Protease inhibitors on trial for inflammatory bowel disease
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ProtoMed Inc. (San Diego, CA, USA) has received a Small Business Innovation Research (SBIR) grant of over $740 000 from the US National Institutes of General Medical Sciences to support a Phase I/II clinical trial of BBI, a protease inhibitor derived from soybean, in the form of a drug called BBIC. Proteolytic activity is a major component of inflammatory bowel disease, and in animal models BBIC has shown potent anti-inflammatory properties and the ability to reduce abnormally high levels of proteolytic activity. ‘Inflammatory bowel disease, which includes ulcerative colitis and Crohn’s disease, affects about one million Americans’, says Ann R. Kennedy, the scientific founder of ProtoMed and Richard Chamberlain professor of research oncology at the University of Pennsylvania. ‘Current treatments, such as corticosteroids and immunosuppressant drugs, are primarily palliative’, states Kennedy. BBIC has been extensively studied in rat, mouse and hamster models of various diseases, in which it suppresses both inflammation and malignant transformation. It inhibits several proteases, including chymotrypsin, trypsin, cathepsin G, elastase and chymase; the anti- carcinogenic activity of BBIC is thought to reside in its ability to inhibit chymotrypsin. Most of the trypsin inhibitory activity of whole soybean extract, which can trigger a potentially toxic feedback response in rats, is removed during the production of BBIC from acetone- defatted soybean flour. ‘How BBIC reduces the inflammatory response is unknown, but several different reactions could contribute to this activity’, Kennedy suggests. For example, mast cell chymase, which is inhibited by BBI, has a number of pro-inflammatory functions, including the activation of procollagenase and the conversion of interleukin 1b from its inactive to its biologically active form. ‘The conversion of this cytokine from an inactive to an active form is thought to have a critical role in initiating the inflammatory process’, explains Kennedy. ‘Moreover BBI, like other anti-carcinogenic protease inhibitors, prevents the influx of polymorphonuclear leukocytes into areas of inflammation, which would be expected to contribute to anti-inflammatory activity.’ BBIC also inhibits an intracellular 44-kDa protease that could be involved in inflammatory processes. ‘This protease must normally be activated by other proteases, which, we assume, are inhibited by BBI’, notes Kennedy. The activation of intracellular proteases by proteolytic cascades is a well-studied phenomenon. The 44-kDa protease has been found in an activated form, independent of proteolytic activation, in regions of the colon affected by ulcerative colitis, suggesting that it could be a causative factor in the production of ulcers in patients with this disease. Kennedy speculates that BBIC treatment will greatly reduce the proteolytic activity of this protease, ‘which appears to be expressed in an uncontrolled fashion in the involved regions of the colon in patients with ulcerative colitis’. BBIC has already been shown to have a major inhibitory effect on the levels of proteolytic activity in a rat model of ulcerative colitis. The results of studies on dimethylhydrazine (DMH)-induced colon cancer in animals suggested that BBIC might be useful in the treatment of ulcerative colitis. DMH is used to induce colon cancer but it also produces inflammation in the colon. BBIC prevents cancer and reduces inflammation in the colons of DMH- treated animals, thus indicating its potential role in the treatment of ulcerative colitis. In addition to ulcerative colitis, ProtoMed plans to evaluate the anti-inflammatory effects of BBIC in Crohn’s disease, and the product is already in clinical development for several other conditions. The National Cancer Institute is funding a Phase II clinical trial of BBIC in patients with oral leukoplakia (a pre-malignant lesion that is a precursor for oral cancer), and ProtoMed is sponsoring a Phase I/II clinical study in patients with benign prostatic hyperplasia. The company is also evaluating a lozenge formulation of BBIC to treat radiation and chemotherapy-induced inflammation in patients with lung cancer. Dorothy Bonn 461 N e w s MOLECULAR MEDICINE TODAY, NOVEMBER 1998 ISSN/98/$ - see front matter © 1998 Elsevier Science All rights reserved. Protease inhibitors on trial for inflammatory bowel disease Rapid update A bioreactor that cultures the placenta A bioreactor in which human placental cells can grow and replicate has been designed by Douglas Kniss and colleagues from Ohio State University. The bioreactor, composed of a polyester-fibre matrix, has succeeded where the petri dish has previously failed, allowing healthy human trophoblast cells to divide and differentiate in culture for the first time. Kniss and colleagues stress that they are not attempting to grow organisms out of the womb – they developed the bioreactor to provide a more accurate in vitro method of assessing the effects of drugs on placental development and function. Prostate cancer linked to the X chromosome An international collaboration of researchers has announced the discovery of a prostate cancer susceptibility locus on the X chromosome. The gene shows linkage to Xq27–28 in a study comprising 360 prostate cancer families sampled from North America, Finland and Sweden. It is the second hereditary prostate cancer (HPC) predisposing gene that this collaboration has identified. Called HPCX and reported in the October issue of Nature Genetics, the gene is thought to account for 16% of HPC cases. A new research collaboration for atherosclerosis Oxagen and Astra AB have announced a new collaboration to isolate therapeutic targets for atherosclerosis. The initiative will involve a European consortium of leading clinical research centres in the UK, Germany, Sweden and Italy. This new collaboration between research and industry will be funded by Astra AB over five years, and the company will financially reward the successful research groups with ‘milestone payments’ and with royalties on the therapeutic or diagnostic products that are developed as a result. Involvement of ERK in stroke Researchers at Harvard Medical School have discovered that ERK, a member of the MAP kinase family, is involved in stroke-induced neuronal cell death. Neuronal cells die both immediately during stroke and as a consequence of the compounds released by dying neurons around them. Among these, glutamate is known to have excitotoxic effects but until now it was not known how. Ed Furshpan and colleagues report that cultured hippocampal cells are protected from seizure-induced damage by an ERK-blocking drug called PD 098050. In 25 September issue of Proc. Natl. Acad. Sci. U. S. A., the researchers propose that ERK could act as a molecular gatekeeper, triggering one or more glutamate- activated excitotoxic pathways. Jane Alfred
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Transcript of Protease inhibitors on trial for inflammatory bowel disease
ProtoMed Inc. (San Diego, CA, USA) hasreceived a Small Business Innovation Research(SBIR) grant of over $740 000 from the USNational Institutes of General Medical Sciencesto support a Phase I/II clinical trial of BBI, aprotease inhibitor derived from soybean, in theform of a drug called BBIC.
Proteolytic activity is a major component ofinflammatory bowel disease, and in animalmodels BBIC has shown potent anti-inflammatoryproperties and the ability to reduce abnormallyhigh levels of proteolytic activity. ‘Inflammatorybowel disease, which includes ulcerative colitisand Crohn’s disease, affects about one millionAmericans’, says Ann R. Kennedy, the scientificfounder of ProtoMed and Richard Chamberlainprofessor of research oncology at the University ofPennsylvania. ‘Current treatments, such ascorticosteroids and immunosuppressant drugs, areprimarily palliative’, states Kennedy.
BBIC has been extensively studied in rat,mouse and hamster models of various diseases,in which it suppresses both inflammation andmalignant transformation. It inhibits severalproteases, including chymotrypsin, trypsin,cathepsin G, elastase and chymase; the anti-carcinogenic activity of BBIC is thought toreside in its ability to inhibit chymotrypsin.Most of the trypsin inhibitory activity of wholesoybean extract, which can trigger a potentiallytoxic feedback response in rats, is removedduring the production of BBIC from acetone-defatted soybean flour.
‘How BBIC reduces the inflammatoryresponse is unknown, but several differentreactions could contribute to this activity’,Kennedy suggests. For example, mast cellchymase, which is inhibited by BBI, has anumber of pro-inflammatory functions, includingthe activation of procollagenase and theconversion of interleukin 1b from its inactive toits biologically active form. ‘The conversion ofthis cytokine from an inactive to an active formis thought to have a critical role in initiating theinflammatory process’, explains Kennedy.‘Moreover BBI, like other anti-carcinogenicprotease inhibitors, prevents the influx ofpolymorphonuclear leukocytes into areas of
inflammation, which would be expected tocontribute to anti-inflammatory activity.’
BBIC also inhibits an intracellular 44-kDaprotease that could be involved in inflammatoryprocesses. ‘This protease must normally beactivated by other proteases, which, we assume,are inhibited by BBI’, notes Kennedy. Theactivation of intracellular proteases byproteolytic cascades is a well-studiedphenomenon. The 44-kDa protease has beenfound in an activated form, independent ofproteolytic activation, in regions of the colonaffected by ulcerative colitis, suggesting that itcould be a causative factor in the production ofulcers in patients with this disease. Kennedyspeculates that BBIC treatment will greatlyreduce the proteolytic activity of this protease,‘which appears to be expressed in anuncontrolled fashion in the involved regions ofthe colon in patients with ulcerative colitis’.BBIC has already been shown to have a majorinhibitory effect on the levels of proteolyticactivity in a rat model of ulcerative colitis.
The results of studies on dimethylhydrazine(DMH)-induced colon cancer in animalssuggested that BBIC might be useful in thetreatment of ulcerative colitis. DMH is used toinduce colon cancer but it also producesinflammation in the colon. BBIC prevents cancerand reduces inflammation in the colons of DMH-treated animals, thus indicating its potential role inthe treatment of ulcerative colitis.
In addition to ulcerative colitis, ProtoMedplans to evaluate the anti-inflammatory effectsof BBIC in Crohn’s disease, and the product isalready in clinical development for severalother conditions. The National Cancer Instituteis funding a Phase II clinical trial of BBIC inpatients with oral leukoplakia (a pre-malignantlesion that is a precursor for oral cancer), andProtoMed is sponsoring a Phase I/II clinicalstudy in patients with benign prostatichyperplasia. The company is also evaluating alozenge formulation of BBIC to treat radiationand chemotherapy-induced inflammation inpatients with lung cancer.
Dorothy Bonn
461
N e w sMOLECULAR MEDICINE TODAY, NOVEMBER 1998
ISSN/98/$ - see front matter © 1998 Elsevier Science All rights reserved.
Protease inhibitors ontrial for inflammatorybowel disease
Rapid updateA bioreactor that cultures the placentaA bioreactor in which human placental cells cangrow and replicate has been designed by DouglasKniss and colleagues from Ohio State University.The bioreactor, composed of a polyester-fibrematrix, has succeeded where the petri dish haspreviously failed, allowing healthy humantrophoblast cells to divide and differentiate inculture for the first time. Kniss and colleaguesstress that they are not attempting to groworganisms out of the womb – they developed thebioreactor to provide a more accurate in vitromethod of assessing the effects of drugs onplacental development and function.
Prostate cancer linked to the X chromosomeAn international collaboration of researchers hasannounced the discovery of a prostate cancersusceptibility locus on the X chromosome. Thegene shows linkage to Xq27–28 in a studycomprising 360 prostate cancer families sampledfrom North America, Finland and Sweden. It isthe second hereditary prostate cancer (HPC)predisposing gene that this collaboration hasidentified. Called HPCX and reported in theOctober issue of Nature Genetics, the gene isthought to account for 16% of HPC cases.
A new research collaboration foratherosclerosisOxagen and Astra AB have announced a newcollaboration to isolate therapeutic targets foratherosclerosis. The initiative will involve aEuropean consortium of leading clinical researchcentres in the UK, Germany, Sweden and Italy.This new collaboration between research andindustry will be funded by Astra AB over fiveyears, and the company will financially rewardthe successful research groups with ‘milestonepayments’ and with royalties on the therapeutic ordiagnostic products that are developed as a result.
Involvement of ERK in strokeResearchers at Harvard Medical School havediscovered that ERK, a member of the MAPkinase family, is involved in stroke-inducedneuronal cell death. Neuronal cells die bothimmediately during stroke and as a consequenceof the compounds released by dying neuronsaround them. Among these, glutamate is known tohave excitotoxic effects but until now it was notknown how. Ed Furshpan and colleagues reportthat cultured hippocampal cells are protected fromseizure-induced damage by an ERK-blockingdrug called PD 098050. In 25 September issue ofProc. Natl. Acad. Sci. U. S. A., the researcherspropose that ERK could act as a moleculargatekeeper, triggering one or more glutamate-activated excitotoxic pathways.
Jane Alfred
