Playford, RJ

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Recombinant peptides for gastrointestinal ulceration: Still early daysPlayford, RJ       For additional information about this publication click this link.https://qmro.qmul.ac.uk/jspui/handle/123456789/309   Information about this research object was correct at the time of download; we occasionallymake corrections to records, please therefore check the published record when citing. Formore information contact scholarlycommunications@qmul.ac.ukdoi:10.1136/gut.40.2.286  1997;40;286-287 Gut  R J Playford    ulceration: still early days.Recombinant peptides for gastrointestinal http://gut.bmj.comUpdated information and services can be found at:  These include: References http://gut.bmj.com#otherarticles4 online articles that cite this article can be accessed at:    serviceEmail alertingthe top right corner of the article Receive free email alerts when new articles cite this article - sign up in the box at Notes    http://journals.bmj.com/cgi/reprintformTo order reprints of this article go to:  http://journals.bmj.com/subscriptions/ go to: GutTo subscribe to  on 29 July 2008 gut.bmj.comDownloaded from Gut 1997; 40: 286-287CommentaryRecombinant peptides for gastrointestinal ulceration:still early daysOn page 204, Hull and colleagues examine the benefit ofusing basic fibroblast growth factor to decrease aspirininduced gastric and duodenal injury. Administration ofrecombinantly produced, acid stable basic fibroblastgrowth factor (bFGF, CS-23) decreased the amount ofduodenal, but not gastric, injury (erosions) induced by co-administration of aspirin. In the second component of thestudy, they gave indomethacin to the same subjects aftercessation of treatment with bFGF. Subjects who hadreceived bFGF in the first part of the study were found tohave a reduced susceptibility to indomethacin inducedrelapse of artificially induced mini-ulcers. This suggeststhat the mucosa was somehow 'stronger' in subjects whohad been treated with bFGF when compared with thosewho had received placebo. This paper therefore highlightstwo areas of interest; (1) the use of recombinant peptidesfor the treatment of gastrointestinal disease and (2) theconcept of 'quality' of ulcer healing.The most widely prescribed bioactive peptide used inclinical practice is insulin and has been of undoubtedbenefit to many thousands of patients. Peptides purifiedfrom biological material (for example, porcine pancreas)have usually been the initial source of peptides for clinicalusage. The risks of contamination with infectious agents(as seen in patients treated with growth hormone devel-oping Creutzfeldt-Jakob disease) and the development ofantibodies to the administered peptide, however, haveencouraged the development of recombinant peptidetechnology.The most widely prescribed recombinant peptide usedby gastroenterologists is probably interferon a for thetreatment of infective liver disease. Treatment results in along term 'cure' in only about 25% of patients withhepatitis C and this must be borne in mind when oneconsiders the cost of a treatment course on a 'per patient'basis (about £2000 per patient). The economic impli-cations of using this drug are particularly relevant to lesswell developed countries with high prevalence rates ofhepatitis C.One of the most extensively studied peptides for thetreatment of gastrointestinal damage is epidermal growthfactor (EGF). EGF is a potent mitogenic factor normallysecreted into the intestinal lumen by the human salivaryglands and Brunners glands of the duodenum. It wassuggested many years ago that EGF may be a usefultreatment for gastrointestinal ulceration. Despite hundredsof papers showing mitogenic activity and healing responsesin various animals models, it has failed to find a place inclinical practice.One of the major areas of concern of using peptides suchas EGF in the clinical setting is the worry that systemicadministration of growth factors may act to promotetumour growth elsewhere in the body. It is partly for thisreason that there is increasing interest in the potential valueof trefoil peptides to treat human gastrointestinal disease,as they seem to stimulate repair without increasingproliferation. 1Oral, as opposed to systemic, administration of growthfactors provides one possible approach to this problem.However, for EGF and the trefoil peptides, the oral dosesrequired to treat gastrointestinal damage may be up to athousand times greater than when the peptide is givensystematically, making oral therapy economically un-realistic.One possible explanation for this is that the peptides(like any other ingested food product) come into contactwith luminal proteases and may be digested into inactiveforms.2 In the paper by Hull, a recombinant modified formof bFGF has been used to decrease the susceptibility toacid and pepsin degradation. Stabilising against digestionin the small intestine will probably be more difficultbecause of the many different proteolytic enzymes pro-duced by the pancreas. The peptide may have to be co-administered with non-specific serine protease inhibitorsor in a site specific release formulation to overcome theseproblems.Most studies examining the potential value of recom-binant growth factors to treat gastrointestinal disease haveexamined their effects on gastric models of injury. Theirclinical value in peptic ulcer disease is, however, likely tobe small because of the high rate of success of ulcer healingusing acid suppressants and Helicobacter pylon' eradicationregimens. It is also relevant that the third group studiedby Hull and coworkers were treated with cimetidine, anextremely cheap drug.This group showed a similar protective effect againstaspirin induced duodenal injury and, like the bFGF treatedsubjects, resulted in a reduced susceptibility to subsequentindomethacin induced injury compared with placebotreated subjects. Although many peptides have been shownto decrease injury when given before the ulcerogen, thereis much less evidence that these peptides have a majoreffect on the rate of healing when administered after thedamaging agent. These studies would obviously be of morerelevance to the clinical setting.Two human studies that have shown a beneficial effectof oral peptide therapy involved the use of basic fibroblastgrowth factor therapy to treat patients with NSAIDassociated gastric ulcers3 and using oral EGF to treatpatients with duodenal ulcer, where the healing efficacywas similar to that ofusing cimetidine.4 Other peptides thatare presently under investigation include insulin-likegrowth factor 1i and keratinocyte growth factor.6Instead of administering exogenous peptide healingfactors, an alternative approach is to inhibit endogenouspeptide factors which may be exacerbating the injury.Baert et al, for example, have recently shown that admin-istration of a tumour necrosis factor ot neutralising anti-body to patients with Crohn's disease considerably reducesinflammatory activity.7 Tumour necrosis factor (x is286 on 29 July 2008 gut.bmj.comDownloaded from Recombinant peptides for gastrointestinal ulceration: still early daysthought to be an important mediator of the inflammatoryprocess.The concept that ulcers may heal with different 'quality'(that is, differences in the amount of residual submucosalabnormalities seen on histological examination) is com-paratively new and will probably be an important area offurther research.8 Patients who have taken NSAIDs haveimpaired ulcer healing with a tendency to recurrence. Themechanisms by which this occurs are unclear, althoughareas of previous ulceration usually contain scar tissue anddisrupted histology despite appearing endoscopicallynormal. Administration of peptides that stimulate repair,such as bFGF which promotes angiogenesis, may result inthe scarred area having an improved vascular supply,increasing its resilience to further injury.In summary, recombinant peptides are (comparatively)cheap and easy to produce and have the potential to treatgastrointestinal damage in clinical diseases where treat-ment is presently suboptimal. Problems to be overcomeinclude decreasing their susceptibility to luminal digestionand finding peptides that are capable of stimulating healingwhen given after ulceration has occurred. In the next fewyears we will probably see an increasing number of peptidetherapy studies being extended from the laboratoryenvironment into the clinics.University Division of Gastroenterology,Leicester General Hospital NHS Trust,Gwendolen Road,Leicester LE5 4PWR J PLAYFORD1 Otto W, Wright N. Trefoil peptides: coming up clover. Curr Biol 1994; 4:835-8.2 Playford RJ, Woodman AC, Clark P, Watanapa P, Vesey D, Deprez PH,et al. Effect of luminal growth factor preservation on intestinal growth.Lancet 1993; 341: 843-8.3 Hull MA, Cullen DJE, Hudson N, Hawkey CJ. Basic fibroblast growthfactor therapy for non-steroidal anti-inflammatory drug-associated gastriculceration. Gut 1995; 37: 610-2.4 Haedo W, Gonzalez T, Mas JA, Franco S, Gra B, Soto G, et al. Oral humanrecombinant epidermal growth factor in the treatment of patients withduodenal ulcer. Rev Esp Enferm Digest 1996; 88: 409-13.5 Chen K, Okuma T, Okamura K, Tabira Y, Kaneko H, Miyauchi Y. Insulin-like growth factor-I prevents gut atrophy and maintains intestinal integrityin septic rats.3PEN3' Parenter Enteral Nutr 1995; 19: 119-24.6 Werner S, Smola H, Liao X, Longaker MT, Krieg T, Hofschneider PH,et al. The function of KGF in morphogenesis of epithelium andreepithelialization of wounds. Science 1994; 266: 819-22.7 Baert F, Peeters M, D'Haens G, Geboes K, Ectors N, Rutgeerts P.Impressive histologic improvement after TNF antibody (cA2) therapy inactive Crohn's disease. Gut 1996; 39 (suppl 1): A17.8 Tamawski A, Stachura J, Krause WJ, Douglass TG, Gergely H. Quality ofgastric ulcer healing: a new emerging concept. J Clin Gastroenterol 1991;13 (suppl 1): S42-7.287 on 29 July 2008 gut.bmj.comDownloaded from 

Basic fibroblast growth factor therapy for non-steroidal anti-inflammatory drug-associated gastric ulceration. Gut

Effect of luminal growth factor preservation on intestinal growth. Lancet

Impressive histologic improvement after TNF antibody (cA2) therapy in active Crohn's disease. Gut

Insulinlike growth factor-I prevents gut atrophy and maintains intestinal integrity in septic rats.3PEN3' Parenter Enteral Nutr

Oral human recombinant epidermal growth factor in the treatment of patients with duodenal ulcer. Rev Esp Enferm Digest

Quality of gastric ulcer healing: a new emerging concept.

The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science

Recombinant peptides for gastrointestinal ulceration: Still early days

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