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395 RANDOMIZED TRIAL OF CHEMOPREVENTION WITH VITAMIN A AND N-ACETYLCYSTEINE IN PATIENTS WITH CANCER OF THE UPPER AND LOWER AIRWAYS. N.de Vries, U. Pastorino, N. van Zandwijk, O.Dalesio. On behalf of the Euroscan study group/EOTRC Head and Neck and Lung Cancer Co-Operative Groups). Sint Lucas Andreas Hospital, Amserdam, The Netherlands. |
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Objective: To test the value of chemoprevention in early stage head and neck cancer or lung cancer. Methods: Between 1988 and 1994, 2592 patients from 81 European institutes (15 countries) were randomized to retinyl palmitate (300,00/IU and 150,000/IU/day in first and second year respectively), NAC (600 mg/day), both or neither . In 1% no data were obtained. Of 2573 patients, 1065 (41.4%) had laryngeal cancer, 485 (18.8%) oral cancer and 1023 (39.8) lung cancer. Results: At 49 months, first events were recurrence (572), 2nd tumor (SPT), (211) and death without cancer (133). There was no difference in events free survival in 1290 patients with retinyl (465 events ) and without retinyl (451 events in 1283 patients and in NAC (468 events in 1285 patients) and no NAC (448 events in 1288 patients). No differences were observed in survival by retinyl vs no retinyl, or NAC vs no NAC. STP's showed no significant difference, with 115 (8.9%) in retinol arms vs 96 (7.5%) in those with out, and 116 (9.0%) in NAC arms vs 95 (7.4%) in no NAC arms. Conclusions: Two years of supplementation with Vitamin A and or NAC resulted in terms of event-free-or overall survival or incidence of second tumors. |
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396 CYCLOOXYGENASE 2: A TARGET FOR CANCER TREATMENT AND PREVENTION. Raymond N. DuBois, Departments of Medicine and Cell Biology, Vanderbilt University Medical Center, Nashville , TN 37332-2279 |
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Several groups have demonstrated an increase in prostaglandin endoperoxide synthase-2 or cyclooxygenase -2 (COX-2) expression in a variety of cancers (colon, skin. Lung, breast, bladder, prostate). The presence of COX-2 in human lung and colon cancers has been associated with a negative clinical prognosis. Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) results in a 40-50% reduction of risk for colorectal cancer. NSAIDs inhibit both COX-1 and COX-2. COX-2 has been shown to play a role in rodent models of intestinal carcinogenesis and treatment with selective COX-2 inhibitors, such as celecoxib, blocks the growth of a variety of cancers such as skin, colon, head/neck, and bladder. We evaluated the contribution of host-derived COX-1 and COX-2 in tumor growth using both genetic and pharmacologic approaches. Lewis lung carcinoma (LLC) cells grow rapidly as solid timors when implanted in C57BL/6 mice. We found that tumor growth was markedly attenuated in COX-2-/-, but not COX-1-/- or wild type mice. Treatment of wild type C57Bl/6mice bearing LLC tumors with a selective COX-2 inhibitor also reduced tumor growth. A decrease in vascular density was observed in tumors grown in COX-2-/- mice when compared to those in wild type mice. Since COX-2 in expressed in stromal fibroblasts of human and rodent colorectal carcinomas, we evaluated COX-2-/- mouse fibroblasts and found a 94% reduction in their ability to produce the pro-angiogenic factor, VEGF. Additionally, treatment ofwild type mouse fibroblasts with a selective COX-2 inhibitor reduced VEGF production by 92%. These results indicate that host-derived COX-2 is important for efficient tumor growth and that part of the anti-neoplastic effects of nonsteriodal anti-inflammatory drugs (NSAIDs) could be mediated through inhibition of COX-2 expressed in stromal fibroblasts. |
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Recent technologic advances have provided valuable insights into the molecular basis of colorectal carcinogenesis, resulting in incresed opportunities for chemoprevention. Characterization of molecular mechanisms that foster neoplasia have already enhanced our understanding of the chemopreventive activities of difluormethylornithine, cyclooxygenase inhibitors, and other agents. In addition, mechanistic hypotheses based on these data guide us in selecting strategies for development of new agents that target key elements of carcinogenesis including aberrations of : APC,ras,cyyclooxgenases ,matrix metalloproteinases,epidermal growth factor receptor,farnesyltransferase,insulin-like growth factors 1 or 2, and p53. Developmental strategies for identifying promising agents typically begin with preclinical discovery and testing in invitro and in vivo settings which provide critical mechanistic rationales. Several carcinogen-induced and genetically altered rodent models have been predictively validate dwith COX inhibitors, which are among the most active clinical chemopreventive agents identified. Epidemiologic studies may further strengthen the premis for prevention trials by providing preliminary efficacy data on a class of compounds within observational settings. The design paradigm for clinical chemoprevention trials is based on three cardinal elements: agent, cohort, and endpoints. Trial designs-and the overall agent development schema-are optimized by selecting subjects with elevated and or accelerated risk of neoplasia, agents with specific mechanisms and optimal preclinical efficacy, high sensitive assesment technologies, and multiple mutaully corraborative endpoints (e.g. adenomas,aberrant crypt foci, and subcellualar biomarkers.) Such strategies accelerate clinical agent development and the time to iterative testing in lower risk cohorts, thereby conserving precious resources. Several concepyual and practical obstacles that have slowed progress in the field will be discussed. Promising areas for future chemoprevention research include: prevention endpoints nested within therapeutic trials; use of structural or functional image with improved sensitivity for serial assessments; tissue-based biomarker assessments within neoplastic lesions; and combinations of effective agents. It may be wise to consider the formation of a standing collaborative research consortium to pursue these opportunities. |
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398 CLINICAL MODULATION OF ORAL LEUKOPLAKIA AND PROTEASE ACTIVITY BY BOWMAN-BIRK INHIBITOR CONCENTRATE IN A PHASE 11A CHEMOPREVENTION TRIAL Frank L. Meyskens Jr., William B. Armstrong, X. Steven Wan, Thoams H. Taylor, Quoc A. Nguyen, Jerald Jensen, Wayne Thompson, Westley Lagerberg, Ann R. Kennedy. Departments of Otolaryngology, (WBA, QAN) and Medicine (THT,FLM,WL) Chao Family Comprehensive Cancer Center, University of California, Irvine, and Long Beach VA, Medical Center (LBVA,JJ,WT) Orange, CA 92868; Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 |
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BowmaBirk Inhibitor (BBI) is a protease inhibitor derived from soybeans that has demonstrated chemporeventive activity in a number of in vitro and animal systems. To determine whether this drug chemopreventive activity in humans, we conducted a short-term clinical trial of BBI Concentrate (BBIC) in patients with oral leukoplakia . BBIC was administered to thirty-two subjects with oral leukoplakia for one-month to assess toxicity and to measure the surrogate endpoint biomarks (SEBM) clinical and histologic response of the lesions, mucosal cell protease activity (PA) and serum micronutrient levels. Clinical response was assessed by measurement of individual and total lesion areas pre and post treatment, and analysis of blinded clinical judgements of photographs. BBIC was nontoxic in dosed up to 1066 chymotrypsin inhibitory units (CIU) The mean pretreatment total lesion area decreased from 615 mm2 to 438mm2 after BBIC treatment (p<0.004). A linear fit of the dose-response relationship between dose of BBIC and decrease in total lesion area was evident (p<0.08) and analysis of blinded clinical impression from lesion photographs confirmed this relationship (p<0.01) Overall, at all doses tested a 24.2% decrease in total lesion area was observed following treatment (sign rank =142, p<0.001). High pretreatment PA was associated (p<0.02) with greater decreases in PA following BBIC administration. BBIC demonstrated clinical activity following oral administration to patients with oral leukoplakia and indicated that BBIC should be investigated for chemopreventive activity in a randomized clinical trial. Key words: Bowman-Birk Inhbitor, Chemoprevention, Leukoplakia. |
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399 CHEMOPREVENTION OF COLON CANCERS BY CYCLOOXYGENASE AND INOS INHIBITORS AND NOVEL ORGANOSELENIUM: PRECLINICAL EFFICACY STUDIES. Bandaru S. Reddy, American Health Foundation, Valhalla, NY, USA |
| Colorectal cancer is one of the most common human malignancies in Western countries. During recent years, multidisciplinary research in epidemiology and preclinical models have contributed much to our understanding of the etiology of this cancer; more importantly it has enabled us to initiate preventive strategies. Chemoprevention has the potential to me a major component of colon cancer control. Accumulating evidence from human epidemiological and preclinical efficacy studied indicates that nonsteroidal anti-inflammatory drugs (NSAIDs)including aspirin , ibuprofen , piroxicam and sulindac can reduce the incidence of colon cancer. One of the mechanisms by which NSAIDs inhibit colon cancer is through the modulationog cyclooxygenase (COX)-1 and -2 which leads to a reduction of eicosanoid production which in turn affects cell proliferationand tumor growth. NSAIDs can cause unwanted side effects, including gastrointestinal ulceration, bleeding, and renal toxicity, through the inhibition of constitute COX-1 activity. Over expression of COX-2 has been observed in colon tumors. Since many commonly used NSAIDs have very little selectivity for COX-1 or COX-2, more specific yet minimally toxic inhibitors of COX-2 were developed and tested for chemopreventive efficacy. Celecoxib, a selective COX-2 inhibitor not only suppressed the initiation and postinitiation and promotion/progression stages of colon carcinogenesis in preclinical models but was also found to be more effective than commonly used NSAIDs. Preliminary clinical intervention studied also indicate that celecoxib is effective in familial adenomatous polyp patients. Equally exciting are opportunities for effective chemoprevention with phytochemicals including curcumin, iNOS inhibitors and organoselenium compounds. Preclinical studies also provided sound data about innovative combination of agents with different modes of action as a means if increasing efficacy and minimizing toxicity. Important findings were that the lowest dose levels of piroxicam, an NSAID, and difluoromethylornithine OCD inhibitor, when administered together, were more effective in inhibiting colon adenocarcinomas than administration of individual compounds. How best to use such knowledge in finding prevention modality toward reducing colorectal cancer risk is primary challenge for the future. |
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409 CALCIUM AND VITAMIN D IN COLON CANCER RISK REDUCTION. Peter R. Holt, Chief Gastroenterology Division, St. Luke's Roosevelt Hospital Center and Professor of Medicine, College of Physicians & Surgeons Columbia University, New York, NY |
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In many studies, higher calcium and/or Vitamin D intake generally have been associated with lowering in the incidence and mortality of colorectal cancer. Studies of the effect of calcium and Vitamin D on colon cancer cells in-vitro and addition of these nutrients to the diet of carcinogen-treated rodents also have shown a reduction in colon neoplasia development. Furthermore the addition of calcium and/or vitamin D to the diet of similarly treated animals who were provided a "Western Type" diet have shown changes in colonic epithelial cell proliferation and differentiation from a higher risk to a lower risk pattern for colon neoplasia.Prospective studies of calcium supplementation in patients at increased risk foe colon neoplasia because of a strong family history or personal history of colon cancer or previous adenomatous polyps, generally have suggested that early surrogate markers of risk for colon neoplasia, (for example, altered epithelial cell proliferation) are changed from a higher toward a lower risk pattern. A very recent crossover study in 40 subjects in which a similar low fat dairy food supplement intake was provided and directly compared to giving approximately 90mg of calcium supplements per day has conformed that increased dairy food intake altered proliferation of the flat rectal mucosa from a higher to a lower risk pattern. The subjects maintaining their regular diet but given supplemental calcium also significantly improved their proliferative epithelial cell risk pattern in the rectal mucosa. A confounding factor in evaluating the potential beneficial effects of increased calcium intake may be varable a vitamin D ststus. In a prospective study of calcium/vitamin D intake in subjects who had had a polypectomy for colorectal adenomatous polyps demonstrated at the 6 month end point a significant relationship between the serum levels of 25 hydroxy vitamin D (25 OHD3) but not of 1.25 (OH2) D3 and a change in surrogate proliferative markers of risk from higher to a lower risk pattern. These data suggests that the levels of serum 1.25 (OH2) D3 in determining the effects of calcium or vitamin D in colon cancer risk reduction. These observations also imply that there might be local autocrine control of vitamin D metabolism within the colon that helps to determine the effects of calcium upon colonic epithelial cell proliferation and differentiation. Supported in part by the NCI and Dairy Management Incorperated. |