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Biomedical subjects

J M Jessup

Publications and source records attributed to J M Jessup.

At least 19 recordsLinked to original sources
PubMed1998

Role of nitric oxide and superoxide anion in elimination of low metastatic human colorectal carcinomas by unstimulated hepatic sinusoidal endothelial cells.

Human colorectal carcinoma (CRC) cell survival for the first 24 h after implantation in the hepatic sinusoid determines its potential to colonize the liver. Nearly 10-fold more highly metastatic CX-1 cells survive within the livers of nude mice 24 h after intrasplenic injection than weakly metastatic clone A cells. Because CRCs contact sinusoidal endothelial cells (SECs) during implantation, we sought to determine whether SECs were more toxic to clone A than to CX-1 cells. When 2 x 10(4) vital dye-labeled CRC cells were added to murine SEC monolayers, more than 30% of clone A cells lost calcein AM fluorescence compared to fewer than 5% of CX-1 cells after 24 h of coculture with SECs. Kupffer cells did not mediate this effect, because neither enriched Kupffer cells nor SECs treated with a Kupffer cell inhibitor altered the SEC-mediated toxic effect to clone A cells. Pretreatment with a nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine, superoxide dismutase, or dexamethasone, blocked SEC-mediated toxicity to clone A cells, whereas calcium chelation and catalase did not. In addition, clone A cells were more sensitive to a superoxide donor, 3-morpholinosydnonimine N-ethylcarbamide, than were CX-1 cells, and neither cell line was sensitive to sodium nitroprusside, a nitric oxide donor. Thus, unstimulated murine SECs produce reactive oxygen species that are selectively toxic to weakly metastatic clone A cells. This may be a mechanism by which host liver cells eliminate weakly metastatic neoplastic cells.

Animals↗
PubMed1998

Clinical and molecular prognostic factors in sphincter-preserving surgery for rectal cancer.

As many as a third of patients with rectal cancers may be candidates for sphincter preservation surgery. The goal of the conservative management of adenocarcinoma of the distal rectum is to preserve rectal sphincter function without sacrificing local tumor control. To achieve this goal, a combined modality approach is necessary because multimodality therapy for more advanced disease has improved both local control and survival. Candidates for local excision are those with adenocarcinomas with a maximal diameter of less than 4 cm, mobile, and not poorly differentiated or mucinous and within 10 cm of the anal verge--usually within 6 cm. These criteria should be defined objectively by biopsy combined with state-of-the-art endorectal imaging. Newer molecular markers that are associated with prognosis and response to therapy may also be important for assessing prognosis, probability of local recurrence, and whether conservative treatment is appropriate. Patients with T0-3 N0 lesions meeting these standard clinicopathologic criteria have been treated successfully with wide local excision combined with chemotherapy and radiotherapy. Patients with larger or more advanced lesions may undergo low anterior resection with coloanal anastomosis. After resection, radiotherapy to at least 45 to 50 Gy is delivered to the pelvis and tumor bed often with concomitant chemotherapy. The overall rate of local failure in prospective single-institution trials in which local excision is performed with postoperative chemoradiotherapy has been 5% for T1 lesions, 7% for T2 lesions and 24% for T3 lesions. Although single-institution studies have supported the concept of conservative therapy, the safety and efficacy of this approach must still be confirmed in a multicenter, prospective trial, such as that underway in several of the cooperative oncology groups, before it may be considered a standard of practice.

Adenocarcinoma↗
PubMed1997

The growth and maturation of the National Cancer Data Base.

BACKGROUND: The National Cancer Data Base (NCDB), a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, is a cancer management and outcomes data base for health care organizations. It provides a comparative summary of patient care that is used by communities and participating hospitals for self-assessment. The most current (1994) data are described here. METHODS: Six calls for data have yielded a total of 4,580,000 cases for the years 1985-1994. A total of 1735 hospital cancer registries have each participated in at least one of the calls for data. RESULTS: Summing the last year's report from each of the 1227 hospitals that participated in 1994, the cases represent the equivalent of 57% of the estimated 1994 U.S. cancer cases. These data were received from all six regions of the country, including all 50 states. Ninety-seven percent of patients received all or part of their treatment at the reporting hospital. The four most common cancers are carcinomas of the breast (15.7%), lung (14.3%), prostate (13.1%), and colon (7.7%), and collectively they comprise a majority of new cases. CONCLUSIONS: The NCDB is a cancer management and outcomes data base for health care organizations that currently provides data on 57% of the estimated new cases in the U.S. Past data have been used extensively to assess patterns of care and outcomes.

Adolescent↗
PubMed1997

In vivo induction of murine cytokine production by carcinoembryonic antigen.

Carcinoembryonic antigen (CEA) may promote experimental metastasis through production of cytokines. The effect of systemic CEA on the production of proinflammatory cytokines was investigated in mice and compared to levels induced by lipopolysaccharide (LPS). Serum concentrations of interleukin (IL)-6 peaked 1 h after an i.v. CEA injection of 40 microg/mouse to 37-54% of the maximal level induced by a 1 microg/mouse injection of LPS in both normal and immunoincompetent mice. The CEA induction of IL-6 was a specific response, because the peptide PELPK (the pentapeptide on CEA that is the ligand for the CEA receptor on Kupffer cells) conjugated to albumin induced 30% of the maximal CEA response for IL-6, whereas the specificity control PELGK-conjugated albumin did not. IL-1alpha and tumor necrosis factor (TNF)-alpha levels after i.v. injection of CEA were only 3-5% of those induced by LPS. The IL-6 responses of mice pretreated with 100 microg/kg genistein were decreased by more than 40%. However, genistein inhibited the TNF-alpha response to LPS by 46% but increased the CEA-induced response by 300%. When murine Kupffer cells were stimulated with LPS or CEA in vitro, LPS increased tyrosine phosphorylation of a Mr 30,000 protein, whereas CEA decreased phosphorylation of a Mr 60,000 protein and did not increase phosphorylation of the Mr 30,000 protein. Thus, i.v. CEA stimulates production of IL-6 and TNF-alpha after binding to Kupffer cells through signal transduction pathways that appear to be different from those stimulated by LPS.

Animals↗
PubMed1997

Locally advanced rectal carcinoma: pelvic control and morbidity following preoperative radiation therapy, resection, and intraoperative radiation therapy.

PURPOSE: To determine the impact of intraoperative radiation therapy (IORT) combined with preoperative external beam irradiation and surgical resection in patients with locally advanced, unresectable rectal carcinoma. METHODS AND MATERIALS: Between 1982 and 1993, 40 patients with locally advanced colorectal cancer unresectable at initial presentation were treated with preoperative external beam radiation therapy (median dose 50.4 Gy). Thirty patients received concurrent 5-fluorouracil. Twenty-seven patients had primary tumors and 13 had recurrent disease; 1 patient had a solitary hepatic metastasis at the time of surgery. Four to 6 weeks after radiation, surgical resection was undertaken, and if microscopic or gross residual disease was encountered, IORT was delivered to the tumor bed. Patients with an unevaluable or high-risk margin were also considered for IORT. IORT was delivered through a dedicated 300-kVp orthovoltage unit. The median dose of IORT was 12.5 Gy (range 8-20). The dose was typically prescribed to a depth of 1-2 cm. The median follow-up was 33 months (range 5-100). RESULTS: Thirty-three patients were able to undergo a curative resection (83%). Five patients had gross residual disease despite aggressive surgery. Seven patients did not receive IORT: six because of clear margins, and one with gross disease that could not be treated for technical reasons. The remainder of the patients (26) received IORT to the site of pelvic adherence. The crude local control rates for patients following complete resection with negative margins were 92% for patients treated with IORT and 33% for patients without IORT. IORT was ineffective for gross residual disease. Pelvic control was none of four in this setting. The crude local control rate of patients with primary cancer was 73% (16 of 22), as opposed to 27% (3 of 11) for these with recurrent cancer. The 5-year actuarial overall survival and local control rates for patients undergoing gross complete resection and IORT were 64% and 75%, respectively. Seventeen of the 26 patients (65%) who received IORT experienced pelvic complications, as opposed to two patients (28%) who did not receive IORT. The incidence of complications was similar in the patients with primary versus recurrent disease. All cases were successfully treated with the placement of a posterior thigh myocutaneous flap. Of note, no pelvic osteoradionecrosis was seen in this series. CONCLUSION: Patients with locally advanced carcinoma of the rectum were aggressively treated with combined modality therapy consisting of preoperative external beam radiotherapy, surgery, and IORT. The pelvic control rate was 82% for patients with minimal residual disease. IORT failed to control gross residual disease. The incidence of pelvic wound healing problems was 65% in this series; however, a reconstructive procedure which replaced irradiated tissue with a vascularized myocutaneous flap was successful in treating this complication. We believe that IORT has therapeutic merit in the treatment of locally advanced rectal cancer, particularly in the setting of minimal residual disease.

Adult↗
PubMed1997

Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines.

Somatic mutations in DNA mismatch repair genes have been observed in sporadic tumors as well as cell lines and xenografts derived from such tumors implicating genetic defects of mismatch repair genes in the development of such tumors. However, the proportion of sporadic tumors in which mismatch repair genes have been inactivated has not been determined accurately. We have analyzed 66 sporadic colorectal tumors for the expression of hMLH1 by immunohistochemistry and identified 4 tumors that do not express hMLH1. These four colorectal tumors, a colon tumor cell line (SW48) and an endometrial tumor cell line (AN3CA), did not express hMLH1, despite the absence of mutations in its coding sequence. Cytosine methylation of the hMLH1 promoter region was found in these four colorectal tumors, whereas cytosine methylation of the hMLH1 promoter region was absent in adjacent normal tissue or in nine tumors that expressed hMLH1. In addition, cytosine methylation of the hMLH1 promoter region was observed in the SW48 and AN3CA cell lines that do not express hMLH1 but not in four tumor cell lines known to express hMLH1 mRNA. Our data indicate that DNA methylation is likely to be a common mode of mismatch repair gene inactivation in sporadic tumors.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Prospective evaluation of local excision for small rectal cancers.

OBJECTIVE: Most data on local excisions for rectal cancer are based on retrospective studies. We review the results of a prospective registry of patients eligible for local excision of rectal cancer using a transanal, transsphincteric, or transcoccygeal technique combined with multimodality therapy for lesions penetrating the muscularis propria (T2) or perirectal fat (T3). METHODS: Patients with lesions less than 4 cm in diameter and less than 10 cm from the dentate line, with no evidence of distant metastases or invasion into the perirectal fat, were eligible for local excision. Patients with invasion into the muscularis propria (T2) or greater (T3) received adjuvant chemoradiation therapy. RESULTS: Forty-eight patients have been followed prospectively. Average age is 63 years. Thirty-three patients underwent a transanal excision. Fifteen patients underwent either a transsphincteric or technique excision. There was no perioperative mortality. Pathology revealed 1 Tis, 21 T1, 21 T2, and 5 T3 cancers. Mean follow-up is 40.5 months. Cancer-related overall mortality was 4 percent. Overall local or distant recurrence rate was 8 percent (4/48). Recurrence appeared to be related to presence of a positive margin or aggressive histology (lymphatic invasion). Local recurrences were treated with salvage therapy. CONCLUSION: Local excision can be used selectively for small rectal cancers, with minimum morbidity. Recurrence rates are low (8 percent). Patients with either a positive margin or lymphatic invasion need to be considered for further therapy, including abdominoperineal resection, even with T1 lesions. Adjuvant chemoradiation appears to be a benefit for all T2 or T3 cancers.

Adenocarcinoma↗
PubMed1997

Association between sucrase-isomaltase and p53 expression in colorectal cancer.

BACKGROUND: Sucrase-isomaltase (SI) is a tissue-based phenotypic marker that is an independent prognostic factor in colorectal cancer (CRC). DF3 and galectin 3 are two other tissue-based markers that are upregulated during neoplastic transformation. Because p53 mutations are acquired during neoplastic progression, we reasoned that alterations in SI and p53 may be associated despite an apparent lack of biological interaction. METHODS: Paraffin sections from 183 patients who underwent surgery at New England Deaconess Hospital (NEDH) between 1965 and 1977 were analyzed first by immunohistochemistry (IHC) for the expression of the markers SI, DF3, and galectin 3, which were scored as absent or present. Paraffin sections from a second group of 59 patients who underwent surgery at NEDH between 1985 and 1992 were analyzed by IHC for the expression of p53 as well as SI, DF3, and galectin 3. p53 nuclear staining was scored as absent or present. Previous work has shown that p53 is mutated in all cells with nuclear staining and in 10% of tumors that are unstained. RESULTS: SI expression was not associated with the expression of either DF3 or galectin 3, and neither DF3 nor galectin 3 were prognostic factors in CRC. None of the phenotypic markers were associated with any of the clinicopathologic variables. However, 21 of 24 p53-positive cases (88%) expressed SI, whereas 15 of 35 p53-negative cases (43%) were also SI negative (p = 0.02, Fisher exact test). p53 expression was not associated with expression of DF3 or galectin 3. CONCLUSIONS: SI expression and p53 mutation are associated significantly in CRC. Although the mechanism underlying such an association in presently unknown, the association may define a subset of patients with a worse prognosis.

Antigens, Differentiation↗
PubMed1997

Induction of carcinoembryonic antigen expression in a three-dimensional culture system.

MIP-101 is a poorly differentiated human colon carcinoma cell line established from ascites that produces minimal amounts of carcinoembryonic antigen (CEA), a 180 kDa glycoprotein tumor marker, and nonspecific cross-reacting antigen (NCA), a related protein that has 50 and 90 kDa isoforms, in monolayer culture. However, MIP-101 produces CEA when implanted into the peritoneum of nude mice but not when implanted into subcutaneous tissue. We tested whether three-dimensional (3D) growth was a sufficient stimulus to produce CEA and NCA 50/90 in MIP-101 cells, because cells grow in 3D in vivo rather than in two-dimensions (2D) as occurs in monolayer cultures. To do this, MIP-101 cells were cultured on microcarrier beads in 3D cultures, either in static cultures as nonadherent aggregates or under dynamic conditions in a NASA-designed low shear stress bioreactor. MIP-101 cells proliferated well under all three conditions and increased CEA and NCA production three- to four-fold when grown in 3D cultures compared to MIP-101 cells growing logarithmically in monolayers. These results suggest that 3D growth in vitro simulates tumor function in vivo and that 3D growth by itself may enhance production of molecules that are associated with the metastatic process.

Animals↗
PubMed1997

Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas.

The cell-cycle inhibitor p27 is a potential tumor suppressor, but its gene has never been found inactivated in human tumors. Because cell-cycle regulation of p27 cellular abundance occurs at the post-transcriptional level, we analyzed p27 protein expression and degradation in human colorectal carcinomas. Proteasome-mediated degradation activity of p27 was compared with its protein levels in a subset of tumor samples. We found that carcinomas with low or absent p27 protein displayed enhanced proteolytic activity specific for p27, suggesting that low p27 expression can result from increased proteasome-mediated degradation rather than altered gene expression. Patients whose tumors expressed p27 had a median survival of 151 months, whereas patients who lacked p27 (10%) had a median survival of 69 months. By multivariate analysis, p27 was found to be an independent prognostic marker. Lack of p27 was associated with poor prognosis (2.9 risk ratio for death; P = 0.003). The absence of p27 protein expression is thus a powerful negative prognostic marker in colorectal carcinomas, particularly in stage II tumors, and thereby may help in the selection of patients who will benefit from adjuvant therapy. These data suggest that aggressive tumors may result from the selection of a clone or clones that lack p27 due to increased proteasome-mediated degradation.

Adenocarcinoma↗
PubMed1997

Gastric cancer surgical practice guidelines. Gastric Cancer Practice Guideline Committee.

The data described above suggest that the current management of gastric carcinoma requires a surgical resection. Identification of the number of lymph nodes that may be involved with cancer is an important prognosticator. Resection of involved lymph nodes is likely to decrease the morbidity of locoregional recurrence. However, this has not been adequately addressed in the studies performed to date. Nonetheless, accurate staging is an essential goal of the primary therapy of gastric carcinoma. The limits of resection for a gastric cancer are outlined in the guidelines (see page 1068). Administration of adjuvant therapy, such as chemotherapy or radiation therapy, remains controversial and is the subject of ongoing clinical research. Until a prospective, randomized trial demonstrates a significant improvement in survival, there remains little or no basis for the addition of adjuvant therapy outside the context of a clinical trial.

Carcinoma↗
PubMed1996

The DCC protein and prognosis in colorectal cancer.

BACKGROUND: Allelic loss of chromosome 18q predicts a poor outcome in patients with stage II colorectal cancer. Although the specific gene inactivated by this allelic loss has not been elucidated, the DCC (deleted in colorectal cancer) gene is a candidate. We investigated whether the expression of the DCC protein in tumor cells is a prognostic marker in colorectal carcinoma. METHODS: The expression of DCC was evaluated immunohistochemically in 132 paraffin-embedded samples from patients with curatively resected stage II and III colorectal carcinomas. The Cox proportional-hazards model was used to adjust for covariates including age, sex, tumor site, degree of tumor differentiation, and use of adjuvant therapy. RESULTS: The expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas. In patients with stage II disease whose tumors expressed DCC, the five-year survival rate was 94.3 percent, whereas in patients with DCC-negative tumors, the survival rate was 61.6 percent (P<0.001). In patients with stage III disease, the respective survival rates were 59.3 percent and 33.2 percent (P=0.03). CONCLUSIONS: DCC is a prognostic marker in patients with stage II or stage III colorectal cancer. In stage II colorectal carcinomas, the absence of DCC identifies a subgroup of patients with lesions that behave like stage III cancers. These findings may thus have therapeutic implications in this group of patients.

Aged↗
PubMed1996

Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers.

Introduction of tumor markers into routine clinical practice has been poorly controlled, with few criteria or guidelines as to how such markers should be used. We propose a Tumor Marker Utility Grading System (TMUGS) to evaluate the clinical utility of tumor markers and to establish an investigational agenda for evaluation of new tumor markers. A Tumor Marker Utility Grading Worksheet has been designed. The initial portion of this worksheet is used to clarify the precise characteristics of the marker in question. These characteristics include the marker designation, the molecule and/or substance and the relevant alteration from normalcy, the assay format and reagents, the specimen type, and the neoplastic disease for which the marker is being evaluated. To determine the clinical utility of each marker, one of several potential uses must be designated, including risk assessment, screening, differential diagnosis, prognosis, and monitoring clinical course. For each of these uses, associations between marker assay results and expected biologic process and end points must be determined. However, knowledge of tumor marker data should contribute to a decision in practice that results in a more favorable clinical outcome for the patient, including increased overall survival, increased disease-free survival, improvement in quality of life, or reduction in cost of care. Semiquantitative utility scales have been developed for each end point. The only markers recommended for use in routine clinical practice are those that are assigned utility scores of "++" or " " on a 6-point scale (ranging from 0 to ) in the categories relative to more favorable clinical outcomes. Each utility score assignment should be supported by documentation of the level of evidence used to evaluate the marker. TMUGS will establish a standardized analytic technique to evaluate clinical utility of known and future tumor markers. It should result in improved patient outcomes and more cost-efficient investigation and application of tumor markers.

Biomarkers, Tumor↗
PubMed1996

The National Cancer Data Base report on patterns of hospital reporting.

BACKGROUND: Previous Commission on Cancer data from the National Cancer Data Base (NCDB) have examined time trends in stage of disease, treatment patterns, and survival for selected cancers. The most current (1993) data are described here. METHODS: Five calls for data have yielded a total of 3,700,000 cases for the years 1985 through 1993, including 477,679 cases for 1988, and 608,593 cases for 1993, from hospital cancer registries across the U.S. RESULTS: The most recent call for data for 1993 comprised 52% of the estimated new cases of cancer in the U.S. The country was comprised of 6 regions, with the Mountain and Southeast regions having the highest regional reporting of new cases of cancer (69% and 55%, respectively) and the Northeast and Pacific regions having the lowest (47% each). Approximately 96% of patients received their treatment at the reporting hospital. The 4 most common carcinomas were breast (15.7%), lung (14.6%), prostate (14.2%), and colon (7.5%) and comprised the majority of new cases. Trends in patterns of care for breast carcinoma were analyzed for possible bias in the 1988 and 1993 periods. When hospitals reporting only in 1988 or in 1993 were compared with hospitals reporting at both time points, the only differences were small differences in ethnic participation. These differences were less than 1.5% in the proportion of African Americans reported in the different time periods. There were no significant differences in the downstaging of breast carcinoma, or the role of conservative surgery or adjuvant radiation therapy. CONCLUSIONS: The NCDB is a cancer management and outcomes data base for health care organizations that presently comprises 52% of the estimated new cases in the U.S. This will increase to 80% as the approved hospitals of the Commission on Cancer are required to report to the NCDB. Comparison of breast carcinoma findings at two time periods appeared similar regardless of hospital reporting set (i.e., set of hospitals reporting for one period versus both periods).

Adolescent↗
PubMed1996

The National Cancer Data Base. Report on colon cancer.

BACKGROUND: Commission on Cancer data from the National Cancer Data Base (NCDB) report time trends in stage of disease, treatment patterns, and survival for patients with selected cancers. The most current data (1993) for patients with colon cancer are described. METHODS: Five calls for data yielded 3,700,000 cases of cancer for the years 1985 through 1993 from hospital cancer registeries across the U.S., including 36,937 cases of colon cancer from 1988 and 44,812 from 1993. RESULTS: Interesting trends are as follows: (1) the elderly ( > 80 years) present with earlier stage disease than younger patients; (2) the National Cancer Institute recognized cancer centers have more patients with advanced disease than other types of hospitals; (3) all ethnic groups have generally similar stages of disease at presentation, except for African-Americans who have a slightly higher incidence of Stage IV disease; (4) the proximal migration of the primary cancer continues with 54.7% of primary colon cancer arising in the right colon in 1993 compared with 50.9% in 1988; (5) an interaction between grade and stage of cancer seems present; and (6) patients with Stage III colon cancer who received adjuvant chemotherapy had a 5% improvement in 5-year relative survival. CONCLUSIONS: The NCDB data are useful for reporting what cancer treatments are being administered and what outcomes are occurring in the U.S. The data suggest an important biologic role for grade of cancer. They also suggest that African-Americans and other ethnic groups have the same outcome as non-Hispanic whites but that access to medical care may still be less. Finally, the utility of adjuvant therapy for Stage III colon cancer may just be beginning to be appreciated.

Aged↗
PubMed1996

Implantation of human colorectal carcinoma cells in the liver studied by in vivo fluorescence videomicroscopy.

In vivo fluorescence videomicroscopy (IVFM) was used to analyse the behavior of weakly and highly metastatic human colorectal carcinoma (CRC) cells during implantation in the liver. A highly metastatic human CRC cell line, CX-1, and a weakly metastatic line, Clone A, were double-labeled with rhodamine B isothiocyanate-dextran (Rd-Dx) to locate cells and with calcein AM to assess cell metabolic activity in an experimental metastasis model. Double-labeled CRC cells (2.0 x 10(6)) were injected into the spleens of groups of nude mice and the livers observed by IVFM over the next 72 h. CRC cells were implanted within 30 s after injection into either portal venules or the proximal third of hepatic sinusoids. Approximately 0.5% of CRC cells traversed the liver through portal-central venous shunts and implanted in the lung. The number of CX-1 cells in the liver was similar to that of Clone A cells during the first 12 h. However, more CX-1 cells than Clone A cells remained in the liver at 4 h and were in groups of 8-12 cells whereas only a few, single Clone A cells were detected in the liver at 72 h. Not all Clone A cells are committed to die within 4 h of implantation because cells harvested 4 h after hepatic implantation proliferated normally in vitro when removed from the hepatic microenvironment. Since the stress of mechanical deformation during implantation may cause differences in cell survival, CX-1 and Clone A cells were passed through filters with 8 microM pores in vitro at 10-15 cm of water pressure to recreate the trauma of hepatic implantation. Approximately 50% of both CX-1 and Clone A cells were lysed. Furthermore, both CRC lines remained metabolically active when co-cultivated with liver cells for at least 24 h in vitro. Thus, the difference in metastatic potential between the two CRC lines may reside in their response to the combination of mechanical implantation and subsequent growth in the liver parenchyma.

Animals↗
PubMed1996

n-3 fatty acids decrease colonic epithelial cell proliferation in high-risk bowel mucosa.

The n-3 fatty acids (C20:5, eicosapentaenoic acid; c22:6, docosahexaenoic acid) may be important in the development, growth, and metastasis of colon cancer, a leading cause of death in North America. Patients who have had a bowel neoplasm have a high risk of developing a second neoplasm, and this risk is associated with a high percentage of cells correspond to the S phase of bromodeoxyuridine (BrdUrd) labeling in mucosal epithelial cells. To determine the effect of n-3 fatty acid supplementation on DNA synthesis of rectal mucosa, patients with stage 1 or stage 2 colon carcinoma or adenomatous polyps were randomized to consume either 9 g/d n-3 fatty acid capsules or 9 g/d placebo capsules. Plasma phospholipid fatty acid analysis and proctoscopic mucosal biopsies were performed at baseline, 3, and 6 mon. Colonic crypts were isolated from the mucosa, disassociated with enzymes, and incubated with BrdUrd, and %S phase was measured by flow cytometry. The plasma phospholipid n-6/n-3 ratio was determined by gas chromatography. Supplement compliance was assessed by plasma phospholipid n-6/n-3 ratio. Mean capsule consumption in these two group was 82%. Prior to supplementation, there were no significant differences in the %S phase and the plasma n-6/n-3 ratio between these groups. Patients whose colonic epithelial cells indicated hyperproliferation at baseline showed a strongly positive correlation to the %S phase of BrdUrd uptake and the n-6/n-3 ratio. There was no significant change after n-3 treatment in patients with low baseline. Those in the placebo group showed no significant difference in n-6/n-3 ratio, although there was an increase in the %S phase of BrdUrd uptake at 6 mon. The n-3 group did not have significant side effects, and polyps were not found after completing 12 mon of n-3 fatty acid supplementation. This study suggests that n-3 fatty acid may be a useful chemopreventive agent in some patients as reflected in a plasma biomarker of colon tumor growth and metastasis. A low plasma phospholipid n-6/n-3 fatty acid ratio may serve as a nutritional marker that is associated with colonic epithelial cell hyperproliferation in the n-3-supplemented group as compared with the placebo group. Characteristics of mucosal proliferation at baseline may be a crucial factor for the effect of n-3 fatty acid supplementation.

Cell Division↗