摘要:

AbstractDietary, environmental and genetic factors contribute to the etiology, pathogenesis and risk for gastrointestinal cancers. Measurements of cell proliferation and differentiation further identify abnormal cellular properties associated with increased susceptibility to gastrointestinal cancer. In precancerous esophagus, the proliferative compartment increases in size, increased ploidy and dysplasia develop, and epithelial cells express abnormal cytokeratins and ectopic tumor‐associated antigens. In precancerous stomach, increased proliferative activity and metaplasia develop. Intestinal enzymes and mucins are expressed and normal gastric antigens are replaced by intestinal or embryonic antigens. In flat colonic mucosa and in colonic adenomas, expansions of the proliferative compartment occur. Gene expression is modified gene deletions occur and blood group‐related antigens are modified as the cells undergo abnormal differentiation and develop into adenomas and carcinomas. Chemopreventive regimens are now being tested to determine whether they modify such intermediate biomarkers toward normal levels characteristic of lower risk for neoplasia. It is anticipated that the utilization of intermediate biomakers in chemoprevention studies may permit more novel chemopreventive regimens to be tested in human subjects than heretofore was possible. © 1992 Wiley‐Lis

ISSN:0730-2312    

DOI:10.1002/jcb.240501102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe Chemoprevention Branch of the National Cancer Institute has established a progam for the development of safe and effective cancer chemopreventive agents. This program includes identification of new agents, testing for efficacyin vitroand in animals, studies in animals to model clinical use, and preclinical toxicity and metabolism evaluation. Ultimately, the most promising agents progress to clinical trials. The long period required for cancer onset presents a significant challenge to the design of clinical trials for chemoprevention. Phase 111 trials in which cancer reduction is the endpoint require large subject group (tens of thousands) and follow‐up duration of more than five years. Because of these requirements, the costs of such trials are high. The Chemoprevention Branch is addressing this challange by expansion of the preclinical and Phase II clinical efficacy efforts to include intermediate biomarkers of carcinogenesis as study endpoints.The Chemoprevention Branch's studies focus on the development of biomarkers with high reliability and predictive value for cancer. Both single markers and batteries of complementary and parallel markers are evaluated. Among the criteria for biomarkers for chemoprevention studies are the following: (1) differential expression in normal and high risk tissue, (2) appearance early in carcinogenesis (the earlier a reliable biomarker appears, the greater is the chance for successful intervention with a chemopreventive agent), (3) high sensitivity, specificity, and accuracy relative to cancer, (4) ease of measurement (use of non‐invasive techniques and small tissue samples is preferable), (5) demonstration of modulation by chemopreventive agents, and (6) correlation of modulation with decreased cancer incidence. © 1992 Wiley‐Lis

ISSN:0730-2312    

DOI:10.1002/jcb.240501103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe development of carcinomas, definedas invasive epithelial neoplasma, is preceded by a preinvasive stage termed intraepithelial neoplasia that typically lasts for years. Intraepithelial neoplasia is the target tissue for the action of chmopreventive agents and the site where biomarkers frequently develop. the term “dysplasia” refers to the morphological alteration that characterize intraepithelial neoplasia and, according to many authors, consists of seven basic changes that are the same for the majority of epithelia. These are increased nuclear size, abnormal nuclear shape, increased nuclear stain uptake, nuclear pleomorphism (increased variation in size, shape, and stain uptake), increased mitoses, abnormal mitoses, and disordered or absent differentiation. Clonal evolution appears to begin early in the neoplastic process during intraepithelial neoplasia. The use of intraepithelial neoplasia as an intermediate endpoint biomarker requires that effective chemopreventive agents cause it to regress. Two examples are the regression of dysplastic oral leukoplakia produced by beta‐carotene and the regression of colonic polyps in familial polyposis patients following treatment with the nonsteroidal antiinflammatory drug sulindac. There is a critical need to identify and develop biomarkers that correlate with the appearance and regression of intraepithelial neoplasia. © 1992 Wiley‐L

ISSN:0730-2312    

DOI:10.1002/jcb.240501104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractUsing an intermediate marker of precancer as an endpoint for evaluating agents that may prevent cancer involves a presumption that the modification of the marker will be accompanied by a modification of cancer incidence. This presumption can hold only if the marker is on or very colsely linked to a causal pathway. Epidemiologists have discussed the nature of evidence required to infer causal relationships, and we briefly survey their work. Studies relating exposure (E) to marker (M) provide only indirect evidence for causality. Those relating marker (M) to disease (D) are more relevant. We propose a new validation criterion based on an analysis of the three‐way relationship of exposure (E), marker (M) and disease (D). We discuss the level of evidence required for using intermediate markers as endpoints for Phase II and Phase III trials, and propose very stringent criteria for Phase III trials. For Phase II trials, we propose less stringent criteria, but still recommend that the marker (M) should have been shown to have a strong association with disease (D). © 1992 Wiley‐Liss,

ISSN:0730-2312    

DOI:10.1002/jcb.240501105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractChemoprevention trials in lung and upper aerodigestive tract (UADT) cancer are guided by the field cancerization hypothesis. Inhaled carcinogens place the entire epithelial lining at risk for the development of cancer. The hypothesis is supported by the occurrence of premalignant lesions, such as leukoplakia or squamous metaplasia, and multiple primary tumors within the field. The concept of carcinogenesis as a multistep process suggests the possibility of blocking or reversing the progression to invasive cancer with systemic treatment. A series of ongoing clinical trials will determine the efficacy of retinoid chemoprevention and will attempt to develop intermediate biomarkers. Biomarkers which reliably reflect progression towards cancer could be used to dramatically improve the efficiency of chemoprevention trials and also would aid in screening potential chemoprevention agents. Genomic biomarkers include non‐specific estimates of ongoing DNA injury, such as micronuclei, as well as development of aneuploidy and alterations in oncogenes. A class of biomarkers of increasing importance assess proliferation and growth regulation, and include proliferating cell nuclear antigen (PCNA), TGF‐β, EGFR and retinoid receptors. Other markers, such as the blood group antigens, reflect differentiation and may be associated with the development of premalignant lesions. Preliminary data from several of these markers has suggested and association with carcinogenic exposures and premalignant lesions, but none of these markers either alone or in panels have yet been validated as a reliable surrogate for the development of invasive cancer. © 1992 Wiley‐Li

ISSN:0730-2312    

DOI:10.1002/jcb.240501106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0730-2312    

DOI:10.1002/jcb.240501107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractMost adenocarcinomas of the colorectum arise in a visible benign precursor lesion, the adenoma, which is a monoclonal proliferation of dysplastic nonmalignant epithelial cells. The resultant adenoma‐adenocarcinoma sequence represents the predominant pathogenetic pathway, in contrast tode novocarcinoma. Therefore, the adenoma is a tempting endpoint for chemoprevention trials.The adenoma‐adenocarcinoma sequence occurs in diverse clinical settings. In familial adenomatous polyposis (FAP) syndrome, autosomal dominant inheritance of the mutated APC (adenomatous polyposis coli) gene on chromosome 5q21 typically results in thousands of adenomas in the colorectum and in lesser numbers in the proximal small bowel. Adenocarcinoma usually develops in only a few of these adenomas, typically in the left colon and duodenum. In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, autosomal dominant inheritance of an unidentified gene appears to result in small numbers of adenomas which progress frequently to adenocarcinoma, predominantly in the right or transverse colon. In familial aggregation of colorectal cancer without a recognizable syndrome, cancer and/or adenomas occur in pedigree members. In “sporadic” cancers and adenomas, family history is absent and the tumors are mainly in the left colon.Colorectal adenomas have variable characteristics including size, shape (polypoid vs. flat), villous architecture, and dysplasia. A variety of oncogenes and tumor suppressor genes are altered during progression. Epigenetic factors are important as evidenced by the disappearance of adenomas in FAP patients after ileorectal anastomosis or treatment with the nonsteroidal antiinflammatory drug sulindac.Several variations on the theme of the adenoma‐carcinoma sequence are evident. Identification of the inherited and acquired genetic alterations as well as the interacting environmental factors will provide a rational basis for chemoprevention. Conversely, effective chemopreventive agents will contribute to understanding of the critical pathogenetic mechanisms. © 1992 Wiley

ISSN:0730-2312    

DOI:10.1002/jcb.240501108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe risk of colorectal carcinoma is increased among patients with longstanding ulcerative colitis and Crohn's disease. The development of cancer in inflammatory bowel disease is hypothesized to evolve by a multistep process involving genetic instability, clonal expansion and the development of a malignant phenotype. The contribution of nutritional factors such as folate deficiency is of great interest; molecular genetic mechanisms are under study. In contrast to sporadic colorectal carcinoma, carcinomas in ulcerative colitis are associated with a long prior history of chronic inflammation and the subsequent development of epithelial dysplasia. Dysplasia is defined as an unequivocal neoplastic alteration of the colonic mucosa. The object of surveillance is prevention of death from cancer by detection at a premalignant or early curable stage. Patients at greatest risk of cancer who customarily undergo endoscopic surveillance are those with extensive colitis of more than 8 years duration. Dysplastic epithelium may occur in flat mucosa, and may produce a plaque or a nodular/villiform appearance. Dysplasia is not present in all patients with cancer in colitis. It is important to develop more sensitive and specific markers for the presence of precancer or cancer in colitis. Under study are proliferation‐associated markers detected by immunohistochemistry, lectin binding, flow cytometry and laser‐induced fluorescence coupled with endoscopy. © 1992 Wiley‐Lis

ISSN:0730-2312    

DOI:10.1002/jcb.240501109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractSingle and multiple colonic crypts exhibiting dysplasia that are detectablein situby staining of rat colon with methylene blue are called aberrant crypts (AC) and may serve as an intermediate marker for colon cancer. In a characterization study, we have established the kinetics of AC growth and development over a period of 20 d following injection of rats with the carcinogen azoxymethane (AOM). AC are not present at 5 d post‐injection, but are a constant feature at 10 d and thereafter. Multiple AC, presumably clonal, begin to evolve at 10 d and are consistent by 20 d, forming incipient microdenomata. We have examined 20 candidate chemopreventive agents for inhibition of AC. All agents were given in AIN‐76diet, at two dose levels, with injections of AOM. AC were measured after 5 weeks of growth. Among the most active AC‐inhibiting agents were BHA, DFMO, quercetin, diallyl sulfide, 18β‐glycyrrhetinic acid, and ascorbyl palmitate. In a postinitiation study, the differentiating agent sodium butyrate was ineffective, but piroxicam was highly effective in modulating AC growth. Further, piroxicam inhibited AC development at all stages of growth from single to polycryptal clusters of AC. The AC assay shows marked sensitivity and specificity for screening agents for chemoprevention of colon cancer. © 1992 Wiley

ISSN:0730-2312    

DOI:10.1002/jcb.240501110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractAberrant crypts are recognized in methylene blue‐stained, unsectioned, colonic mucosa by their increased size, elliptical lumenal opening, thicker epithelial layer, and increased pericryptal region. Aberrant crypt foci in rodents are observed as early as 2 weeks and for at least 9 months after a single dose of carcinogen, have a distribution that parallels that of tumors, and have an increased number of aberrant crypts per focus with time after the carcinogen dose. The ability to quantify these lesions in the entire colon of rodents in less than an hour suggests that aberrant crypts may provide a highly efficientin vivobioassay for colon carcinogens. Since aberrant crypt foci appear to be the earliest identifiable putative precursors of colon cancer, they represent lesions that can be characterized further for the earliest genetic and biochemical alterations. In F344 rats, we have demonstrated that aberrant crypts have multiple histochemically‐detectable enzyme alterations. Using similar techniques, we were the first to demonstrate aberrant crypts in unsectioned human mucosa. After embedding and sectioning, these microscopic aberrant crypts resemble rare lesions described earlier in the literature after extensive serial sectioning. In rats and humans, aberrant crypts may be histologically normal or display varying degrees of dysplasia and histochemically‐detectable altered enzyme activities. These putative, preneoplastic lesions should reveal early changes that precede colon cancer and ways to alter their progre

ISSN:0730-2312    

DOI:10.1002/jcb.240501111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY