Biomedical subjects

Lance K Heilbrun

Publications and source records attributed to Lance K Heilbrun.

At least 19 recordsLinked to original sources

PubMed2005

Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design.

PURPOSE: BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated titration "2B" design, of BMS-247550 given as a 1-hour infusion every 3 weeks. EXPERIMENTAL DESIGN: Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles (1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m2. All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists. RESULTS: First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m2. Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m2. Grade 1 to 2 peripheral neuropathy was also observed. Other grade 1 to 2 toxicities were myalgias, arthralgias, rash, hand/foot syndrome, and mucositis. AUC and C(max) seemed proportional to the dose and the DLT. Development of neutropenia with BMS-247550 is related to the duration of drug exposure above a threshold. CONCLUSIONS: The maximum tolerated dose (MTD) of BMS-247550 is 40 mg/m2 given every 3 weeks. Neutropenia is the DLT. The accelerated titration "2B" design may help in determining MTD with fewer patients enrolled and more being treated closer to the MTD. However, the accelerated titration design did not seem to shorten the study duration.

Adult↗

PubMed2005

A simplified analysis of [18F]3'-deoxy-3'-fluorothymidine metabolism and retention.

PURPOSE: [18F]3'-deoxy-3'-fluorothymidine (FLT) is a thymidine analog developed for imaging tumor proliferation with positron emission tomography (PET). To quantitatively assess images, the blood activities of FLT and its glucuronidated metabolite were measured and its kinetics analyzed. This study sought to limit the number of blood samples needed to measure FLT retention. METHODS: Total FLT activity was measured from 18 venous samples obtained over the first hour and dynamic imaging performed on 33 patients (average dose 350 MBq/mmol). The 5-, 10-, 30- and 60-min samples were analyzed to measure the fraction of activity in FLT and its glucuronide. HPLC analysis was compared against a two-step column (Sep-Pak) and metabolic rates measured using full and limited sampling. Probenecid (2 g, oral) was given to two patients to determine whether imaging of the liver improved. RESULTS: At 60 min, 74% of the blood activity was unmetabolized (range 57-85%). HPLC and Sep-Pak gave comparable results (r=0.97; average difference 2.1%). For kinetic analysis, eight venous samples were sufficient to accurately measure total activity; for metabolite analysis, a single sample at 60 min yielded data with mean errors of 2.2%. The metabolic rate correlated with average SUV (r2=0.85; p=0.0002). An aorta input function gave kinetic results comparable to venous blood (r2=0.82). Probenecid did not improve imaging of the liver. CONCLUSION: Dynamic measurements of FLT retention can be used to calculate metabolic rates using a limited set of samples and correction for metabolites measured in a single sample obtained at 60 min.

Computer Simulation↗

PubMed2005

The impact of CAG repeats in exon 1 of the androgen receptor on disease progression after prostatectomy.

BACKGROUND: The authors examined the impact of the number of CAG repeats in exon 1 of the androgen receptor on disease progression among men with prostate carcinoma after prostatectomy. This polymorphism has been associated with alterations in activity of the androgen receptor in in vitro systems and with the risk of clinically diagnosed prostate carcinoma in some epidemiologic studies. An earlier series found that, among men at low risk of progressive disease, a small number of CAG repeats predicted a high risk of recurrence, and the impact of CAG repeats varied among men with different risks of progressive disease. METHODS: The authors analyzed specimens from a large clinical series of fixed tissue specimens from men who underwent prostatectomy at a single institution, including 413 American white men (WM) and 298 African-American men (AAM), with 5-10 years of available clinical follow-up. RESULTS: There was little association between the number of CAG repeats and extent of disease, Gleason score, and preoperative PSA level at diagnosis. Overall, patients who had > 18 CAG repeats had a greater risk of recurrence compared with patients who had </= 18 CAG repeats (hazard ratio [HR] = 1.52; P = 0.03). Excess risk was not found among men who were at low risk of recurrence (HR = 0.93; P = 0.96); however, among men who were at high risk of recurrence, the risk elevated for WM (HR = 1.75; P = 0.28), AAM (HR = 1.49; P = 0.06), and both races combined (HR = 1.53; P = 0.03). CONCLUSIONS: Overall, men with prostate carcinoma who had > 18 CAG repeats had an estimated 52% increased risk of disease recurrence. The increased risk could be attributed to men who were at high risk of recurrence.

Adenine↗

PubMed2005

A phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer. METHODS: The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1,000 mg/m(2) over 100 minutes, cisplatin 35 mg/m(2) I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days. RESULTS: Twenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6-7.6 months). The probability of survival at 6 months was 46% (90% CI, 27-62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients. CONCLUSIONS: The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.

Adenocarcinoma↗

PubMed2005

Phase II trial of fenretinide in advanced renal carcinoma.

PURPOSE: Fenretinide, a synthetic form of retinoid, induced apoptosis even in chemotherapy resistant cell lines. A phase II study was hence conducted to evaluate toxicity and efficacy of fenretinide in metastatic renal cancer. METHODS: Eligibility included unresectable or metastatic renal cell carcinoma (RCC), adequate organ function and Zubrod performance status < or =2. Prior immunotherapy and a maximum of one prior chemotherapy regimen were allowed. Fenretinide was administered at a dose of 900 mg/m(2) twice daily orally for 7 days in a 21-day cycle. Toxicity was assessed at the start of each cycle, and response every 2 cycles. RESULTS: Nineteen eligible patients enrolled of which fifteen had visceral/bone metastases. Seventeen patients had prior nephrectomy and 11 had prior immunotherapy. 76 cycles of therapy were delivered. Therapy was very well tolerated with few severe toxicities consisting of thrombosis in 1 individual and grade 3 fatigue, nausea and diarrhea in 1 patient. 5 patients had grade 2 nyctalopia and 3 patients had transient grade 2 visual toxicity. No objective responses were noted. Stable disease was seen in seven of nineteen cases (37%, 90% C.I. 0.21-0.59). Median time to progression was 1.5 months and median duration of stable disease was 5.8 months (90% C.I. 3.0-8.4). Median survival was 10 months. Tumor fenretinide levels were obtained in three patients and were in the lower end of the therapeutic range. CONCLUSION: Fenretinide was well tolerated but demonstrated minimal activity that was consistent with results of intratumoral drug measurements. Strategies are needed that will increase systemic and tumor levels of fenretinide.

Administration, Oral↗

PubMed2005

A phase II study of carboplatin and paclitaxel in adenocarcinoma of unknown primary.

BACKGROUND: Cisplatin-based combination chemotherapy is commonly used in the treatment of carcinoma of unknown primary site. Paclitaxel has shown promising activity as a single agent in a number of malignancies. This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with adenocarcinoma of unknown primary site (ACUP). METHODS: Twenty-two patients with ACUP were enrolled in the study. Patients were treated with 200 mg/m2 paclitaxel intravenously (IV) over 3 hours followed by carboplatin IV with a targeted plasma area under the curve (AUC) of 5 mg/h/mL. RESULTS: A total of 73 treatment courses were administered with a median of 5 courses per patient. Five of the 22 registered patients had a major response for an objective response rate of 23% (90% confidence interval [CI], 0.11-0.40) by intention-to-treat analysis. The median response duration was 4.1 months (90% CI, 3.6-7.1). The median survival time was 6.5 months (90% CI, 5.5-10.1) and the 1-year survival rate was 27% (90% CI, 0.11-0.42). The major toxicity observed was neutropenia, with grade 3-4 neutropenia occurring in 3 patients (14%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is a tolerable and moderately active regimen in ACUP.

Adenocarcinoma↗

PubMed2004

Vitamin D receptor gene polymorphisms and disease free survival after radical prostatectomy.

BACKGROUND: Vitamin D has been linked with prostate cancer risk in epidemiologic studies and has antiproliferative, prodifferentiation, and antimetastatic properties in experimental systems. Its hormonal activity is mediated by the vitamin D receptor. We investigated whether germ-line genetic variation in the vitamin D receptor impacts progression of prostate cancer after radical prostatectomy. METHODS: We analyzed BsmI and TaqI polymorphisms using archived specimens from a large series of radical prostatectomy patients at a single institution. Our series included 428 white men (WM) and 310 African-American men (AAM) who were carefully and uniformly staged and followed for 5-10 years. RESULTS: The distribution of polymorphisms varied between WM and AAM. There was little association between genotype and extent of disease at diagnosis, Gleason score, preoperative PSA, or recurrence overall. Among WM with locally advanced disease, however, the BsmI B allele protected against recurrence in models examining gene dose (P = 0.04) and dominant effects (P = 0.05). CONCLUSIONS: Overall vitamin D receptor polymorphisms did not predict pathologic features of prostate cancer but may impact on risk of recurrence among men in certain risk groups. Analysis of polymorphisms may provide clues about the mechanisms through which vitamin D exerts its inhibitory effects on prostate cancer in vivo in men.

Black or African American↗

PubMed2004

Cytochrome p450 and glutathione transferase expression in squamous cell cancer.

PURPOSE: The cytochrome P-450 (CYP) and glutathione S-transferase (GST) enzyme systems modulate the carcinogenic effects of tobacco. Therefore, the expression of these enzymes may be in part responsible for the observed interindividual and inter-racial differences in the risk of development of squamous cell carcinoma of the head and neck (SCCHN). The first aim of this study was to evaluate the feasibility of measuring the expression of the CYP and GST in target tissue from the head and neck. The second aim was to compare the expression of CYPs 1A1, 2E1, and 3A4 in squamous epithelium from African-American and Caucasian pediatric patients. The third aim was to compare the expression of CYPs 1A1, 2E1, 3A4, and GST-pi on the p16 expression in patients with SCCHN. EXPERIMENTAL DESIGN: The expression of CYP 1A1, 2E1, 3A4, GST-pi, and p16 was quantified by immunoblotting. Expression of CYPs 1A1, 2E1, and 3A4 was quantified in tissue from 160 pediatric patients undergoing tonsillectomy. Expression of CYPs 1A1, 2E1, 3A4, GST-pi, and p16 was determined in 46 resected SCCHN patients. RESULTS: Large interindividual variability in the expression of these enzymes was observed in the pediatric and adult populations. No significant difference was observed in CYP 1A1, 2E1, and 3A4 expression of Caucasian and African-American patients. There was no correlation between p16 and enzyme expression in patients with SCCHN. CONCLUSION: Evaluation of CYP expression in the target tissue of interest is feasible. The clinical significance of CYPs and GST-pi alterations in the risk of developing SCCHN will need to be investigated in larger trials.

Blotting, Western↗

PubMed2004

CYP3A4 genetic variant and disease-free survival among white and black men after radical prostatectomy.

PURPOSE: Prostate cancer is an androgen sensitive disease. Cytochrome P450 3A4 (CYP3A4) oxidatively deactivates testosterone by converting it to biologically less active metabolites. Previous studies suggest that a germline genetic variant in the 5' regulatory region of the gene may interfere with deactivation and increase the risk of clinically advanced prostate cancer. We investigated the impact of this polymorphism on the risk of recurrence after prostatectomy. MATERIALS AND METHODS: We assembled clinical data and analyzed specimens from a large series of patients who underwent prostatectomy who were carefully staged at a single institution and had 5 to 10 years of prospective clinical followup. The series included 428 white men and 309 black men. RESULTS: Stage, Gleason score or preoperative prostate specific antigen strongly predicted progression-free survival (PFS) but were not associated with CYP3A4 genotypes. There was a strong association between race and genotype (p = 0.00002) in that 8% of white men and 83% of black men had 1 or more copies of the G allele. When both races were included genotype was associated with PFS (hazard ratio [HR] 1.27, CI 1.08-1.27, p = 0.005). In race specific analyses increasing copies of the G allele were associated with poorer PFS among white men (HR 1.98, CI 1.06-3.70, p = 0.03) but had little impact on PFS among black men (HR 1.004, CI 0.77-1.32, p = 0.97). CONCLUSIONS: The CYP3A4 genotype studied was not associated with pathological features of prostate cancer for men of either race. Unstratified analyses of men of both races and stratified analyses of white men demonstrated poorer PFS after prostatectomy for those with the G allele, but the G allele did not predict PFS among black men.

Aged↗

PubMed2004

Efficacy and safety of reteplase for central venous catheter occlusion in patients with cancer.

PURPOSE: To evaluate the efficacy and safety of reteplase for central venous catheter (CVC) occlusion in patients with cancer. MATERIALS AND METHODS: An open-label, single-arm, prospective study was conducted. Reteplase (0.4 U) was instilled into each catheter lumen with a dwell time of 30 minutes in patients with cancer with a dysfunctional CVC. If the function of the catheter was not restored in 30 minutes, an additional dwell time of 30 minutes was allowed (a total of 60 minutes possible dwell time for the first dose). A second dose was repeated at 60 minutes after the first dose if catheter function was not restored (a total of 120 minutes for up to two doses). The primary efficacy outcome was the restoration of CVC function. RESULTS: Of 139 patients who received reteplase, the first-attempt success rate after a 30-minute dwell time was 66.9%. The cumulative success rates at 60, 90, and 120 minutes were 88.5%, 94.7%, and 94.7%, respectively. The variation of patient age, catheter age, CVC occlusion age, CVC type, number of lumen, or occlusion type was not associated with the efficacy of reteplase. There were no treatment-associated adverse events reported during the study period. CONCLUSION: Reteplase at 0.4-U dosing per catheter lumen is an effective and safe alternative that rapidly restores the patency of occluded CVCs in patients with cancer.

Adult↗

PubMed2004

Effects of low-fat and/or high-fruit-and-vegetable diets on plasma levels of 8-isoprostane-F2alpha in the Nutrition and Breast Health study.

Dietary patterns that involve both a decrease in fat and an increase in fruit and vegetable (FV) intake may decrease cancer risks. In this study, a total of 122 premenopausal women with a family history of breast cancer were randomized into one of four diets for 12 mo: nonintervention, low-fat (15% of energy from fat), high-FV(9 servings/d), and combination low-fat/high-FV Fasting blood samples were obtained at baseline and after 3, 6, and 12 mo. Levels of 8-isoprostane-F2a in plasma were deter-mined by immunoassay kits. Statistical analyses indicated that levels of 8-isoprostane-F2a decreased significantly with time in the low-fat arm, which is the only intervention that resulted in weight loss; there were no significant changes in the other three diet arms. It is unlikely that this is due to changes in levels of blood lipids because there was little change overtime in plasma total cholesterol, high-density lipoprotein,low-density lipoprotein (LDL), or triglyceride levels in any diet arm, although mean LDL did decrease slightly in women who reduced fat intake after adjustment for change in body mass index (BMI). Levels of baseline 8-isoprostane-F2a were significantly higher in obese women than in overweight or normal weight women, and change in BMI was significantly correlated with change in 8-isoprostane-F2a levels. These results indicate that low-fat diets or high-FV diets are unlikely to affect plasma levels of 8-isoprostane-F2a in healthy,premenopausal women who do not lose weight during dietary change.

Adult↗

PubMed2003

Plasma carotenoids, tocopherols, and antioxidant capacity in a 12-week intervention study to reduce fat and/or energy intakes.

OBJECTIVE: We examined plasma levels of carotenoids, tocopherols, and total antioxidant activity in women before and after dietary intervention to reduce fat and/or energy intakes. Dietary fat and energy may affect intake and bioavailability of carotenoids and tocopherols, and these micronutrient levels in turn can contribute to the antioxidant capacity of plasma. METHODS: Women were randomized onto one of four diets for 12 wk: non-intervention, low fat (15% of energy from fat with maintenance of energy intake), low energy (25% energy reduction with maintenance of percentage of energy from fat), and combined low fat and low energy. Fasting plasma was available for analysis from a subset (n = 41) of women enrolled in the study. RESULTS: Levels of carotenoids and tocopherols did not change significantly over 12 wk on any diet arm, despite a modest but statistically significant increase in fruit and vegetable intake in the women following the low-fat diet (from 3.3 to 5.2 servings/d excluding potatoes). Levels of Trolox-equivalent antioxidant capacity (TEAC), total cholesterol, and two major plasma antioxidants (urate and bilirubin) also did not change significantly. Of the individual micronutrients measured, lycopene and lutein/zeaxanthin correlated most strongly with TEAC values, and the correlation with lycopene was statistically significant before intervention. CONCLUSION: The decreases in dietary fat and energy intakes in this study were quite large, but this did not appear to have detrimental effects on plasma micronutrient levels, nor did it appreciably affect plasma antioxidants. Because lycopene levels were significantly associated with plasma TEAC before intervention, interventions that increase levels of lycopene might be more likely to increase the antioxidant capacity of plasma.

Adult↗

PubMed2003

A phase II study of rebeccamycin analog (NSC-655649) in metastatic renal cell cancer.

OBJECTIVE: Rebeccamycin analog (NSC-655649) is an antibiotic with antitumor properties demonstrated in preclinical and phase I studies. We conducted a phase II trial to evaluate the efficacy and toxicity of this agent in patients with advanced renal cell cancer (RCC). METHODS: Eligible patients had histologically or cytologically confirmed diagnosis of RCC that was either locally advanced unresectable, locally recurrent, or metastatic. Patients had to have measurable disease, no prior chemotherapy, life expectancy of greater than 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate-organ function, and be >/=18 years old. Patients were treated with NSC-655649 at a dose of 165 mg/m(2) daily i.v. over 30-60 min for 5 days. Treatment was repeated every 21 days. Response was assessed every two courses. RESULTS: Twenty-four patients were enrolled. There were sixteen males and eight females with a median age of 60.5 years (range 42-76). Nineteen were Caucasians, seventeen had prior nephrectomy, and thirteen had prior immunotherapy. The major toxicity was myelosuppression with grade 3 and 4 neutropenia in 38% of patients and anemia in 33% of patients. There were two partial responses (2/24, 8%) and 11 patients (46%) achieved stable disease (SD). The 6-month progression-free rate for patients with SD was 30%. Of the seventeen patients with progressive disease at registration, one had a PR and eight had SD. The overall median survival time for all 24 patients was 10.0 months (90% CI=5.2, 17.4 months). The 12-month survival rate was 39%, with 90% CI=(0.21, 0.58). Nine patients are still alive with survival times ranging from 3.8 to 24.2 months, at a median follow-up time of 11.9 months. CONCLUSION: Rebeccamycin analog (NSC-655649) is well tolerated and has modest antitumor activity in patients with advanced RCC.

Adult↗

PubMed2003

Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer.

5-Fluorouracil-based combination chemotherapy is commonly used in patients with advanced gastric cancer, but results with such therapy are fairly modest. Evaluation of newer agents is therefore required in this disease. Paclitaxel has shown promising activity as a single agent in gastric cancer. In vitro, paclitaxel exhibits sequence-dependent synergy with platinum compounds against gastric cancer. This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with advanced gastric cancer. Twenty-seven patients with measurable or evaluable advanced gastric cancer were enrolled on the study from April 1996 to July 2000. Patients were treated with paclitaxel 200 mg/m intravenously during 3 hours followed by carboplatin at projected area under the curve 5 mg x h x ml (as per the Calvert formula). Twenty-six patients were assessable for toxicity, and 25 patients were assessable for objective response. Nine of the 27 enrolled patients had a major response for an objective response rate of 33% (95% CI 0.17-0.54) by intention-to-treat analysis. The median response duration was 4.9 months (95% CI 2.8-7.3), and median survival was 7.5 months. The 1-year survival rate was 23%. One hundred seventeen courses were administered with a median of four courses per patient administered. The major toxicity was neutropenia, with grade III to IV neutropenia observed in 9 patients (33%) and neutropenic fever in only 1 patient. Grade III peripheral neuropathy developed in two patients, and grade III myalgia and grade III fatigue developed in one patient each. There were no treatment-related deaths. The combination of carboplatin and paclitaxel is a highly tolerable, regimen with activity comparable to that of other regimens in advanced gastric cancer. This regimen needs to be further evaluated in combination with other agents and as a component of multimodality therapy in gastric cancer.

Adult↗

PubMed2003

Chemoradiotherapy in the treatment of regional pancreatic carcinoma: a phase II study.

In locally advanced pancreatic cancer, the utilization of chemotherapy and radiotherapy is increasing, although in view of the reported long-term results of several contemporary trials, further improvements are certainly needed. Encouraging results using the combination of cisplatin, cytarabine, caffeine, and continuous infusion (CI) 5-fluorouracil (5-FU) (PACE) for the treatment of advanced pancreatic carcinoma prompted a phase II study using PACE followed by external beam radiotherapy with CI of 5-FU (PACE-RT) for localized disease. Forty-one patients were treated with PACE-RT as adjuvant therapy after surgical resection (21 patients), or as primary therapy for locally advanced, unresectable disease (20 patients), with reevaluation for resection after completion of treatment. PACE consisted of cisplatin 100 mg/m2 IV on day 1, cytarabine 2 g/m2 IV every 12 hours x 2 doses, and caffeine 400 mg/m2 subcutaneously after each cytarabine dose; and days 3 to 21, 5-FU 250 mg/m2/d given by CI. Cycles were repeated every 28 days. After 2 cycles of PACE, radiation therapy was given concurrently with 5-FU at 200 mg/m2/d. In the adjuvant setting, the tumor bed and the draining lymph node basin received 50.4 Gy and 45 Gy, respectively. In the neoadjuvant setting, the primary and regional lymph nodes were to receive 39.6 Gy followed by a neutron boost of 8 NGy to the gross tumor volume. Photon therapy was delivered at 1.8 Gy per fraction and neutron therapy at 0.8 NGy per fraction, 5 days a week. All patients were evaluable for toxicity and survival. The most common toxicity was myelosuppression, with grade III to IV neutropenia occurring in 59% of the patients. The median survival times in the locally advanced and adjuvant patients were 13.4 and 18.1 months, with 1-year survival rates of 52% and 65%, respectively. Nine of 20 patients receiving PACE-RT for unresectable carcinoma had sufficient tumor regression to meet clinical criteria for exploration; three were resected with curative intent. The survival of these three patients undergoing resection after neo-adjuvant therapy was 22.4, 24.3 and 40 months. The treatment program was active, but only moderately well tolerated. Modification of this regimen with newer, less toxic drugs may provide better results and reduced toxicity.

Adenocarcinoma↗

PubMed2003

Cytochrome p450 and glutathione transferase expression in human breast cancer.

PURPOSE: The cytochrome P-450 (CYP) and glutathione S-transferase (GST) enzyme systems may influence the biological effects of carcinogens, including estrogens. As such, these enzymes may predict the developmental risk of breast cancer, as well as be potential targets for chemoprevention. The purpose of this study was to compare the expression of GST-Pi and CYPs 1A1, 2B6, 2E1, and 3A4 in paired samples of normal and malignant breast tissue from patients with breast cancer and women undergoing reduction mammoplasty. EXPERIMENTAL DESIGN: Expression of CYPs 1A1, 2B6, 2E1, 3A4, and GST-Pi was quantified in breast tissue from 33 patients with breast cancer and in 17 women without history of cancer who underwent reduction mammoplasty. The expression of CYP 1A1, 2B6, 2E1, 3A4, and GST-Pi was quantified by immunoblotting. RESULTS: CYP 1A1, 2E1, and 3A4 expression was significantly lower (P < 0.05) in malignant tissue as compared with morphologically normal adjacent tissue. Conversely, GST-Pi expression was marginally lower in the normal tissue (P = 0.08). No significant difference in enzyme expression was seen between the tissue from reduction mammoplasty and normal tissue from breast cancer patients. There was a trend for higher expression of CYP 2B6 and GST-Pi in the estrogen receptor expressing tumors than those tumors without expression (P > 0.28). CONCLUSION: The expression of these enzymes was similar in morphologically normal breast tissue from patients with or without breast cancer. The expression of CYPs was down-regulated in the tumor tissue. The clinical significance of CYP alterations in breast cancer will need further characterization.

Aryl Hydrocarbon Hydroxylases↗

PubMed2002

Effect of low-fat and/or low-energy diets on anthropometric measures in participants of the women's diet study.

OBJECTIVE: To compare the effects of low-fat, low-energy and combination low-fat/low-energy intervention on changes in six anthropometric measures in Caucasian and African-American free-living women. METHODS: The effects of dietary counseling strategies for fat and/or energy reduction were examined on anthropometric measures in 86 pre-menopausal women, average BMI of 28 kg/m2, who participated in a 12-week intervention trial called the Women's Diet Study. The dietary goals were 15% of energy from fat and/or 25% reduction in energy intake, relative to reported baseline intake, using a 2 x 2 factorial design. Analysis of covariance models were constructed to evaluate changes in anthropometric measures over the 12 weeks of study. RESULTS: The biggest difference by race was in women who were relatively heavier at baseline, in which case African-American women lost significantly less weight but decreased their waist:hip ratio to a significantly greater extent than Caucasian women. With regard to the effects of diet arm, weight loss varied depending on baseline weight, and in women with higher baseline weights, the combination low-fat/low-energy diet resulted in the most weight loss (6.7 kg, p < 0.05). Decreases in the other anthropometric measures at week 12 were more uniform across diet arms and did not depend on baseline values. After controlling for previous weight history and race, the decreases in BMI, percent body fat and waist circumference after 12 weeks were statistically equivalent with the low-fat, low-energy or combination low-fat/low-energy diets. The relatively greater decreases in percent body fat and waist circumference with the combination diet versus the low-fat or low-energy diets were not statistically significant. CONCLUSION: The low-fat, low-energy and combination diets all resulted in similar and statistically significant decreases in BMI, percent body fat and waist circumference over 12 weeks of intervention. The extent of weight loss, however, varied depending on baseline weight, and the combination diet was the only intervention to result in significant weight loss for women who were heavier at baseline. This indicates that, although there may be an advantage for reducing dietary fat in initially heavier women, any of these counseling strategies could be effective for improving anthropometric predictors of health risks associated with overweight status. This is useful since flexibility in dietary choices may facilitate adherence to dietary counseling in some individuals.

Adult↗

PubMed2002

Methods to increase fruit and vegetable intake with and without a decrease in fat intake: compliance and effects on body weight in the nutrition and breast health study.

Dietary patterns that involve a decrease in fat and an increase in fruit and vegetable (FV) intake have been suggested to decrease cancer risks. In this study, intervention methods to selectively modify dietary fat and/or FV intakes were developed. Compliance to the diets and the effects on body weight are shown, because both of these dietary changes can impact on and be confounded by changes in energy intake. A total of 122 women with a family history of breast cancer were randomized onto one of four diets for 12 mo. Counseling methods were devised to increase amount and variety of FV consumed with or without a decrease in fat intake using modified exchange list diets. Women on the low-fat and combination low-fat/high-FV diet arms decreased their fat intakes to approximately 16% of energy. Women on the high-FV and the combination low-fat/high-FV diet arms increased FV intakes to approximately 11 servings/day. Despite counseling efforts to maintain baseline energy intakes, mean body weight increased significantly by 6 pounds in women in the high-FV diet arm and decreased significantly by 5 pounds in women in the low-fat diet arm. Percent body fat also was increased in the high-FV diet arm and decreased in the low-fat diet arm. Body weight and percent body fat in the combination diet arm did not change significantly. Control of energy intake, therefore, appears to have been achieved only when the addition of FV to the diet was balanced by a decrease in fat intake and both dietary components were enumerated daily. Maintenance of energy intake, therefore, did not appear to be attained intrinsically when individuals were counseled to make changes in the composition of their diets.

Adipose Tissue↗