Aust. N . Z .
515
J. Surg. 1990, 60, 515-518
REVIEW ARTICLE GASTROINTESTINAL HORMONES: FROM BASIC SCIENCE TO A CLINICAL PERSPECTIVE ARTHURSHULKES Department of Surgery, University of Melbourne, Austin Hospital, Melbourne, Victoria, Australia The gastrointestinal tract is the largest endocrine organ in the body. However, gastrointestinal hormones are not confined to the gut and many of them are delivered to their target tissue by neural and paracrine routes as well as the circulation, Regulatory peptide is therefore a more appropriate term than gastrointestinal hormone. The functions of these regulatory peptides include effects on intake, digestion and absorption of food, and changes in gut secretions, motility and growth. Since these peptides do not act alone but in concert it has been difficult to ascribe particular functions to individual peptides. However, the recent and on-going development of specific regulatory peptide agonists and antagonists has resulted in major advances in our understanding of the physiology of these peptides. In turn these findings are creating new therapeutic avenues providing some return from all the research on these gastrointestinal regulatory peptides. The somatostatin derivative (octreotide or sandostatin) is the most obvious example. Although only approved in Australia for treatment of carcinoids and VIPomas, the prospects include treatment of other gastroenteropancreatic tumours, acromegaly, idiopathic diarrhoea, fistula closure, dumping, and ERCP or post-operative pancreatitis. A new gastrokinetic agent, that acts via the motilin receptor, is undergoing trials for the treatment of impaired gastric emptying. The trophic effect of gastrointestinal peptides has clinical significance. For instance, gastrin antagonists inhibit cell proliferation of colon carcinoma cell lines. Furthermore the trophic effect of gastrin must be considered when potent gastric acid inhibitors, which cause a reflex increase in gastrin, are used. The outlook is for more mammalian regulatory peptides to be discovered adding further to the complexity. However, the continuing development of specific antagonists and agonists should help our understanding of the roles and interactions between the various components of the regulatory peptide systems. Key words: gastrin, gastrointestinal hormones, motilin, octreotide, somatostatin, vasoactive intestinal peptide.
Introduction It might be argued that the general surgeon could maintain a high level of competence with no knowledge of gut hormones, other than an awareness of gut hormone-producing tumours. However, times are changing. The intention of this review is to outline the major principles guiding gut hormone research today and highlight some of the recent developments which are more likely to be relevant to diseases of the gastrointestinal tract. A compendium of the physiology of the vast number of gastrointestinal hormones is provided by several recent books. FUNCTIONS
Functions of gut hormones include effects on intake, digestion and absorption of food, and changes in gut secretions, motility and growth. Since gut Correspondencc: A . Shulkes, Departmcnt of Surgery, Austin Hospital, Heidelberg, Vic. 3084, Australia. Acccpted for publication 7 February 1990.
peptides are localized in both endocrine cells and nerves, and are present in many organ systems outside the gut, ‘regulatory peptide’ is probably a more appropriate term than the traditional ‘gastrointestinal hormone’. More recently, with the awareness of the immunoregulatory effects of the gut peptides (e.g. stimulation of immunoglobulin synthesis by cholecystokinin; somatostatin inhibition of T cell proliferation) and the discovery that non-immune cells synthesize gut peptides (e.g. somatostatin synthesis by basophils; vaso-active intestinal peptide by mast cells) the concept of bidirectional communication between the immune and endocrine systems has been a ~ c e p t e d . ~ . ‘ MECHANISM OF ACTION
An appreciation of the phenomena of interaction and potentiation is important in determining particular roles for gastrointestinal hormones. The best example of potentiation is in the control of pancreatic exocrine secretions. Cholecystokinin potentiates the effects of secretin on bicarbonate
576
SHULKES
secretion, while secretin potentiates the enzymestimulating effect of cholecystokinin. Potentiation occurs when secretagogues use different intracellular mediators. In this example, cholecystokinin acts via mobilization of calcium, while secretin activates adenylate c y c l a ~ e . ~ An illustration of intermtion is vaso-active intestinal peptide (VIP) and acetycholine present in the parasympathetic nerves supplying the submandibular gland. The peptide and neurotransmitter are co-secreted in varying amounts, depending on the stimulus, with VIP amplifying the secretory effect of acetylcholine, as well as having a direct neurotransmitter In terms of mechanism of action, the gastrointestinal hormones function as paracrine (local action following secretion into the interstitial fluid) and neuracrine agents (release from nerve terminals), as well as classical hormones. Autocrine regulation involves the release of a substance that then acts an the releasing cell. An example of this is small-cell lung cancers that produce and respond to the growth-promoting peptide bombesin.'
Basic science and clinical perspective The apportionment between basic science and therapeutic application is arbitrary and ever changing. Today's basic science is tomorrow's therapy. Current findings which have therapeutic potential are described briefly below. A Ci 0 N I S T S A N U A N T A G 0 N ISTS
Two of the major handicaps in gut-regulatory peptide research have been the very short half-life of most of the biologically active peptides and the absence of specific antagonists. The synthesis of potent peptide analogues resistant to proteolytic degradation has been a major advance. The somatostatin derivative, sandostatin, is the most obvious example, with a half-life of several hours, as opposed to minutes for the natural substance. However, peptide analogues generally have poor oral bio-availability and are rapidly cleared by the gut and liver. Intravenous or subcutaneous administration is therefore necessary. Non-peptide ligands which mimic the action of the natural peptide are now being reported." The classical one is morphine, which is the non-peptide ligand for opioid peptides. Ligands specific to opioid receptor subtypes have also been synthesized. Kondo ef al. have recently reported that the macrolide antibiotic, erythromycin, mimics the action of motilin. I' (Motilin is a gut hormone that stimulates gastrointestinal motility, especially in the inter-digestive phase.) Clinical trials with erythromycin have shown that it is a potent gastrokinetic agent, which normalizes impaired gastric emptying in diabetic
gastroparesis. Unlike other gastrokinetic agents, the effectiveness is sustained over many months. l i Analogues of erythromycin without antibiotic activity have been synthesized and will soon be undergoing trials for a variety of motility disorders, including postoperative ileus. As well as non-peptide agonists, non-peptide antagonists are now available. For instance cholecystokinin antagonists that can be given orally are being used. Examples are loxigluniide and MK329, which are specific for the gut cholecystokinin receptor, but have little effect on the structurally related gastrin. I4 Antagonists to gastrin that do not block cholecystokinin's pancreatic activities are also available (e.g. L-365260). I' The development of the somatostatin analogue, sandostatin, is an example of where the future lies. l o In Australia it is currently approved for treatment of carcinoids and VIPomas. For metastatic carcinoid tumours, it appears to be the treatment of choice, giving a better median survival than strcptozotocin. l 6 Admittedly, few patients fall into the two approved categories; however, prospects include treatment of other gastro-enteropancreatic tumours, acromegaly, idiopathic diarrhoea, fistula closure, dumping, and ERCP or postoperative pancreatitis. Encouraging results in all these areas have been reported. I" The presence of high-affinity somatostatin receptors on tumours has enabled i~ vivo localization of metastases, using labelled somatostatin analogues. I 7 The measurement of these receptors also enables prediction of responsiveness and monitoring of progress. The outlook includes long-lasting oral formulations, and designer analogues targeted for specific roles, such as inhibiting only growth hormone. or having antiproliferative effects. BRAIN-GUT
AXIS
Although many of the regulatory peptides are found in both the gut and brain, they generally have distinct and different functions. However brain-gut peptides are also two-way mediators of information between the brain and gut. This may involve the transmission of visceral information to the central nervous system, such as inhibition of gastric emptying by a protein-rich meal. The mechanism. as proposed by Dockray, is that cholecystokinin released by a meal activates receptors o n gastric vagal afferents, initiating a vagal-vagal reflex integrated at the level of the dorso-medial medulla. I" A similar mechanism is probably applicable to the satiety effect of cholecystokinin, since the inhibition of feeding by exogenous cholecystokinin requires an intact vagus.'" In relation to central influences, administration of neuropeptides to animals via the third ventricle has widespread effects on gastrointestinal func-
577
GASTROINTESTINAL HORMONES
tions, including gastric acid and pancreatic secretions. This topic has been reviewed by Tache.” These demonstrations of the integrative role of the peptides on functions such as motility and satiety suggest that some of the common disorders of the gastrointestinal tract such as the so-called functional disorders may be treatable by either peptide agonist or antagonists. It has been shown, encouragingly, that when the impaired cholecystokinin secretion in the overeating disorder, bulimia nervosa, is increased to normal levels, the satiety mechanism is restored.’’ GASTROINIESTINAL CANCER AND G U T PEPTIDES
The trophic or growth-stimulating effects of gastrin and other gastrointestinal hormones on the normal gastrointestinal tract is well known.’3 The demonstration that gastrointestinal hormones can also influence the growth of .gastrointestinal tumours is in accord with these earlier findings.”,” Gastrin stimulates growth of both transplanted and chemically induced tumours in the gastrointestinal tract. The group led by Townsend and Thompson has shown that there is a good correlation between the trophic effect and the presence of gastrin recept o r ~ . ’ ~ . ’The ~ analogy with steroid receptors and breast cancer treatment is obvious. The reported antiproliferative effect of gastrin antagonists on human colon carcinoma cell lines’6 supports an autocrine role whereby gastrin synthesized by the tumour stimulates its own growth: the same concept originally described for bombesin in small-cell carcinoma of the lung.’ The recent availability of’ high-affinity antagonists to these peptides indicates that studies in man will soon be possible. However as with steroid receptors in breast cancer, not all gastrin receptor-positive cell lines respond to gastrin antagonists.”.” There is increasing awareness that the interaction between the mechanisms controlling secretion and the trophic effects of gastrin is of clinical significance: the so-called achlorhydria-hypergastrinaemiacarcinoid sequence.” The new generation of gastric acid inhibitors (e.g. omeprazole), which inhibit the parietal cell H+-pump, can block acid secretion completely, causing a substantial reflex increase in circulating gastrin. In rats, the hypergastrinaemia results in carcinoids of the oxyntic mucosa.2XThis gastrin-mediated achlorhydria-carcinoid progression is observed in patients with long-term hypergastrinaemia, resulting from achlorhydria (e.g. pernicious anaemia), or gastrin-secreting t u m o ~ r s . ” . ’ ~However, patients treated with a therapeutic dose of omeprazole are probably not at risk, because only a mild hypergastrinaemia occurs. Nevertheless, these events emphasize the importance of understanding the interactions between the regulatory peptides and target organs.
Outlook Novel mammalian regulatory peptides will continue to be discovered by both chemical and molecular biological techniques. The isolation of pancreastatin - an inhibitor of insulin secretion - is an example of the former.3” Calcitonin gene-related peptide (CGRP), a potent vasodilator and inhibitor of gastric mucosal damage, is an example of the use of recombinant-DNA technology to reveal a novel neuropeptide.” Finally, the development of specific antagonists and the correlation between structural, chemical and physiological studies will allow a better understanding of the roles and interactions between the various components of the regulatory peptide systems.
References J. C . , G K ~ E L EGY. H . , RAYFORD P. L. & I . THOMPSON TOWNSEND C. M . JK (eds) (1987) Gnsfr-oirite.stirttl Gidorrinology. McGraw-Hill, New York. G . J. (1987) Physiology of enteric neuro2. DOCKKAY peptides. In: Physiology of the Gastrointe.sti,i~l Trcict, 2nd edn (Ed. L. R. Johnson), Chapter 2. Raven Press, New York. 3. W A L s t j J. H. (1987) Gastrointestinal hormones. In: Physiology o j the Castroiittestirial Trtrcr, 2nd edn (Ed. L. R. Johnson), Chapter 7. Raven Press. New York. 4 . FURNESS J. B. & Cos-rA M . (1987) The Oiferic Nemous Systern. Churchill Livingstone, London. M . , S-lANlSL A . & SrtAl) R. 5. BIENENSIOCK J . , PERDUE ( 1987) Neurohormonal regulation of gastrointestinal immunity. Gasrroeriterolugy 93, 143 1-3. J . E. (1989) A molecular basis for bidirec6 . BLALOCK tional communication between the immune and neuro-endocrine systems. Physiol. Rev. 69, 1-32, J . D. & JENSEN R. T. (1986) Receptors and 7 . GARDNER cell activation associated with pancreatic enzyme secretion. A m . Re\,. Physiol. 48, 103-17. 8 LUNDBERG T . (1983) Co-existence J. M . & HOKFELT of peptides and classical neurotransmitters. Trerids in Neitroscierices 6 , 325-33. N ~MOODY 9 CIJTWRA F., C A K N ~D.Y N., M U L S I I IJ.. T. W . , FEDORKO J . . FlSCliLtR A . & MlNNA J . D. (1985) Bombeain-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nriture 316. 823-6. P., COME R. J . , MATON P. N.& GO v. L. W . 10 GOKDEN ( 1989) Somatostatin and somatostatin analogues in treatment of hormone-secreting tumours of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Am?. /ntern. Med. 110. 35-50. 1 1 FREIDINGER R. M . (1989) Non-peptide ligands for peptide receptors. Tred.7 ;,I P h ~ r r . r ~ ~ c r ~ e uScitc~~~i/ e w e s 10, 270-4. 12 KONIXY . , ToKKll K . , O M U K s. A & ITOH z. (1988) Erythromycin and its derivatives with motilin-like biological activities inhibit the specific binding of ‘”I-motilin to duodenal muscle. Biochem. Biophys. Res. Cornmuti. 150. 877-82. J . , PETERST . L., VANTRAPPEN 13 JANSSENS G. er d .
578
14.
15.
16. 17.
18.
19. 20.
2I. 22.
SHULKES
(1990) Improvement of gastric emptying in diabetic gastroparesis by erythromycin: Preliminary studies. New Engl. J . Med. 322, 1028-3 I . EVANS B . E., BOCKM. G . , R i T r L E K. E., DIPARDO R. M., WHIITER W. I . , VEBERD. F . , ANDERSON P. S . & FRElDlNGER R . M. (1986) Design O f potent Orally effective, non-peptidal antagonists of the peptide hormone cholecystokinin. P roc. Natl Acad. Sci. 83, 49 18-22, L o m V . J. & CHANG R . S . L. (1989) A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365260. Europ. J . Pharmacol. 162, 273-80. KVOLS L. K. (1988) The carcinoid syndrome: A treatable malignant disease. Oncology 2, 33-9. KRENNING E. P., BAKKER W. H., BREEMAN W. A . P., KOPEK J. W., KOOIJP. P. M., AUSEMA L., LAMERIS J . S . , REUBIJ . C. & LAMRERTS S . W. J . (1989) Localization of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet i , 242-4. M. & SCHALLY A. V . LIEUOW C., RE1Li.Y C., SERRANO (1989) Somatostatin analogues inhibit growth of pancreatic cancer by stimulating tyrosine phosphatase. Proc. Natl Acud. Sci. 86, 2003-7. G. J . (1988) Regulatory peptides and the DOCKRAY neuro-endocrinology of gut-brain relations. Quarr. J . Exp. Physiol. 73, 703-27. C. & NORGRENR . (1985) SMim G . P., JEROME Afferent axons in abdominal vagus mediate satiety effect of cholecystokinin. Amer. J . Physiol. 249, R638-41. TACHE Y. ( 1988) CNS peptides and regulation of gastric acid secretion. Ann. Rev. Physiol. 50, 19-40. GERACIOITI T. D. JR & LIDDLE R. A. (1988) Impaired cholecystokinin secretion in bulimia nervosa. New Engl. J . Med. 319, 683-8.
23. JOHNSON L. R . (1977) New aspects of trophic action of gastrointestinal hormones. Gastroenferology 72, 788-92. 24. TOWNSEND C. M. JR, SINGHP. & THOMPSON J . C. (1986) Gastrointestinal hormones and gastrointestinal and pancreatic carcinomas. GLisrroenterologji 91, 1002-6. 25. TOWNSEND C. M. J R , B ~ A U C H A R.MD., P SINGH P. & THOMPSON J. C. (1988) Growth factors and intestinal neoplasms. Amer. J . Surgery 155, 526-36. N. M., KlENER P. A . , CURRY R . c.,ROVATI 26. HOOSEIN D. K. & BRATTAIN M. G. (1988) L. C . , MCGILBRA Antiproliferative effects of gastrin-receptor antagonists and antibodies to gastrin on human colon carcinoma cell lines. Cnncer Research 48, 7179-83. 27. CREUTZFELDT W. ( 1987) The achlorhydria-carcinoid sequence: Role of gastrin. Digestion 19, 61-79. 28. LARSSON H., CARLSSON E., MATTSSON H., LUNDELL L., SUNDLER F . , SUNDELL G., WALLMARK B., WATANABE T. & HAKANSON R. (1986) Plasma gastrin and gastric enterochromaffin-cell activation and proliferation: Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology 90, 39 1-9. M . , CADIOT G . , ELOUAER-BLANC L., 29. LEHY T . , MIGNON RUSZNlEWSKl P., LEWIN M. J . M . & BONFILS s. (1989) Gastric endocrine cell behaviour in Zollinger-Ellison patients upon long-term potent antisecretory treatment. Gastroenterology 96, 1029-40. 30. TATEMOTO K., EFENDIC S . , MUTTv., MAKK G . , FEim NER G. J. & BARCHAS J. D. (1986) Pancreastatin, a novel pancreatic peptide that inhibits insulin secretion. Ncirure 324, 476-8. A. D., BROWNM. J . , MACDONALD 31. STRUTHERS D. W. R., BEACHAM J. L., STEVENSON J. C., MORRIS H. R. & MAC~NTYRE I. (1986) Human calcitonin gene-related peptide: A potent endogenous vasodilator in man. Clin. Sci. 70, 389-93.
515
J. Surg. 1990, 60, 515-518
REVIEW ARTICLE GASTROINTESTINAL HORMONES: FROM BASIC SCIENCE TO A CLINICAL PERSPECTIVE ARTHURSHULKES Department of Surgery, University of Melbourne, Austin Hospital, Melbourne, Victoria, Australia The gastrointestinal tract is the largest endocrine organ in the body. However, gastrointestinal hormones are not confined to the gut and many of them are delivered to their target tissue by neural and paracrine routes as well as the circulation, Regulatory peptide is therefore a more appropriate term than gastrointestinal hormone. The functions of these regulatory peptides include effects on intake, digestion and absorption of food, and changes in gut secretions, motility and growth. Since these peptides do not act alone but in concert it has been difficult to ascribe particular functions to individual peptides. However, the recent and on-going development of specific regulatory peptide agonists and antagonists has resulted in major advances in our understanding of the physiology of these peptides. In turn these findings are creating new therapeutic avenues providing some return from all the research on these gastrointestinal regulatory peptides. The somatostatin derivative (octreotide or sandostatin) is the most obvious example. Although only approved in Australia for treatment of carcinoids and VIPomas, the prospects include treatment of other gastroenteropancreatic tumours, acromegaly, idiopathic diarrhoea, fistula closure, dumping, and ERCP or post-operative pancreatitis. A new gastrokinetic agent, that acts via the motilin receptor, is undergoing trials for the treatment of impaired gastric emptying. The trophic effect of gastrointestinal peptides has clinical significance. For instance, gastrin antagonists inhibit cell proliferation of colon carcinoma cell lines. Furthermore the trophic effect of gastrin must be considered when potent gastric acid inhibitors, which cause a reflex increase in gastrin, are used. The outlook is for more mammalian regulatory peptides to be discovered adding further to the complexity. However, the continuing development of specific antagonists and agonists should help our understanding of the roles and interactions between the various components of the regulatory peptide systems. Key words: gastrin, gastrointestinal hormones, motilin, octreotide, somatostatin, vasoactive intestinal peptide.
Introduction It might be argued that the general surgeon could maintain a high level of competence with no knowledge of gut hormones, other than an awareness of gut hormone-producing tumours. However, times are changing. The intention of this review is to outline the major principles guiding gut hormone research today and highlight some of the recent developments which are more likely to be relevant to diseases of the gastrointestinal tract. A compendium of the physiology of the vast number of gastrointestinal hormones is provided by several recent books. FUNCTIONS
Functions of gut hormones include effects on intake, digestion and absorption of food, and changes in gut secretions, motility and growth. Since gut Correspondencc: A . Shulkes, Departmcnt of Surgery, Austin Hospital, Heidelberg, Vic. 3084, Australia. Acccpted for publication 7 February 1990.
peptides are localized in both endocrine cells and nerves, and are present in many organ systems outside the gut, ‘regulatory peptide’ is probably a more appropriate term than the traditional ‘gastrointestinal hormone’. More recently, with the awareness of the immunoregulatory effects of the gut peptides (e.g. stimulation of immunoglobulin synthesis by cholecystokinin; somatostatin inhibition of T cell proliferation) and the discovery that non-immune cells synthesize gut peptides (e.g. somatostatin synthesis by basophils; vaso-active intestinal peptide by mast cells) the concept of bidirectional communication between the immune and endocrine systems has been a ~ c e p t e d . ~ . ‘ MECHANISM OF ACTION
An appreciation of the phenomena of interaction and potentiation is important in determining particular roles for gastrointestinal hormones. The best example of potentiation is in the control of pancreatic exocrine secretions. Cholecystokinin potentiates the effects of secretin on bicarbonate
576
SHULKES
secretion, while secretin potentiates the enzymestimulating effect of cholecystokinin. Potentiation occurs when secretagogues use different intracellular mediators. In this example, cholecystokinin acts via mobilization of calcium, while secretin activates adenylate c y c l a ~ e . ~ An illustration of intermtion is vaso-active intestinal peptide (VIP) and acetycholine present in the parasympathetic nerves supplying the submandibular gland. The peptide and neurotransmitter are co-secreted in varying amounts, depending on the stimulus, with VIP amplifying the secretory effect of acetylcholine, as well as having a direct neurotransmitter In terms of mechanism of action, the gastrointestinal hormones function as paracrine (local action following secretion into the interstitial fluid) and neuracrine agents (release from nerve terminals), as well as classical hormones. Autocrine regulation involves the release of a substance that then acts an the releasing cell. An example of this is small-cell lung cancers that produce and respond to the growth-promoting peptide bombesin.'
Basic science and clinical perspective The apportionment between basic science and therapeutic application is arbitrary and ever changing. Today's basic science is tomorrow's therapy. Current findings which have therapeutic potential are described briefly below. A Ci 0 N I S T S A N U A N T A G 0 N ISTS
Two of the major handicaps in gut-regulatory peptide research have been the very short half-life of most of the biologically active peptides and the absence of specific antagonists. The synthesis of potent peptide analogues resistant to proteolytic degradation has been a major advance. The somatostatin derivative, sandostatin, is the most obvious example, with a half-life of several hours, as opposed to minutes for the natural substance. However, peptide analogues generally have poor oral bio-availability and are rapidly cleared by the gut and liver. Intravenous or subcutaneous administration is therefore necessary. Non-peptide ligands which mimic the action of the natural peptide are now being reported." The classical one is morphine, which is the non-peptide ligand for opioid peptides. Ligands specific to opioid receptor subtypes have also been synthesized. Kondo ef al. have recently reported that the macrolide antibiotic, erythromycin, mimics the action of motilin. I' (Motilin is a gut hormone that stimulates gastrointestinal motility, especially in the inter-digestive phase.) Clinical trials with erythromycin have shown that it is a potent gastrokinetic agent, which normalizes impaired gastric emptying in diabetic
gastroparesis. Unlike other gastrokinetic agents, the effectiveness is sustained over many months. l i Analogues of erythromycin without antibiotic activity have been synthesized and will soon be undergoing trials for a variety of motility disorders, including postoperative ileus. As well as non-peptide agonists, non-peptide antagonists are now available. For instance cholecystokinin antagonists that can be given orally are being used. Examples are loxigluniide and MK329, which are specific for the gut cholecystokinin receptor, but have little effect on the structurally related gastrin. I4 Antagonists to gastrin that do not block cholecystokinin's pancreatic activities are also available (e.g. L-365260). I' The development of the somatostatin analogue, sandostatin, is an example of where the future lies. l o In Australia it is currently approved for treatment of carcinoids and VIPomas. For metastatic carcinoid tumours, it appears to be the treatment of choice, giving a better median survival than strcptozotocin. l 6 Admittedly, few patients fall into the two approved categories; however, prospects include treatment of other gastro-enteropancreatic tumours, acromegaly, idiopathic diarrhoea, fistula closure, dumping, and ERCP or postoperative pancreatitis. Encouraging results in all these areas have been reported. I" The presence of high-affinity somatostatin receptors on tumours has enabled i~ vivo localization of metastases, using labelled somatostatin analogues. I 7 The measurement of these receptors also enables prediction of responsiveness and monitoring of progress. The outlook includes long-lasting oral formulations, and designer analogues targeted for specific roles, such as inhibiting only growth hormone. or having antiproliferative effects. BRAIN-GUT
AXIS
Although many of the regulatory peptides are found in both the gut and brain, they generally have distinct and different functions. However brain-gut peptides are also two-way mediators of information between the brain and gut. This may involve the transmission of visceral information to the central nervous system, such as inhibition of gastric emptying by a protein-rich meal. The mechanism. as proposed by Dockray, is that cholecystokinin released by a meal activates receptors o n gastric vagal afferents, initiating a vagal-vagal reflex integrated at the level of the dorso-medial medulla. I" A similar mechanism is probably applicable to the satiety effect of cholecystokinin, since the inhibition of feeding by exogenous cholecystokinin requires an intact vagus.'" In relation to central influences, administration of neuropeptides to animals via the third ventricle has widespread effects on gastrointestinal func-
577
GASTROINTESTINAL HORMONES
tions, including gastric acid and pancreatic secretions. This topic has been reviewed by Tache.” These demonstrations of the integrative role of the peptides on functions such as motility and satiety suggest that some of the common disorders of the gastrointestinal tract such as the so-called functional disorders may be treatable by either peptide agonist or antagonists. It has been shown, encouragingly, that when the impaired cholecystokinin secretion in the overeating disorder, bulimia nervosa, is increased to normal levels, the satiety mechanism is restored.’’ GASTROINIESTINAL CANCER AND G U T PEPTIDES
The trophic or growth-stimulating effects of gastrin and other gastrointestinal hormones on the normal gastrointestinal tract is well known.’3 The demonstration that gastrointestinal hormones can also influence the growth of .gastrointestinal tumours is in accord with these earlier findings.”,” Gastrin stimulates growth of both transplanted and chemically induced tumours in the gastrointestinal tract. The group led by Townsend and Thompson has shown that there is a good correlation between the trophic effect and the presence of gastrin recept o r ~ . ’ ~ . ’The ~ analogy with steroid receptors and breast cancer treatment is obvious. The reported antiproliferative effect of gastrin antagonists on human colon carcinoma cell lines’6 supports an autocrine role whereby gastrin synthesized by the tumour stimulates its own growth: the same concept originally described for bombesin in small-cell carcinoma of the lung.’ The recent availability of’ high-affinity antagonists to these peptides indicates that studies in man will soon be possible. However as with steroid receptors in breast cancer, not all gastrin receptor-positive cell lines respond to gastrin antagonists.”.” There is increasing awareness that the interaction between the mechanisms controlling secretion and the trophic effects of gastrin is of clinical significance: the so-called achlorhydria-hypergastrinaemiacarcinoid sequence.” The new generation of gastric acid inhibitors (e.g. omeprazole), which inhibit the parietal cell H+-pump, can block acid secretion completely, causing a substantial reflex increase in circulating gastrin. In rats, the hypergastrinaemia results in carcinoids of the oxyntic mucosa.2XThis gastrin-mediated achlorhydria-carcinoid progression is observed in patients with long-term hypergastrinaemia, resulting from achlorhydria (e.g. pernicious anaemia), or gastrin-secreting t u m o ~ r s . ” . ’ ~However, patients treated with a therapeutic dose of omeprazole are probably not at risk, because only a mild hypergastrinaemia occurs. Nevertheless, these events emphasize the importance of understanding the interactions between the regulatory peptides and target organs.
Outlook Novel mammalian regulatory peptides will continue to be discovered by both chemical and molecular biological techniques. The isolation of pancreastatin - an inhibitor of insulin secretion - is an example of the former.3” Calcitonin gene-related peptide (CGRP), a potent vasodilator and inhibitor of gastric mucosal damage, is an example of the use of recombinant-DNA technology to reveal a novel neuropeptide.” Finally, the development of specific antagonists and the correlation between structural, chemical and physiological studies will allow a better understanding of the roles and interactions between the various components of the regulatory peptide systems.
References J. C . , G K ~ E L EGY. H . , RAYFORD P. L. & I . THOMPSON TOWNSEND C. M . JK (eds) (1987) Gnsfr-oirite.stirttl Gidorrinology. McGraw-Hill, New York. G . J. (1987) Physiology of enteric neuro2. DOCKKAY peptides. In: Physiology of the Gastrointe.sti,i~l Trcict, 2nd edn (Ed. L. R. Johnson), Chapter 2. Raven Press, New York. 3. W A L s t j J. H. (1987) Gastrointestinal hormones. In: Physiology o j the Castroiittestirial Trtrcr, 2nd edn (Ed. L. R. Johnson), Chapter 7. Raven Press. New York. 4 . FURNESS J. B. & Cos-rA M . (1987) The Oiferic Nemous Systern. Churchill Livingstone, London. M . , S-lANlSL A . & SrtAl) R. 5. BIENENSIOCK J . , PERDUE ( 1987) Neurohormonal regulation of gastrointestinal immunity. Gasrroeriterolugy 93, 143 1-3. J . E. (1989) A molecular basis for bidirec6 . BLALOCK tional communication between the immune and neuro-endocrine systems. Physiol. Rev. 69, 1-32, J . D. & JENSEN R. T. (1986) Receptors and 7 . GARDNER cell activation associated with pancreatic enzyme secretion. A m . Re\,. Physiol. 48, 103-17. 8 LUNDBERG T . (1983) Co-existence J. M . & HOKFELT of peptides and classical neurotransmitters. Trerids in Neitroscierices 6 , 325-33. N ~MOODY 9 CIJTWRA F., C A K N ~D.Y N., M U L S I I IJ.. T. W . , FEDORKO J . . FlSCliLtR A . & MlNNA J . D. (1985) Bombeain-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nriture 316. 823-6. P., COME R. J . , MATON P. N.& GO v. L. W . 10 GOKDEN ( 1989) Somatostatin and somatostatin analogues in treatment of hormone-secreting tumours of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Am?. /ntern. Med. 110. 35-50. 1 1 FREIDINGER R. M . (1989) Non-peptide ligands for peptide receptors. Tred.7 ;,I P h ~ r r . r ~ ~ c r ~ e uScitc~~~i/ e w e s 10, 270-4. 12 KONIXY . , ToKKll K . , O M U K s. A & ITOH z. (1988) Erythromycin and its derivatives with motilin-like biological activities inhibit the specific binding of ‘”I-motilin to duodenal muscle. Biochem. Biophys. Res. Cornmuti. 150. 877-82. J . , PETERST . L., VANTRAPPEN 13 JANSSENS G. er d .
578
14.
15.
16. 17.
18.
19. 20.
2I. 22.
SHULKES
(1990) Improvement of gastric emptying in diabetic gastroparesis by erythromycin: Preliminary studies. New Engl. J . Med. 322, 1028-3 I . EVANS B . E., BOCKM. G . , R i T r L E K. E., DIPARDO R. M., WHIITER W. I . , VEBERD. F . , ANDERSON P. S . & FRElDlNGER R . M. (1986) Design O f potent Orally effective, non-peptidal antagonists of the peptide hormone cholecystokinin. P roc. Natl Acad. Sci. 83, 49 18-22, L o m V . J. & CHANG R . S . L. (1989) A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365260. Europ. J . Pharmacol. 162, 273-80. KVOLS L. K. (1988) The carcinoid syndrome: A treatable malignant disease. Oncology 2, 33-9. KRENNING E. P., BAKKER W. H., BREEMAN W. A . P., KOPEK J. W., KOOIJP. P. M., AUSEMA L., LAMERIS J . S . , REUBIJ . C. & LAMRERTS S . W. J . (1989) Localization of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet i , 242-4. M. & SCHALLY A. V . LIEUOW C., RE1Li.Y C., SERRANO (1989) Somatostatin analogues inhibit growth of pancreatic cancer by stimulating tyrosine phosphatase. Proc. Natl Acud. Sci. 86, 2003-7. G. J . (1988) Regulatory peptides and the DOCKRAY neuro-endocrinology of gut-brain relations. Quarr. J . Exp. Physiol. 73, 703-27. C. & NORGRENR . (1985) SMim G . P., JEROME Afferent axons in abdominal vagus mediate satiety effect of cholecystokinin. Amer. J . Physiol. 249, R638-41. TACHE Y. ( 1988) CNS peptides and regulation of gastric acid secretion. Ann. Rev. Physiol. 50, 19-40. GERACIOITI T. D. JR & LIDDLE R. A. (1988) Impaired cholecystokinin secretion in bulimia nervosa. New Engl. J . Med. 319, 683-8.
23. JOHNSON L. R . (1977) New aspects of trophic action of gastrointestinal hormones. Gastroenferology 72, 788-92. 24. TOWNSEND C. M. JR, SINGHP. & THOMPSON J . C. (1986) Gastrointestinal hormones and gastrointestinal and pancreatic carcinomas. GLisrroenterologji 91, 1002-6. 25. TOWNSEND C. M. J R , B ~ A U C H A R.MD., P SINGH P. & THOMPSON J. C. (1988) Growth factors and intestinal neoplasms. Amer. J . Surgery 155, 526-36. N. M., KlENER P. A . , CURRY R . c.,ROVATI 26. HOOSEIN D. K. & BRATTAIN M. G. (1988) L. C . , MCGILBRA Antiproliferative effects of gastrin-receptor antagonists and antibodies to gastrin on human colon carcinoma cell lines. Cnncer Research 48, 7179-83. 27. CREUTZFELDT W. ( 1987) The achlorhydria-carcinoid sequence: Role of gastrin. Digestion 19, 61-79. 28. LARSSON H., CARLSSON E., MATTSSON H., LUNDELL L., SUNDLER F . , SUNDELL G., WALLMARK B., WATANABE T. & HAKANSON R. (1986) Plasma gastrin and gastric enterochromaffin-cell activation and proliferation: Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology 90, 39 1-9. M . , CADIOT G . , ELOUAER-BLANC L., 29. LEHY T . , MIGNON RUSZNlEWSKl P., LEWIN M. J . M . & BONFILS s. (1989) Gastric endocrine cell behaviour in Zollinger-Ellison patients upon long-term potent antisecretory treatment. Gastroenterology 96, 1029-40. 30. TATEMOTO K., EFENDIC S . , MUTTv., MAKK G . , FEim NER G. J. & BARCHAS J. D. (1986) Pancreastatin, a novel pancreatic peptide that inhibits insulin secretion. Ncirure 324, 476-8. A. D., BROWNM. J . , MACDONALD 31. STRUTHERS D. W. R., BEACHAM J. L., STEVENSON J. C., MORRIS H. R. & MAC~NTYRE I. (1986) Human calcitonin gene-related peptide: A potent endogenous vasodilator in man. Clin. Sci. 70, 389-93.
