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Bile, eicosanoids, and colonic cell proliferation
444
SELECTED
GASTROENTEROLOGY
SUMMARIES
increase in ODC and DNA synthesis, however, was abolished by phenidone. A selective inhibitor of thromboxane synthetase, UK 37,248, did not affect ODC activity or DNA synthesis. Indomethacin and phenidone did not inhibit the DOC-mediated increase in [‘4C]arachidonate release. Phenidone pretreatment inhibited the bile acid-induced increases in 12-HETE and ODC activity. Comment.
Bile acids represent one of several intraluminal factors that modulate colonic epithelial proliferative activity. Until this publication it had generally been accepted that bile acids stimulate colonic mitotic activity solely by producing inflammation and superficial lysis of the colonic epithelium. An increase in bile acid production and the subsequent stimulation of colonic cytokinetics has been postulated as an explanation for the promoter action of high dietary fat on colonic cancer (Cancer Res 1981; 41:37OO-5). This report now delineates a second pathway by which bile acids produce a mitogenic response in the colon, namely, the increased accumulation of colonic lipoxygenase products. The stimulation of ODC activity in noninflamed mucosa by bile acids further supports the dissociation of this mitogenic event from colonic cell damage. Bile acids thus increase the generation of both prostanoids (inhibitors of cell proliferation) and lipoxygenase products (enhancers of proliferation). Presumably, a delicate balance must therefore exist within the colonic epithelium between inhibitors and enhancers of cell growth. This balance appears to be helped by the fact that PGE, is generated predominantly in the submucosa, whereas lipoxygenase products may be preferentially formed in the colonic mucosa. A growing body of evidence supports the role of cell proliferation as a critical factor in malignant transformation, in both the colon and other report protissues (Cancer Res 1984;44:4217-23). The present vides new and important information about the factors controlling colonic cell turnover. This type of data may one day enable clinicians to embark on chemoprevention trials designed to regulate colonic cell proliferation, especially in those subjects known to be at high risk for developing large bowel cancer, in whom abnormal patterns of cell proliferation have already been well characterized (Cancer 1974;34:878-88). L.R.JACOBS, M.D.
Reply. The results of our studies with indomethacin indicated that end products of the cyclooxygenase pathway (i.e., prostaglandins and thromboxane) do not mediate bile salt-induced increases in proliferative activity of colonic epithelium. The results with phenidone suggested a role for lipoxygenase products in this action. However, in addition to its effects as an inhibitor of cyclooxygenase and lipoxygenase activities, it should be emphasized that phenidone also is an antioxidant. Thus, our studies with phenidone did not exclude the possibility that bile salt actions on proliferative activity may be mediated by reactive oxygen moieties generated during the oxygenation of arachidonate, rather than by end products of the lipoxygenase pathway. F.K. DKRUBERTIS, M.D.
DETECTING COLON CANCER IN THE CANCER FAMILY SYNDROME Love RR, Morrissey JF (Departments of Human Oncology and Medicine, University of Wisconsin Center for Health Sciences, and the Cancer Prevention Program, Wisconsin Clinical Center, Madison, Wis.) Colonoscopy in asymptomatic individuals with a family history of colorectal cancer. Arch Intern Med 1984;144:2209-11.
Vol.
89, No.
2
The criteria for cancer family syndrome (CFS) have been defined to include (a) an increased frequency of adenocarcinema with a predominance of colon cancer, breast cancer, and endometrial cancer; (b) an early age of onset of the cancers; (c) a high frequency of multiple primary cancers; (d) an autosomal dominant mode of inheritance by segregation ratios; and [e) a high frequency of proximal colon lesions (Gastroenterology 1967;53:517-27). In this report 42 consecutive, asymptomatic members of four kindreds with CFS were screened with colonoscopy. Eight patients had been previously diagnosed as having cancer; of these, 5 patients had had a colorectal malignancy. Patients without a prior cancer diagnosis were all firstdegree relatives of afflicted members of their kindreds. Colonoscopy in these 42 patients revealed seven (17%) “adenomatous/villous polyps.” Two of these seven polyps had invasive cancer, one was a Dukes’ C carcinoma, and the other was a Dukes’ A lesion. Only 2 of the 7 patients with polyps had lesions in the rectosigmoid within reach of a 25-cm sigmoidoscope. Three patients had multiple polyps. Two of the 7 asymptomatic patients found to have neoplasms had had a previous diagnosis of cancer, and 1 patient had asymptomatic ulcerative colitis. The authors concluded that colonoscopy is a useful screening procedure in asymptomatic members of the CFS kindred. Comment. Attempts have been made to control colorectal cancer by improving the early identification of population groups at increased risk for developing this malignancy. It has been assumed that if we can predict groups at increased risk for developing colon cancer we might be able to intervene and prevent these neoplasms, or detect them at an early and curable stage. Screening guidelines for high-risk groups have been suggested but not standardized, and include fecal occult blood tests, sigmoidoscopy and barium enema, and colonoscopy. The most cost-efficient approach to management of high-risk groups has not been clearly defined: however, a multicenter, prospective study is in progress (Am J Gastroenterol 1984;79:824). The authors found a prevalence for adenomas of 17% in their “asymptomatic” patients. The majority of these polyps were beyond the reach of a 25-cm sigmoidoscope. Carcinoma was found in 2 of these patients. However, 1 patient had ulcerative colitis and 2 had had a previous diagnosis of colon cancer, thus placing these 3 patients in a high-risk category for the development of colon cancer, regardless of their family history of cancer. It is unclear in this report which of these 3 patients accounted for the 2 who were found to have cancer. Lynch (Prog Cancer Res Ther Genet Hum Cancer 1977:3:23556) has clearly shown that members of the CFS kindreds have a significant risk of developing colon cancer. We have observed high frequencies of colon cancer in our population registry of familial cancer groups as well, and agree with the need for selective surveillance in this group. Without a control group, however, it is difficult to interpret the significance of the prevalence data for adenomas presented in this paper. Because previous clinical and necropsy studies have reported prevalence rates of adenomas ranging from 7% to 51% in all patients, and as high as 34% for patients under 60 yr of age (Gut 1982;23:835-42, Cancer 1973;31:1260-70, Cancer 1977;39:2258-64, Cancer 1978; 42:2839-48), it would be difficult to support selective screening with colonoscopy based on the 17% adenoma prevalence rate alone. This suggested guideline is based on the predominance of colon cancer in kindreds of the CFS and the autosomal dominant mode of inheritance of adenocarcinomas in this group.
SELECTED
GASTROENTEROLOGY
SUMMARIES
increase in ODC and DNA synthesis, however, was abolished by phenidone. A selective inhibitor of thromboxane synthetase, UK 37,248, did not affect ODC activity or DNA synthesis. Indomethacin and phenidone did not inhibit the DOC-mediated increase in [‘4C]arachidonate release. Phenidone pretreatment inhibited the bile acid-induced increases in 12-HETE and ODC activity. Comment.
Bile acids represent one of several intraluminal factors that modulate colonic epithelial proliferative activity. Until this publication it had generally been accepted that bile acids stimulate colonic mitotic activity solely by producing inflammation and superficial lysis of the colonic epithelium. An increase in bile acid production and the subsequent stimulation of colonic cytokinetics has been postulated as an explanation for the promoter action of high dietary fat on colonic cancer (Cancer Res 1981; 41:37OO-5). This report now delineates a second pathway by which bile acids produce a mitogenic response in the colon, namely, the increased accumulation of colonic lipoxygenase products. The stimulation of ODC activity in noninflamed mucosa by bile acids further supports the dissociation of this mitogenic event from colonic cell damage. Bile acids thus increase the generation of both prostanoids (inhibitors of cell proliferation) and lipoxygenase products (enhancers of proliferation). Presumably, a delicate balance must therefore exist within the colonic epithelium between inhibitors and enhancers of cell growth. This balance appears to be helped by the fact that PGE, is generated predominantly in the submucosa, whereas lipoxygenase products may be preferentially formed in the colonic mucosa. A growing body of evidence supports the role of cell proliferation as a critical factor in malignant transformation, in both the colon and other report protissues (Cancer Res 1984;44:4217-23). The present vides new and important information about the factors controlling colonic cell turnover. This type of data may one day enable clinicians to embark on chemoprevention trials designed to regulate colonic cell proliferation, especially in those subjects known to be at high risk for developing large bowel cancer, in whom abnormal patterns of cell proliferation have already been well characterized (Cancer 1974;34:878-88). L.R.JACOBS, M.D.
Reply. The results of our studies with indomethacin indicated that end products of the cyclooxygenase pathway (i.e., prostaglandins and thromboxane) do not mediate bile salt-induced increases in proliferative activity of colonic epithelium. The results with phenidone suggested a role for lipoxygenase products in this action. However, in addition to its effects as an inhibitor of cyclooxygenase and lipoxygenase activities, it should be emphasized that phenidone also is an antioxidant. Thus, our studies with phenidone did not exclude the possibility that bile salt actions on proliferative activity may be mediated by reactive oxygen moieties generated during the oxygenation of arachidonate, rather than by end products of the lipoxygenase pathway. F.K. DKRUBERTIS, M.D.
DETECTING COLON CANCER IN THE CANCER FAMILY SYNDROME Love RR, Morrissey JF (Departments of Human Oncology and Medicine, University of Wisconsin Center for Health Sciences, and the Cancer Prevention Program, Wisconsin Clinical Center, Madison, Wis.) Colonoscopy in asymptomatic individuals with a family history of colorectal cancer. Arch Intern Med 1984;144:2209-11.
Vol.
89, No.
2
The criteria for cancer family syndrome (CFS) have been defined to include (a) an increased frequency of adenocarcinema with a predominance of colon cancer, breast cancer, and endometrial cancer; (b) an early age of onset of the cancers; (c) a high frequency of multiple primary cancers; (d) an autosomal dominant mode of inheritance by segregation ratios; and [e) a high frequency of proximal colon lesions (Gastroenterology 1967;53:517-27). In this report 42 consecutive, asymptomatic members of four kindreds with CFS were screened with colonoscopy. Eight patients had been previously diagnosed as having cancer; of these, 5 patients had had a colorectal malignancy. Patients without a prior cancer diagnosis were all firstdegree relatives of afflicted members of their kindreds. Colonoscopy in these 42 patients revealed seven (17%) “adenomatous/villous polyps.” Two of these seven polyps had invasive cancer, one was a Dukes’ C carcinoma, and the other was a Dukes’ A lesion. Only 2 of the 7 patients with polyps had lesions in the rectosigmoid within reach of a 25-cm sigmoidoscope. Three patients had multiple polyps. Two of the 7 asymptomatic patients found to have neoplasms had had a previous diagnosis of cancer, and 1 patient had asymptomatic ulcerative colitis. The authors concluded that colonoscopy is a useful screening procedure in asymptomatic members of the CFS kindred. Comment. Attempts have been made to control colorectal cancer by improving the early identification of population groups at increased risk for developing this malignancy. It has been assumed that if we can predict groups at increased risk for developing colon cancer we might be able to intervene and prevent these neoplasms, or detect them at an early and curable stage. Screening guidelines for high-risk groups have been suggested but not standardized, and include fecal occult blood tests, sigmoidoscopy and barium enema, and colonoscopy. The most cost-efficient approach to management of high-risk groups has not been clearly defined: however, a multicenter, prospective study is in progress (Am J Gastroenterol 1984;79:824). The authors found a prevalence for adenomas of 17% in their “asymptomatic” patients. The majority of these polyps were beyond the reach of a 25-cm sigmoidoscope. Carcinoma was found in 2 of these patients. However, 1 patient had ulcerative colitis and 2 had had a previous diagnosis of colon cancer, thus placing these 3 patients in a high-risk category for the development of colon cancer, regardless of their family history of cancer. It is unclear in this report which of these 3 patients accounted for the 2 who were found to have cancer. Lynch (Prog Cancer Res Ther Genet Hum Cancer 1977:3:23556) has clearly shown that members of the CFS kindreds have a significant risk of developing colon cancer. We have observed high frequencies of colon cancer in our population registry of familial cancer groups as well, and agree with the need for selective surveillance in this group. Without a control group, however, it is difficult to interpret the significance of the prevalence data for adenomas presented in this paper. Because previous clinical and necropsy studies have reported prevalence rates of adenomas ranging from 7% to 51% in all patients, and as high as 34% for patients under 60 yr of age (Gut 1982;23:835-42, Cancer 1973;31:1260-70, Cancer 1977;39:2258-64, Cancer 1978; 42:2839-48), it would be difficult to support selective screening with colonoscopy based on the 17% adenoma prevalence rate alone. This suggested guideline is based on the predominance of colon cancer in kindreds of the CFS and the autosomal dominant mode of inheritance of adenocarcinomas in this group.