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D S Alberts

Publications and source records attributed to D S Alberts.

At least 73 records · Page 4Linked to original sources
PubMed1997

1,4-disubstituted anthracene antitumor agents.

Three different types of 1,4-disubstituted anthracenes were synthesized, and their cytotoxicity in a panel of tumor cells was compared with that of the corresponding 9,10-disubstituted anthracenes. The panel contained human myeloma, melanoma, colon, and lung cancer cells and sensitive and multidrug-resistant murine L1210 leukemia cells. These compounds had [[(dimethylamino)ethyl]amino]methyl, N-[(dimethylamino)ethyl]carbamoyl, and carboxaldehyde (4,5-dihydro-1H-imidazol-2-yl)hydrazone side chains. The 1,4-diamide was more potent across the tumor panel than the corresponding 9,10-isomer, but the 1,4-diamine and the 1,4-hydrazone were less potent than their 9,10-isomers. Although the 1,4-hydrazone was active against P388 leukemia in mice, it was inactive against L1210 leukemia. Within each pair of compounds, the one with greater average potency against tumor cells gave a greater increase in the transition melt temperature of DNA.

Animals↗
PubMed1997

Band 1p36 abnormalities and t(1;17) in ovarian carcinoma.

In a series of 128 karyotyped ovarian carcinomas, 42% of cases with chromosome 1 clonal structural abnormalities had breaks at band 1p36 (usually involving translocations of unknown material). Fluorescent in situ hybridization (FISH) studies using combinations of 1 centromere and 1p36.3-specific probes (16 cases) or 1 centromeric and 17 whole-chromosome paint probes (11 cases with 1p+) revealed a trend toward deletion of 1pter relative to 1 centromere (63%); intratumor heterogeneity; and the origin of 1p+ in 3/11 cases (27%) from chromosome 17 [t(1;17)(p36;?)]. The frequency of this specific breakpoint and its involvement in recurrent translocations suggest that these regions are loci for genes important in the pathogenesis of a subset of sporadic ovarian carcinomas.

Adenocarcinoma↗
PubMed1997

Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac, have cancer chemopreventive properties by a mechanism that has been suggested to involve cyclooxygenase inhibition and reduction of prostaglandin (PGE2) levels in the target tissue. To test this hypothesis, we studied the effect of dietary sulindac sulfone (500-2000 ppm), a metabolite of sulindac reported to lack cyclooxygenase inhibitory activity, on tumor formation and PGE2 levels in the azoxymethane model of colon carcinogenesis. Rats treated with sulindac at 400 ppm and piroxicam at 150 ppm were used as positive controls. Rats received two s.c. injections of azoxymethane (15 mg/kg) for 2 weeks and were fed either experimental or control diets until necropsy. After 31 weeks of sulfone treatment, a dose-related increase in sulfone levels in both serum and cecal contents was measured; there was no evidence of metabolic conversion to sulindac or other metabolites. Rats treated with sulfone at 1000 and 2000 ppm, sulindac, and piroxicam had significantly fewer colonic adenomas and carcinomas compared with rats fed control diet as measured by tumor incidence, multiplicity, and tumor burden. Sulfone-treated rats also showed a dose-response relationship for inhibiting all tumor parameters. Colons from rats treated with sulindac or piroxicam contained PGE2 levels that ranged from approximately 16-49% of control levels. PGE2 levels in rats treated with sulfone up to 2000 ppm ranged from 78-118% of control levels. Moreover, the effects of sulindac sulfone on various enzymes responsible for regulating prostaglandin levels were evaluated. No significant inhibitory effects were observed for cyclooxygenase, lipoxygenase, or phospholipase A2. These results suggest that reduction of prostaglandin levels in the target tissue may not be necessary for the chemopreventive properties of sulindac.

Animals↗
PubMed1997

In vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human ovarian cancers.

PURPOSE: To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of the standard platinum agents, cisplatin and carboplatin, against fresh human, epithelial ovarian cancers. METHODS: The Hamburger-Salmon human tumor colony-forming assay (HTCA) was used to measure the chemosensitivity of 36 fresh tumor samples obtained during initial exploratory laparotomy from patients with newly diagnosed stage III-IV epithelial ovarian cancer who had received no prior chemotherapy or radiation therapy. Tumor samples were exposed to the platinum analogs for 1 h at concentrations of 10 and 100 micrograms/ml of nedaplatin and cisplatin and 100 and 1000 micrograms/ml of carboplatin. The resulting survival data were used to estimate the IC50 (drug concentration associated with 50% inhibition of tumor colony forming units, TCFUs) of each of the platinum analogs for each of the tumor samples, as well as the estimated survival following exposure to clinically achievable drug levels (i.e. the ultrafiltrable platinum area under the plasma disappearance curve, AUC, achieved in cancer patients following administration of standard or phase II doses). RESULTS: At the lowest concentration tested (i.e. 10 micrograms/ml nedaplatin and cisplatin and 100 micrograms/ml carboplatin) the percentages of tumor samples which were sensitive (as defined by 50% or less survival of TCFUs as compared with controls) were 42, 50, and 40% for nedaplatin, cisplatin and carboplatin, respectively. The median IC50 values were 28.5, 12 and 121 micrograms/ml for nedaplatin, cisplatin and carboplatin, respectively. The estimated percentage of tumors sensitive to clinically achievable dose levels was 42% for nedaplatin and 36% for cisplatin and carboplatin. Nedaplatin and carboplatin proved relatively crossresistant with cisplatin in vitro; of the 18 tumor samples which were resistant to cisplatin, only 5 (28%) were sensitive to nedaplatin and 3 of 17 (18%) were sensitive to carboplatin. CONCLUSION: Nedaplatin was associated with cytotoxicity similar to cisplatin and carboplatin in this study. Although nedaplatin appears to be crossresistant with cisplatin, its high rate of in vitro cytotoxicity, relative lack of neurotoxicity and nephrotoxicity, and large in vivo biovailability establish nedaplatin as a promising platinum analog for further clinical development as a salvage and primary chemotherapeutic agent for patients with advanced ovarian cancer.

Antineoplastic Agents↗
PubMed1997

Phase II evaluation of topotecan in patients with advanced colorectal cancer. A Southwest Oncology Group trial (SWOG 9241).

The topoisomerase-1 inhibitor, topotecan, was tested in 48 eligible patients with advanced colorectal cancer. The patients had no prior chemotherapy and a Southwest Oncology Group performance status of 0-2. Topotecan was administered intravenously at 1.5 mg/m2/day for five days and repeated every 21 days. The major toxicity was hematologic with 19 out of 48 (40%) patients having grade IV granulocytopenia and 4 out of 48 (8%) patients demonstrating grade IV thrombocytopenia. Two patients (4%) demonstrated partial response. Thirty patients have died and the Kaplan-Meier estimate of median survival is 9 months (95% confidence interval; 7-16 months). Topotecan in this dose and schedule does not appear active in patients with advanced colorectal cancer.

Adult↗
PubMed1997

Safety aspects of pegylated liposomal doxorubicin in patients with cancer.

Encapsulation in polyethylene glycol-coated (pegylated; Stealth) liposomes alters the pharmacokinetic characteristics, and hence the safety and tolerability profile, of doxorubicin. Pegylated liposomal doxorubicin administered as a single agent is generally well tolerated. Grade III/IV leucopenia, stomatitis and palmar-plantar erythrodysaesthesia affected 16, 6 and 18% of solid tumour patients, respectively. Other adverse effects included nausea and vomiting and alopecia. Acute hypersensitivity infusion reactions have been reported in up to 9% of patients in some studies. Recently published data from a phase II trial in patients with refractory ovarian cancer showed no alopecia or cardiotoxicity and little nausea and vomiting after pegylated liposomal doxorubicin. Unlike free doxorubicin, pegylated liposomal doxorubicin is not a vesicant. Preliminary data, not yet confirmed in comparative studies, suggest that the pegylated liposomal formulation may be less cardiotoxic than free doxorubicin. Mucositis, however, appears to be increased. Studies to determine optimal dosing schedules and safety of pegylated liposomal doxorubicin in combination with other agents are ongoing.

Antibiotics, Antineoplastic↗
PubMed1997

Surrogate end-point biomarkers as measures of colon cancer risk and their use in cancer chemoprevention trials.

Surrogate end-point biomarkers (SEBs) have become widely used in short-term cancer chemoprevention trials in place of cancer end points. This paper discusses criteria relevant to the selection and validation of SEBs for colon cancer risk and the use of SEBs in colon cancer chemoprevention trials. As with a number of other cancers, colon carcinogenesis is the result of a multistep process in which an increasing number of alterations, including specific gene mutations, occur as cells progress from normal to precancerous states of increasing size and dysplasia to cancer and finally to metastatic disease. Ideally, a SEB would show differential expression between the various phases of colon carcinogenesis (i.e., normal, premalignant, and malignant tissues) and be associated with risk of colon cancer. Some SEBs that do not meet these criteria may still be useful for demonstrating the effect of a particular agent. It is also necessary that a SEB be measured in tissues (or other sample material) accessible for multiple and sequential sampling and allow for development of appropriate quality control procedures. Some SEBs must have the potential for modulation by chemopreventive agents. Validation of SEBs for use in chemoprevention studies requires that a relationship between the marker and subsequent risk of cancer be established. Also, the assay reliability and accuracy for each SEB must be determined adequately in well-designed prospective studies.

Apoptosis↗
PubMed1997

The effect of wheat bran fiber and calcium supplementation on rectal mucosal proliferation rates in patients with resected adenomatous colorectal polyps.

Colorectal cancers continue as the second most common cause of death from cancer in the United States. Only a few prospective, randomized clinical trials have been performed to evaluate the potential preventive effects of dietary fiber or calcium in patients with an increased risk for the development or recurrence of colorectal cancer. We designed and conducted a double-blinded, placebo-controlled randomized trial involving supplementation of fiber and calcium intake and measurements of [3H]thymidine labeling index (LI) percentages in rectal mucosal biopsies obtained from patients with resected colorectal adenomas to examine the potential mechanisms by which dietary interventions might reduce colorectal cancer risk. We performed a randomized, double-blinded, Phase II study, using a factorial design to measure the effects of supplemental dietary wheat bran fiber (2.0 or 13.5 g/day) and calcium carbonate (250 or 1500 mg/day elemental calcium) supplementation on [3H]thymidine LI percentages in rectal mucosal crypts and 24-h in vitro outgrowth cultures. Measurements were made at baseline randomization (i.e., after a 3-month placebo run-in period using 2.0 g of wheat bran fiber plus 250 mg of calcium carbonate) and after 3 and 9 months on treatment in 100 randomized participants who had a history of colon adenoma resection. Neither the wheat bran fiber nor the calcium carbonate supplements significantly reduced [3H]thymidine LI percentages in rectal mucosal crypts (total or compartmental analysis) or 24-h in vitro outgrowth cultures at either 3 or 9 months of daily supplementation in the 93 evaluable participants. We conclude that 9 months of high-dose wheat bran fiber and calcium carbonate supplementation in study participants with a history of recently resected colorectal adenomas does not have a significant effect on cellular proliferation rates in rectal mucosal biopsies, comparing 3- and 9-month results to baseline results. Ultimately, there is great need for the evaluation of these two different nutrient interventions in the setting of Phase III studies wherein adenomatous polyp recurrence, rather than a rectal mucosal biomarker, serves as the primary end point.

Adenomatous Polyps↗
PubMed1997

Use of a food frequency questionnaire to screen for dietary eligibility in a randomized cancer prevention phase III trial.

Cancer prevention clinical trials use food frequency questionnaires (FFQs) to assist in eligibility screening. FFQ reliability and validity studies are available, but these studies do not evaluate FFQs as screening tools. The Wheat Bran Fiber Trial of the University of Arizona used a FFQ as an eligibility screen with the goal of screening out subjects whose true daily calcium intake was less than 500 mg per day (for safety) and whose true dietary fiber intake was greater than 30 g per day (for safety and trial efficiency). Subjects ineligible by FFQ were interviewed for final dietary eligibility determinations. A study was undertaken within the Wheat Bran Fiber Trial to evaluate the sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of the FFQ used in this context. Four-day food records were collected on 183 potential participants before entry into the study. Using the 4-day averages as the "true" value, sensitivity, specificity, positive predictive value, and NPV were calculated for men and women separately under two screening conditions: using the target calcium and dietary fiber values and using "revised" values identified in interim analysis within the study. NPV was acceptable in all analyses. Sensitivity for low calcium intake was inadequate under the original criteria (0.33 for men and 0.09 for women) but acceptable under the revised criteria (0.80 for men and 0.81 for women). With the revised criteria, specificity declined, resulting in heavy screening burdens deemed worthwhile for the safety considerations. Dietary fiber eligibility screening worked well at target values. These differences were not predicted by reliability/validity studies.

Adult↗
PubMed1997

Expression of p53 protein in actinic keratosis, adjacent, normal-appearing, and non-sun-exposed human skin.

Nonmelanoma skin cancer, including both squamous cell carcinoma and basal cell carcinoma, is a significant and increasing health problem in the United States. The precursor lesion of cutaneous squamous cell carcinoma, actinic keratosis (AK), is a major risk factor for nonmelanoma skin cancer, and it is also a marker of long-term sun exposure. AKs themselves can serve as biomarkers in chemopreventive studies, but in addition, they may contain phenotypic and genetic alterations that are related to the process of UV-induced skin carcinogenesis. One of these alterations, the tumor suppressor gene p53, is altered early in UV-induced skin carcinogenesis in humans. p53 protein expression was measured by immunohistochemistry in biopsies from AKs, tissue immediately adjacent to AKs (AK-adjacent), normal-appearing upper medial arm skin, and non-sun-exposed skin from 19 subjects. There was a significant difference and a progressively increasing mean p53 labeling index in total epidermis (basal and suprabasal layers) between upper medial arm skin (0.9 +/- 1.8%) and AK-adjacent (12.1 +/- 14.4%; P = 0.0004) and between AK (27.7 +/- 21.3%) and AK-adjacent skin (P = 0.04), whereas upper medial arm skin was marginally different from non-sun-exposed skin (0.1 +/- 0.2; P = 0.05). This pattern of p53 expression was also seen when epidermis was separated into basal and suprabasal layers. We conclude that epidermal p53 protein expression is associated with histological evidence of chronic sun damage.

Aged↗
PubMed1997

Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.

We conducted a randomized, double-blind, controlled trial to examine the efficacy of retinol supplementation on the incidence of first new nonmelanoma skin cancer in moderate-risk subjects. A total of 2297 free-living subjects were enrolled; subjects resided in Arizona (median age, 63 years) and had a history of more than 10 actinic keratoses and at most 2 squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) skin cancers. Subjects were randomly assigned to receive oral retinol (25,000 IU) or placebo supplementation daily for up to 5 years. The primary end points for the trial were time to first new SCC or BCC. During a median follow-up time of 3.8 years, we found that 526 subjects had a first new skin cancer. Comparing retinol-supplemented subjects with placebo-supplemented subjects showed a hazard ratio for first new SCC of 0.74 (95% confidence interval, 0.56-0.99; P = 0.04). The hazard ratio of first new BCC for the retinol-supplemented subjects compared with those receiving placebo was 1.06 (95% confidence interval, 0.86-1.32; P = 0.36). Potentially adverse symptoms that were judged to be associated with retinol were rare (approximately 1% higher in the retinol group than in the control group). Therefore, we concluded that daily supplementation with 25,000 IU of retinol was effective in preventing SCC, although it did not prevent BCC.

Adult↗
PubMed1997

Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.

The objective of this study was to examine the effect of retinol and isotretinoin on the incidence of nonmelanoma skin cancer in high-risk subjects. A total of 525 participants with a history of at least four basal cell carcinomas (BCCs) and/or cutaneous squamous cell carcinomas (SCCs) were entered into a randomized, double-blind, placebo-controlled trial, performed in free-standing study clinics. Participants were randomly assigned to receive oral retinol (25,000 units), isotretinoin (5-10 mg), or placebo supplementation daily for 3 years. The time to first new occurrence of BCC or cutaneous SCC was used as the outcome measure. During the study period, 319 BCCs and 125 cutaneous SCCs were diagnosed clinically and pathologically. There were no differences between those who received retinol, isotretinoin, or the placebo, with regard to the time to first occurrence or to the total number of tumors noted. No beneficial effects were noted with regard to the prevention of nonmelanoma skin cancer with either retinol or isotretinoin.

Adult↗
PubMed1996

Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.

BACKGROUND: Intravenous platinum-based chemotherapy is the standard primary therapy for advanced ovarian cancer. We conducted a phase 3 trial to compare the effects of intraperitoneal and intravenous cisplatin on the survival of women with previously untreated, stage III, epithelial ovarian cancer. METHODS: The patients underwent an initial exploratory laparotomy and resection of all tumor masses larger than 2 cm. Within four weeks after surgery, six courses of intravenous cyclophosphamide (600 mg per square meter of body-surface area per course) plus either intraperitoneal cisplatin (100 mg per square meter) or intravenous cisplatin (100 mg per square meter) were administered at three-week intervals. RESULTS: Of 654 randomized patients, 546 were eligible for the study. The estimated median survival was significantly longer in the group receiving intraperitoneal cisplatin (49 months; 95 percent confidence interval, 42 to 56) than in the group receiving intravenous cisplatin (41 months; 95 percent confidence interval, 34 to 47). The risk of death was lower in the intraperitoneal group than in the intravenous group (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Moderate-to-severe tinnitus, clinical hearing loss, and neuromuscular toxic effects were significantly more frequent in the intravenous group. CONCLUSIONS: As compared with intravenous cisplatin, intraperitoneal cisplatin significantly improves survival and has significantly fewer toxic effects in patients with stage III ovarian cancer and residual tumor masses of 2 cm or less.

Adult↗
PubMed1996

2-[2'-(Dimethylamino)ethyl]-1,2-dihydro- 3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at positions 4, 8, 9, 10, and 11. Synthesis, antitumor activity, and quantitative structure-activity relationships.

New 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3- diones with substituents at the 4, 8, 9, 10, and 11 positions were synthesized. Diazonium salts prepared from aminoazonafides were key intermediates for many of the analogues. Six of the new compounds were more potent than azonafide in a panel of tumor cells including human melanoma and ovarian carcinoma and murine L1210 leukemias. Three of these compounds, the 10-OCH3, 10-OC2H5, and 10-F analogues, had better ratios of cardiotoxicity to tumor-cell toxicity than azonafide. Eight compounds were not cross-resistant with MDR L1210 leukemia, and the 10-CN analogue was more potent against solid tumor cells than leukemia cells. The 9-OH, 10-CN, and 10-F analogues had high potency against both sensitive and resistant cell lines of MFX 7 breast carcinoma and WiDr colon carcinoma and sensitivity A599 lung carcinoma. Advantages of the 10-Cl, 10-NH2, and 10-CN analogues over azonafide were apparent in P388 leukemia in mice, and the 10-CN analogue was more effective than doxorubicin in this assay. Quantitative structure-activity relationship studies revealed statistically significant correlations between DNA binding strength of 8- and 10-substituted azonafides, as measured by deltaTm, and toxicity to tumor cells. There also were correlations between substituent size, as measured by MR, and cytotoxicity for 9- and 10-substituted azonafides and between MR and deltaTm for 4- and 11-substituted azonafides. Lipophilicity of substituents (pi) correlated with cytotoxicity for 9-, 10-, and 11-substituted azonafides. These results lend support to a model in which DNA binding strength influences cytotoxic potency, and lipophilicity increases DNA binding whereas large substituents decrease it.

Animals↗
PubMed1996

6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships.

New 2-[2'-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic displacement was a key reaction in the syntheses. Ten of the new compounds were more potent than the unsubstituted compound, azonafide, in a panel of tumor cells including human melanoma and ovarian cancer and murine sensitive and MDR L1210 leukemia. They also were less cardiotoxic in cell culture. Four of these compounds were not cross-resistant with the MDR leukemia, and one of them, 6-ethoxyazonafide, was nearly as potent against solid tumor cells as leukemia cells. These compounds also had good potency against human breast, colon, and lung cancer cells, including doxorubicin and mitoxantrone resistant cell lines. Advantages of the new analogues over azonafide were less in vivo, but 6-ethoxyazonafide was more effective against L1210 leukemia and subcutaneous B16 melanoma in mice. Although correlations of antitumor potency in cells and physicochemical properties of substituents were not found, there were statistically significant correlations of DNA melt transition temperature (delta Tm) with potency in solid tumor cells and sensitive and MDR resistant L1210 leukemia cells for 6-substituted azonafides and with solid tumors for 7-substituted azonafides.

Animals↗
PubMed1996

Genetic screening for colorectal cancer and intervention.

There is a complex interaction between environmental/dietary factors and genetics underlying the pathogenesis of colon carcinogenesis. Little data exist concerning the impact of diet on the phenotypic expression of genetically linked colon cancer. As a result, it has been difficult to develop rationally designed dietary intervention studies in first-degree relatives of patients with established familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and other familial colon cancer syndromes. Only 2 double-blinded, placebo-controlled trials have been published concerning the use of preventive strategies in patients with genetically inherited colorectal cancer syndromes, both in patients with FAP. One study evaluated the effects of vitamin C plus vitamin E with or without a high-dose wheat bran fiber supplement on the recurrence of rectal adenomas. Over a 48-month intervention period, only the wheat bran fiber intervention significantly reduced polyp growth. A second study reported that intervention with the NSAID sulindac for 9 months in young patients with FAP resulted in a significant reduction in both polyp number and size in the rectosigmoid colon. All of the large-scale (i.e., >500 randomized participants) phase III nutrient or chemopreventive agent intervention studies thus far have targeted participants with a history of non-familial, sporadic colorectal adenomas. Current clinical adenoma trials do not measure whether the regimen being tested can prevent genotoxic events occurring in early stages of abnormal cell development that contribute to the eventual formation of adenomas nor whether the agent(s) can inhibit events occurring during the progression of adenomas to carcinomas. Therefore, future clinical trial designs may have to consider (i) lengthening the clinical trial period before adenomas develop, (ii) testing at early patient ages and/or (iii) measuring the growth of adenomas as they progress to carcinomas.

Clinical Trials as Topic↗
PubMed1996

Randomized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids in patients with resected adenomatous colon polyps.

BACKGROUND: Ongoing epidemiologic and nutritional studies suggest that colorectal carcinogenesis is consistent with complex interactions between genetic susceptibility and environmental and dietary factors. Among the dietary components found to reduce colon cancer risk are high intakes of dietary fiber and calcium. PURPOSE: We designed and conducted a randomized, double-blinded, placebo-controlled trial involving supplementation of the customary dietary intake with fiber and calcium and measurements of fecal bile acids to examine the potential mechanisms by which added dietary interventions might reduce colorectal cancer risk. METHODS: In a randomized, double-blinded, phase II study, we used a factorial design to measure the effects of dietary wheat bran fiber (2.0 or 13.5 g/day) in the form of cereal and supplemental calcium carbonate (250 or 1500 mg/day elemental calcium) taken as a tablet on fecal bile acid concentrations and excretion rates. Measurements were made at base-line randomization (i.e., after a 3-month placebo run-in period using 2.0 g wheat bran fiber plus 250 mg calcium carbonate) and after 3 and 9 months on treatment in a randomly selected 52-patient subsample of the 95 fully assessable study participants who had a history of colon adenoma resection. Concentrations of fecal bile acids, total, primary (i.e., chenodeoxycholic and cholic), and secondary (i.e., deoxycholic, lithocholic, and ursodeoxycholic), were measured in 72-hour stool samples by gas-liquid chromatography. All P values resulted from two-sided tests. RESULTS: All geometric mean fecal bile acid concentrations and excretion rates were lower at 9 months than at 0 months or 3 months on treatment in the high-dose fiber, high-dose calcium, and high-dose fiber/high-dose calcium treatment groups. The high-dose fiber effect at 9 months of supplementation was statistically significant with respect to virtually all geometric mean fecal bile acid concentrations and excretion rates. For example at 9 months versus 0 months, high-dose fiber supplementation caused a reduction in fecal concentrations of total bile acids (52% reduction; P = .001) and deoxycholic acid (48% reduction; P = .003). High-dose calcium supplementation also had a significant, but lower, effect at 9 months versus 0 months on the geometric mean total bile acid (35% reduction; P = .044) and deoxycholic fecal bile acid (36% reduction; P = .052) concentrations. CONCLUSIONS: High-dose wheat bran fiber and calcium carbonate supplements given for 9 months are associated with statistically significant reductions in both total and secondary fecal bile acid concentrations and excretion rates in patients with resected colon adenomas. This study supports the hypothesis that one of the important ways in which a high intake of wheat bran fiber and calcium may reduce the risk of colorectal neoplasia and cancer is by reduction of the concentrations of fecal bile acids. IMPLICATION: Phase III studies of these agents in the prevention of adenoma recurrence are necessary to confirm this hypothesis and have now been initiated at multiple institutions.

Adenomatous Polyposis Coli↗