenous pancreatic hyperplasial5 7-9 and, in long term CCK.21 42 A similar dose of devazepide was studies, causes pancre.atic tumours even in the also able to reduce the effect on pancreatic absence of carcinogen5.36 We have previously growth by pancreaticobiliary diversion but not Profound duodenogastric reflux causes pancreatic growth in rats 141

significantly affect the size of the normal 16 Tayor PR, Dowling RH, Palmer TJ, Hanley DC, Murphy GM, Mason RC, McColl I. Induction of pancreatic pancreas.9 In the present study, we also found tumours by longterm duodenogastric reflux. Gut 1989; significantly increased plasma gastrin con- 30: 1596-600. 17 Mack TM, Yu MC, Hanisch R, Henderson BE. Pancreas centrations in the duodenogastric reflux rats, cancer and smoking, beverage consumption and an increase which could be expected after alka- past medical history. J Natl Cancer Inst 1986; 76: 49-60.

linisation of the stomach. This is in agreement 18 Caygill CPJ, Hill MJ, Hall CN, Kirkham JS, Northfield TC. Gut: first published as 10.1136/gut.36.1.137 on 1 January 1995. Downloaded from with Taylor's observations.31 The effect of Increased risk for cancer at multiple sites after gastric surgery for peptic ulcer. Gut 1987; 28: 924-8. gastrin on pancreatic growth is contro- 19 Caygill CPJ, Hill MJ. Malignancy following surgery for versial.243 In some studies, however, it has benign peptic disease: a review. Italian Journal of Gastroenterology 1992; 24: 218-24. been shown to have a weak trophic effect on 20 Chang RSL, Lotti VJ. Biochemical and pharmacological the pancreas.2 44 It is thus possible that gastrin, characterization of an extremely potent and selective non- peptide cholecystokinin antagonist. Proc Natl Acad Sci in combination with an increase in CCK con- USA 1986; 83: 4923-6. centration, could contribute to the growth 21 Zucker KA, Adrian TE, Bilchik AJ, Modlin IM. Effects of the CCK receptor antagonist L364,718 on pancreatic effects observed in this model. growth in adult and developing animals. Am J Physiol Pronounced duodenogastric reflux in rats 1989; 257: G511-6. 22 Labarca C, Paigen K. A simple, rapid and sensitive DNA results in pancreatic hyperplasia, due at least assay procedure. Anal Biochem 1980; 102: 344-52. partly to increased plasma CCK concentra- 23 Joekel CS, Herrington MK, Vanderhoff JA, Adrian TE. Postnatal development of circulating cholecystokinin and tions. The mechanism by which CCK is secretin, pancreatic growth, and exocrine function in increased, however, still has to be elucidated. guinea pigs. Int_J Pancreatol 1993; 13: 1-13. 24 Bryant MG, Adrian TE. Gastrin. In: Bloom SR, Long RG, CCK does not seem to be the sole responsiblet eds. Radioimmunoassay of gut regulatory peptides. growth factor in this experimental model. Philadelphia: Saunders, 1982: 51-9. 25 Schindlbeck NE, Heinrich C, Stellaard F, Paumgartner G, Among other possible candidates is gastrin, Muller-Lissner SA. Healthy controls have as much bile which, in some animal studies, has been shown reflux as gastric ulcer patients. Gut 1987; 28: 1577-83. 26 Ritchie WP. Alkaline reflux gastritis. An objective assess- to have trophic effects on the pancreas.2 44 The ment of its diagnosis and treatment. Ann Surg 1980; 192: trophic mechanism is of importance as it may 288-98. 27 Mason RC. Duodenogastric reflux in rat gastric carcinoma. contribute to the increased incidence of pan- BrJFSurg 1986; 73: 801-3. creatic cancer reported after gastric surgery. 28 Taylor PR, Mason RC, Filipe MI, Vaja S, Hanley DC, Murphy GM, et al. Gastric carcinogenesis in the rat MK329 was kindly donated by V J Lotti, MSD Research induced by duodenogastric reflux without carcino- Laboratories, West Point, Pennsylvania. Support for this study gens: morphology, mucin histochemistry, polyamine was provided by NIH Grants no DK40381 and CA44799. metabolism and labelling index. Gut 1991; 32: 1447-54. 29 Lin KM, Ueda RK, Hinder RA, Stein HJ, DeMeester TR. 1 Lebenthal E, Leung Y. Fetal and neonatal development of Etiology and importance of alkaline esophageal reflux. the exocrine pancreas. In: Morriset J, Solomon TE, eds. AmJtSurg 1991; 162: 553-7. Growth of the gastrointestinal tract: gastrointestinal hormones 30 Seto Y, Kobori 0, Shimizu T, Morioka Y. The role of alka- and growthfactors. Boston: CRC Press, 1990; 73-88. line reflux in esophageal carcinogenesis induced by 2 Johnson LR. Trophic effects of gut peptides. In Rauner BB, N-amyl-N-methylnitrosamine in rats. Int J Cancer 1991; ed. Handbook of physiology (the gastrointestinal system). 49: 758-63. Bethesda, MA: American Physiological Society, 1989: 31 Taylor PR, Houghton A, Mason RC. Trophic gut 291-310. hormones and pancreatic tumour formation in the rat.

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