sulindac and Colorectal-Neoplasms--Hereditary-Nonpolyposis

Colorectal cancer is a common and often fatal malignancy. Currently, the modifications that alter disease outcome include early symptom recognition, population screening as well as improved surgical and adjuvant treatments. Preventative strategies have been limited with little evidence that lifestyle changes significantly alter risk. There is however a growing awareness of a potential role for chemoprevention in some patient groups. This study aimed to review the literature associated with chemoprevention in colorectal cancer.. An electronic literature search of MEDLINE and Embase databases was performed on PubMed for studies detailing the use of chemoprevention agents in colon and rectal cancer. The search was limited to clinical trials on adult humans (>16 years of age) published in English since 1990.. The strongest evidence is for non-steroidal anti-inflammatory drugs slowing polyp progression, notably Sulindac and aspirin in patients with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, respectively. There is also increasing evidence that continuing use of low-dose aspirin reduces long-term incidence of colorectal cancers. Cyclooxygenase 2 inhibitors also have a potential role but cardiac toxicity currently limits their use. Folic acid, statins, antioxidants, calcium and 5-aminosalicylic acid lack evidence to support their use at present.. Currently, there is not enough evidence to support the implementation of a chemopreventative agent for general use. However, there appears to be a role for aspirin in selected subgroups.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cardiotoxicity; Chemoprevention; Clinical Trials as Topic; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Cyclooxygenase 2 Inhibitors; Disease Progression; Humans; Incidence; Meta-Analysis as Topic; Middle Aged; Sulindac; Young Adult

Colorectal cancer (CRC) is potentially preventable. Chemoprevention, a focus of research for the past three decades, aims to prevent or delay the onset of cancer through the regression or prevention of colonic adenomas. Ideal pharmacological agents for chemoprevention should be cheap and nontoxic. Although data indicate that aspirin can reduce the risk of CRC in the general population, the highest return from chemopreventive strategies would be expected in patients with the highest risk of developing the disease, particularly those with a defined hereditary predisposition. Despite compelling data showing that a large number of chemopreventive agents show promise in preclinical CRC models, clinical studies have yielded conflicting results. This Review provides a historical and methodological perspective of chemoprevention in familial adenomatous polyposis and Lynch syndrome, and summarizes the current status of CRC chemoprevention in humans. Our goal is to critically focus on important issues of trial design, with particular attention on the choice of appropriate trial end points, how such end points should be measured, and which patients are the ideal candidates to be included in a chemopreventive trial.

Topics: Adenomatous Polyposis Coli; Animals; Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspirin; Chemoprevention; Clinical Trials as Topic; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Curcumin; Cyclooxygenase 2 Inhibitors; Drug Discovery; Fatty Acids, Omega-3; Humans; Mice; Randomized Controlled Trials as Topic; Rats; Sulindac

To reduce the morbidity and mortality from colorectal cancer (CRC), current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients at risk for CRC. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with a sporadic or genetic risk of CRC. It will also discuss therapeutic end points under evaluation in current efforts to develop drugs for treating CRC risk factors.

Topics: Adenomatous Polyposis Coli; Antineoplastic Agents; Chemoprevention; Clinical Trials as Topic; Colonoscopy; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Eflornithine; Genetic Predisposition to Disease; Humans; Inflammatory Bowel Diseases; Neoplasm Recurrence, Local; Sulindac

Fascinating progress has been made in the past 2 years in our understanding of the genetic alterations associated with colorectal cancer predisposition and development. First, the genotype-phenotype relationship of the cancer susceptibility syndrome associated with familial adenomatous polyposis has been shown to depend on mutation type. Second, hereditary nonpolyposis colorectal cancer syndromes have been recognized as being frequently associated with a defect in the DNA mismatch-repair pathway. A gene on chromosome 2 called hMSH2, which demonstrates homology with the bacterial repair gene MutS, has been shown to be altered in some families with hereditary nonpolyposis colorectal cancer. A defect on chromosome 3 may act by impairing the same pathway. Genotyping of particular loci, termed microsatellite, provides an easy identification of tumors deficient in mismatch repair. Third, the mechanisms by which the inactivation of tumor-suppressor genes such as p53 and APC may contribute to the tumorigenic process have begun to be elucidated. These different discoveries will have important impacts in the prevention and management of colorectal carcinoma, one of the most frequent human cancers.

Topics: Adenomatous Polyposis Coli; Animals; Cell Transformation, Neoplastic; Chromosome Mapping; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 3; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA-Binding Proteins; DNA, Neoplasm; DNA, Satellite; Genes, APC; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Humans; Mice; Mutation; MutS Homolog 2 Protein; Oncogenes; Proto-Oncogene Proteins; Sulindac; Syndrome

Non-steroidal anti-inflammatory drugs, e.g. sulindac have been extensively studied for chemoprevention in familial adenomatous polyposis, but not in hereditary non-polyposis colorectal cancer (HNPCC). We evaluated these effects in HNPCC using surrogate end-points for cancer risk. In a randomised double-blind cross-over study, 22 subjects (9 female; age 30-66 years, mean 44), all ascertained or probable mutation carriers for HNPCC, were included. Sulindac 150 mg b.i.d. and placebo were given for 4 weeks each, with 4 weeks in between, with biopsies taken from ascending, transverse and sigmoid colon and rectum by colonoscopy after both periods. Proliferation was determined by Ki-67 staining and apoptosis by staining of cytokeratin 18 cleavage products. Expression of cyclins B1, D3 and E and p21, p27, bax, bcl2 and cox-2 was studied immunohistochemically. Proliferation was higher during sulindac treatment than drug placebo treatment in ascending and transverse colon, but not in sigmoid and rectum. Apoptosis was not affected. Besides an increase in cyclin D3, no differences were found in expression of regulating proteins in the proximal colon.. Sulindac induces an increase in epithelial cell proliferation in the proximal colon of subjects with HNPCC. Since colorectal cancer predominantly arises in the proximal colon in HNPCC, these results cast doubts on the potential chemopreventive effects of sulindac in HNPCC.

Topics: Adult; Aged; Antineoplastic Agents; Apoptosis; Cell Proliferation; Colorectal Neoplasms, Hereditary Nonpolyposis; Cross-Over Studies; Double-Blind Method; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Sulindac

We have previously reported that sulindac, a non-steroidal anti-inflammatory drug, inhibited tumor formation in the small intestine but increased tumors in the colon of Apc(Min/+) mice, a model of human familial adenomatous polyposis. To further explore intestinal regional responses, we studied effects of sulindac on additional gene-targeted mouse models of human intestinal tumorigenesis; these were (i) Apc(1638N/+) mouse (chain termination mutation in exon 15 of the Apc gene); (ii) Mlh1(+/-) mouse (DNA mismatch repair deficiency, a mouse model of human hereditary non-polyposis colorectal cancer) and (iii) double-heterozygous Mlh1(+/-)Apc(1638N/+) mutant mouse. Mice were fed AIN-76A control diet with or without 0.02% sulindac for 6 months. Intestinal regional tumor incidence, multiplicity, volume and degree of inflammation were used as end points. The results showed the following: (i) sulindac inhibited tumor development in the small intestine of Apc(1638N/+) mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1(+/-)Apc(1638N/+) mutant mice; (iii) sulindac increased tumors in the cecum of all mice regardless of genetic background; (iv) sulindac decreased inflammation in the small intestine of Apc(1638N/+) mice, but it increased inflammation in the small intestine of Mlh1(+/-) mice and Mlh1(+/-)Apc(1638N/+) mice and (v) sulindac enhanced inflammation in the cecum of all mutant mice. Findings indicate that the effects of sulindac in the intestine of these mutant mouse models are probably related to genetic background and appear to be associated with its inflammatory-inducing response.

Topics: Adaptor Proteins, Signal Transducing; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cecum; Cell Transformation, Neoplastic; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease Models, Animal; Humans; Inflammation; Intestine, Small; Mice; Mutation; MutL Protein Homolog 1; Nuclear Proteins; Sulindac

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Aftercare; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Child; Colectomy; Colorectal Neoplasms, Hereditary Nonpolyposis; Combined Modality Therapy; Endoscopy, Gastrointestinal; Female; Humans; Male; Sulindac

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known cancer preventives, which have been largely attributed to their antiproliferative and apoptosis-inducing activities. In this study, we show that microsatellite instability (MSI) in colorectal cancer cells deficient for a subset of the human mismatch repair (MMR) genes (hMLH1, hMSH2, and hMSH6), is markedly reduced during exposure to aspirin or sulindac [or Clinoril, which is chemically related to indomethacin (Indocin)]. This effect was reversible, time and concentration dependent, and appeared independent of proliferation rate and cyclooxygenase function. In contrast, the MSI phenotype of a hPMS2-deficient endometrial cancer cell line was unaffected by aspirin/sulindac. We show that the MSI reduction in the susceptible MMR-deficient cells was confined to nonapoptotic cells, whereas apoptotic cells remained unstable and were eliminated from the growing population. These results suggest that aspirin/sulindac induces a genetic selection for microsatellite stability in a subset of MMR-deficient cells and may provide an effective prophylactic therapy for hereditary nonpolyposis colorectal cancer kindreds where alteration of the hMSH2 and hMLH1 genes are associated with the majority of cancer susceptibility cases.

Topics: Adaptor Proteins, Signal Transducing; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Aspirin; Carrier Proteins; Chemoprevention; Clone Cells; Cloning, Molecular; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Repair; DNA-Binding Proteins; Fungal Proteins; Humans; Microsatellite Repeats; Mutation; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Phenotype; Proto-Oncogene Proteins; Saccharomyces cerevisiae Proteins; Sulindac; Time Factors; Tumor Cells, Cultured