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How selective are the cholecystokinin antagonists in the dog?
GASTROENTEROLOGY 1995;108:1953-1963
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY.Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten double-spaced and submitted in triplicate.
Plasminogen Activation System and Colorectal Cancer Biology Dear Sir: The recent editorial by Jessup ~ gives a comprehensive overview of the different components of the plasminogen activation system that are involved in the neoplastic progression of colorectal cancer, He correctly mentioned that the knowledge of the expression and function of the urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA), their inhibitors PAI-1 and PAI-2, and the urokinase receptor (u-PAR) in malignant processes has increased enormously during the last decade. In general, colorectal cancer has been found to be associated with an up-regulation of uPA, u-PAR, PAI-1, and PAI-2 and with a down-regulation of t-PA. The interaction of the different components of this rather complex system seems to provide the phenotypes of enhanced proteolytic invasive carcinomas and expanding but noninvasive metastases.2 In his discussion, Dr. Jessup mentions that these findings are relevant to the understanding of the biology of colorectal neoplasia but that it would be of interest to know the relation of these findings to the outcome of these patients. In that respect, we 3 and others4 found recently that the u-PA level in the carcinomas is of prognostic impact to the overall survival of patients with colorectal cancer. Furthermore, PAI-23 and u-PAR S levels in the carcinomas as well as t-PA levels in the normal colonic mucosa3 were also found to be prognostic parameters for the overall survival of these patients. Moreover, and more importantly, these parameters were found to predict overall survival independent from prognostic variables, such as Dukes' stage, age, localization, and differentiation of the tumor. Therefore, these observations may provide both criteria to identify high-risk patients eligible for adjuvant therapy and new targets for intervention therapy in colorecral cancer. HEIN W. VERSPAGET
Department of Gastroenterology-Hepatology Univers#y Hospital Building 1, C4-P P.O. Box 9600 2300 RC Leide< The Netherlands 1. Jessup JM. Role of urokinase, its receptor, and serpins in colerectal carcinoma. Gastroenterology 1994; 1 0 7 : 1 5 5 5 - 1 5 5 9 . 2. Sier CFM, Vloedgraven HJM, Ganesh S, Griffioen G, Quax PHA, Verheijen JH, Dooijewaard G, Welvaart K, van de Velde CJH, Lamers CBHW, Verspaget HW. Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis. Gastroenterology 1994; 1 0 7 : 1 4 4 9 - 1 4 5 6 . 3. Ganesh S, Sier CFM, Griffioen G, Vloedgraven HJM, de Boer A, Welvaart K, van de Velde CJH, van Krieken JHJM, Verheijen JH, Lamers CBHW, Verspaget HW. Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res 1994; 5 4 : 4 0 6 5 - 4 0 7 1 . 4. Mulcahy HE, Duffy M J, Gibbons D, McCarthy P, Parfrey NA, O'Donoghue DP, Sheahan K. Urokinase-type plasminogen activator and outcome in Dukes' B colorectal cancer. Lancet 1 9 9 4 ; 3 4 4 : 5 8 3 584. 5. Ganesh S, Sier CFM, Heerding MM, Griffioen G, Lamers CBHW,
Verspaget HW. Urokinase receptor and colorectal cancer survival (letter). Lancet 1994; 3 4 4 : 4 0 1 - 4 0 2 .
How Selective Are the Cholecystokinin Antagonists in the Dog? Dear Sir: The October 1994 issue of GASTROENTEROLOGY contains two articles concerning cholecystokinin (CCK) receptors in the canine gastrointestinal tract: "Localization of Cholecystokinin A and Cholecystokinin B/Gastrin Receptors in the Canine Upper Gastrointestinal Tract" by Mantyh et al. l and "Cholecystokinin and Nitric Oxide in Transient Lower Esophageal Sphincter Relaxation to Gastric Distention in Dogs" by Boulant et al. 2 Mantyh et ah, using both agonists and antagonists concludes that predominantly CCK-B receptors are found in myenteric neurons, whereas CCK-A receptors are primarily mucosal. In agreement with observations of Beinborn et al. 3 who found that the canine CCK-B receptor has a single amino acid substitution at 349, Mantyh er al. notes that L365,260 (B selective in other species) did not displace [3HJCCK-8 from gastrin-17 displaceable sites in various neurons. Boulant et al., using the antagonists L365,260 and devazepide, which Beinborn et al. showed did not distinguish the CCK,A from the CCK-B receptors, found that devazepide was more effective at blocking the nitric oxide-dependent relaxation of the canine lower esophageal sphincter induced by gastric distention and concluded that CCK-A receptors were involved. The data concerning the involvement of both endogenous CCK and NO in transient relaxations of the lower esophageal sphincter caused by gastric distention are very important. However, it is also important to recognize that the use of these antagonists does not distinguish the CCK-A from the CCK-B receptor in the dog. It is unfortunate that the discrepancy between the two article was not identified before publication. The incorrect interpretation of the C C K - 8 - A and - B receptor population in the Boulant et al. article will perpetuate the impression that the A series of antagonists are selective for canine CCK receptors and can distinguish canine CCKA from CCK-B receptors. We suggest that the editors and reviewers should be on alert for such statements in the future. JO-ANN E. T. FOX-THRELKELD, R.N., Ph.D.
School of Nursing and Department of Biomedical &'iences EDWIN E. DANIEL
Department of Biomedical Sciences McMaster University Hamilton, Ontario, Canada 1. Mantyh CR, Pappas TN, Vigna SR. Localization of cholecystokinin A and cholecystokinin B/gastrin receptors in the canine upper gastrointestinal tract. Gastroenterology 1994; 1 0 7 : 1 0 1 9 - 1 0 3 0 . 2. Boulant J, Fioramenti J, Dapoigny M, Bommelaer G, Bueno L. Cholecystokinin and nitric oxide in transient lower esophageal sphincter relaxation to gastric distention in dogs. Gastroenterology 1994; 1 0 7 : 1 0 5 9 - 1 0 6 6 . 3. Beinbern et al. Nature 1 9 9 3 ; 3 6 2 : 3 4 8 - 3 5 0 .
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY.Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten double-spaced and submitted in triplicate.
Plasminogen Activation System and Colorectal Cancer Biology Dear Sir: The recent editorial by Jessup ~ gives a comprehensive overview of the different components of the plasminogen activation system that are involved in the neoplastic progression of colorectal cancer, He correctly mentioned that the knowledge of the expression and function of the urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA), their inhibitors PAI-1 and PAI-2, and the urokinase receptor (u-PAR) in malignant processes has increased enormously during the last decade. In general, colorectal cancer has been found to be associated with an up-regulation of uPA, u-PAR, PAI-1, and PAI-2 and with a down-regulation of t-PA. The interaction of the different components of this rather complex system seems to provide the phenotypes of enhanced proteolytic invasive carcinomas and expanding but noninvasive metastases.2 In his discussion, Dr. Jessup mentions that these findings are relevant to the understanding of the biology of colorectal neoplasia but that it would be of interest to know the relation of these findings to the outcome of these patients. In that respect, we 3 and others4 found recently that the u-PA level in the carcinomas is of prognostic impact to the overall survival of patients with colorectal cancer. Furthermore, PAI-23 and u-PAR S levels in the carcinomas as well as t-PA levels in the normal colonic mucosa3 were also found to be prognostic parameters for the overall survival of these patients. Moreover, and more importantly, these parameters were found to predict overall survival independent from prognostic variables, such as Dukes' stage, age, localization, and differentiation of the tumor. Therefore, these observations may provide both criteria to identify high-risk patients eligible for adjuvant therapy and new targets for intervention therapy in colorecral cancer. HEIN W. VERSPAGET
Department of Gastroenterology-Hepatology Univers#y Hospital Building 1, C4-P P.O. Box 9600 2300 RC Leide< The Netherlands 1. Jessup JM. Role of urokinase, its receptor, and serpins in colerectal carcinoma. Gastroenterology 1994; 1 0 7 : 1 5 5 5 - 1 5 5 9 . 2. Sier CFM, Vloedgraven HJM, Ganesh S, Griffioen G, Quax PHA, Verheijen JH, Dooijewaard G, Welvaart K, van de Velde CJH, Lamers CBHW, Verspaget HW. Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis. Gastroenterology 1994; 1 0 7 : 1 4 4 9 - 1 4 5 6 . 3. Ganesh S, Sier CFM, Griffioen G, Vloedgraven HJM, de Boer A, Welvaart K, van de Velde CJH, van Krieken JHJM, Verheijen JH, Lamers CBHW, Verspaget HW. Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res 1994; 5 4 : 4 0 6 5 - 4 0 7 1 . 4. Mulcahy HE, Duffy M J, Gibbons D, McCarthy P, Parfrey NA, O'Donoghue DP, Sheahan K. Urokinase-type plasminogen activator and outcome in Dukes' B colorectal cancer. Lancet 1 9 9 4 ; 3 4 4 : 5 8 3 584. 5. Ganesh S, Sier CFM, Heerding MM, Griffioen G, Lamers CBHW,
Verspaget HW. Urokinase receptor and colorectal cancer survival (letter). Lancet 1994; 3 4 4 : 4 0 1 - 4 0 2 .
How Selective Are the Cholecystokinin Antagonists in the Dog? Dear Sir: The October 1994 issue of GASTROENTEROLOGY contains two articles concerning cholecystokinin (CCK) receptors in the canine gastrointestinal tract: "Localization of Cholecystokinin A and Cholecystokinin B/Gastrin Receptors in the Canine Upper Gastrointestinal Tract" by Mantyh et al. l and "Cholecystokinin and Nitric Oxide in Transient Lower Esophageal Sphincter Relaxation to Gastric Distention in Dogs" by Boulant et al. 2 Mantyh et ah, using both agonists and antagonists concludes that predominantly CCK-B receptors are found in myenteric neurons, whereas CCK-A receptors are primarily mucosal. In agreement with observations of Beinborn et al. 3 who found that the canine CCK-B receptor has a single amino acid substitution at 349, Mantyh er al. notes that L365,260 (B selective in other species) did not displace [3HJCCK-8 from gastrin-17 displaceable sites in various neurons. Boulant et al., using the antagonists L365,260 and devazepide, which Beinborn et al. showed did not distinguish the CCK,A from the CCK-B receptors, found that devazepide was more effective at blocking the nitric oxide-dependent relaxation of the canine lower esophageal sphincter induced by gastric distention and concluded that CCK-A receptors were involved. The data concerning the involvement of both endogenous CCK and NO in transient relaxations of the lower esophageal sphincter caused by gastric distention are very important. However, it is also important to recognize that the use of these antagonists does not distinguish the CCK-A from the CCK-B receptor in the dog. It is unfortunate that the discrepancy between the two article was not identified before publication. The incorrect interpretation of the C C K - 8 - A and - B receptor population in the Boulant et al. article will perpetuate the impression that the A series of antagonists are selective for canine CCK receptors and can distinguish canine CCKA from CCK-B receptors. We suggest that the editors and reviewers should be on alert for such statements in the future. JO-ANN E. T. FOX-THRELKELD, R.N., Ph.D.
School of Nursing and Department of Biomedical &'iences EDWIN E. DANIEL
Department of Biomedical Sciences McMaster University Hamilton, Ontario, Canada 1. Mantyh CR, Pappas TN, Vigna SR. Localization of cholecystokinin A and cholecystokinin B/gastrin receptors in the canine upper gastrointestinal tract. Gastroenterology 1994; 1 0 7 : 1 0 1 9 - 1 0 3 0 . 2. Boulant J, Fioramenti J, Dapoigny M, Bommelaer G, Bueno L. Cholecystokinin and nitric oxide in transient lower esophageal sphincter relaxation to gastric distention in dogs. Gastroenterology 1994; 1 0 7 : 1 0 5 9 - 1 0 6 6 . 3. Beinbern et al. Nature 1 9 9 3 ; 3 6 2 : 3 4 8 - 3 5 0 .