Myokines derived from contracting skeletal muscle suppress anabolism in MCF7 breast cancer cells by inhibiting mTOR.

There is strong evidence that physical activity has a profound protective effect against multiple types of cancer. Here, we show that this effect may be mediated by factors released from skeletal muscle during simulated exercise, in situ, which suppress canonical anabolic signaling in breast cancer. We report attenuated growth of MCF7 breast cancer cells in the presence of a rodent-derived exercise conditioned perfusate, independent of prior exercise training. This reduction was concomitant with increased levels of DEPTOR protein and reduced mTOR activity.

Effects of chronic heavy alcohol consumption and endurance exercise on cancellous and cortical bone microarchitecture in adult male rats.

BACKGROUND: Bone health is influenced by numerous lifestyle factors, including diet and exercise. Alcohol is a major nonessential constituent of diet and has dose- and context-dependent effects on bone. Endurance exercise is associated with increased risk of stress fractures. The purpose of this study was to determine the long-term independent and combined effects of chronic heavy alcohol consumption and endurance exercise (treadmill running) on bone mass and microarchitecture in young adult male Sprague-Dawley rats. METHODS: Six-month-old male rats were randomized into 4 groups (9 to 13 rats/group): sedentary + control diet, sedentary + ethanol (EtOH) diet, exercise + control diet, or exercise + EtOH diet. EtOH-fed rats consumed a liquid diet (EtOH comprised 35% of caloric intake) ad libitum. Control rats were pair-fed the same diet with isocaloric substitution of EtOH with maltose-dextran. Exercise was conducted on a motorized treadmill (15% grade for 30 minutes) 5 d/wk for 16 weeks. Femur and 12th thoracic vertebra were analyzed for bone mineral content (BMC) and density (BMD) using densitometry and cortical and cancellous bone architecture using microcomputed tomography. RESULTS: EtOH consumption resulted in lower femur length, BMC, and BMD, and lower midshaft femur cortical volume, cortical thickness, and polar moment of inertia. In addition, trabecular thickness was lower in vertebra of EtOH-fed rats. Endurance exercise had no independent effect on any end point evaluated. A significant interaction between endurance exercise and EtOH was detected for several cancellous end points in the distal femur metaphysis. EtOH-consuming rats that exercised had lower distal femur metaphysis bone volume/tissue volume, trabecular connectivity density, and trabecular thickness compared to exercising rats that consumed control diet. CONCLUSIONS: The results obtained in this model suggest that chronic heavy alcohol consumption may reduce skeletal integrity by reducing bone size, mass, and density, and by negatively altering bone microarchitecture and may increase fracture risk associated with endurance exercise at weight-bearing skeletal sites.

Daidzein-metabolizing phenotypes in relation to bone density and body composition among premenopausal women in the United States.

BACKGROUND: Bone density has been suggested as a marker of cumulative hormone exposure. Small studies also suggest that patterns of daidzein metabolism may be related to hormone concentrations. To our knowledge, no studies in premenopausal women have compared bone density by daidzein-metabolizing phenotypes in the absence of a soy intervention. OBJECTIVE: The objective was to evaluate the relationship between daidzein-metabolizing phenotypes [equol and O-desmethylangolensin (ODMA) production] and bone density and body composition in premenopausal women in the United States. MATERIALS/METHODS: Two hundred and three women attended a clinic visit during which their bone density and body composition were measured by DXA, and 200 (99 %) provided a urine sample following a 3-day soy challenge. Samples were analyzed for isoflavones to determine daidzein-metabolizing phenotypes. RESULTS: In adjusted analyses, there were no differences in hip, spine, femoral neck, or head bone mineral density (BMD) or body composition between producers and non-producers of either equol or ODMA (P > .05). CONCLUSIONS: In this population of low-soy consuming premenopausal women, there were no associations between daidzein-metabolizing phenotypes and hip, spine, femoral neck, or head BMD or body composition, suggesting that these phenotypes per se do not influence premenopausal bone density or body composition.

Fruit intake associated with urinary estrogen metabolites in healthy premenopausal women.

Urinary concentrations of 2:16-hydroxyestrone (2:16-OHE1) approximate concentrations of 2-OHE1 and 16α -OHE1 in breast tissue. As estrogens are purported to be involved in breast cancer development, the 2:16-OHE1 ratio can provide an indication of estrogen metabolite exposure in the breast. With prior studies observing associations between urinary estrogen metabolites and dietary intake of fruits, vegetables, and fiber ascertained from food questionnaires, we examined associations between dietary factors ascertained through 3-day food records and urinary 2:16-OHE1 in 191 pre-menopausal healthy women. Fruit consumption was positively associated with 2:16-OHE1 after adjustment for total energy, ethnicity, body mass index, parity, smoking history, and serum estradiol (p= 0.003). Fruit consumption was positively associated with 2- OHE1 concentrations (p=0.006), but was not associated with 16α-OHE1 (p=0.92). The Musaceae botanical grouping (comprised primarily of bananas) was positively associated with the 2:16-OHE1 ratio, and Rosaceae (comprised of citrus fruits) and Musaceae botanical groupings were positively associated with 2-OHE1 (but not 16α-OHE1) concentrations, after adjustment for confounders. Our data suggest that dietary fruit intake is associated with urinary 2- OHE1 and the 2:16-OHE1 ratio and that breast tissue exposure to estrogen metabolites may thus be influenced by diet.

Associations between polymorphisms in glucuronidation and sulfation enzymes and sex steroid concentrations in premenopausal women in the United States.

Glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGT) and sulfation, catalyzed by sulfotransferases (SULT), are pathways through which sex steroids are metabolized to less active compounds. These enzymes are highly polymorphic and genetic variants frequently result in higher or lower activity. The phenotypic effects of these polymorphisms on circulating sex steroids in premenopausal women have not yet been investigated. One hundred and seventy women aged 40-45 years had a blood sample drawn during the follicular phase of the menstrual cycle for sex steroid measures and to obtain genomic DNA. Urine was collected for 2-hydroxy (OH) estrone (E(1)) and 16α-OH E(1) measures. Generalized linear regression models were used to assess associations between sex steroids and polymorphisms in the UGT1A and UGT2B families, SULT1A1, and SULT1E1. Women with the UGT1A1(TA7/TA7) genotype had 25% lower mean estradiol (E(2)) concentrations compared to the wildtype (TA6/TA6) (p=0.02). Similar associations were observed between SULT1A1(R213/H213) and E(1) (13% lower mean E(1) concentration vs. wildtype; p-value=0.02) and UGT2B4(E458/E458) and dehydroepiandrosterone (DHEA) (20% lower mean DHEA vs. wildtype; p-value=0.03). The SULT1E1(A/C) and the UGT1A1(TA7)-UGT1A3(R11) haplotypes were associated with reduced estrogen concentrations. Further study of UGT and SULT polymorphisms and circulating sex steroid measures in larger populations of premenopausal women is warranted.

Urinary estrogen metabolites and prostate cancer: a case-control study and meta-analysis.

OBJECTIVE: To investigate prostate cancer (Pca) risk in relation to estrogen metabolism, expressed as urinary 2-hydroxyestrone (2-OHE1), 16alpha-hydroxyestrone (16alpha-OHE1) and 2-OHE1 to 16alpha-OHE1 ratio. METHODS: We conducted a case-control study within the Western New York Health Cohort Study (WNYHCS) from 1996 to 2001. From January 2003 through September 2004, we completed the re-call and follow-up of 1092 cohort participants. Cases (n = 26) and controls (n = 110) were matched on age, race and recruitment period according to a 1:4 ratio. We used the unconditional logistic regression to compute crude and adjusted odds ratios (OR) and 95% confident interval (CI) of Pca in relation to 2-OHE1, 16alphaOHE1 and 2-OHE1 to 16alpha-OHE1 by tertiles of urine concentrations (stored in a biorepository for an average of 4 years). We identified age, race, education and body mass index as covariates. We also conducted a systematic review of the literature which revealed no additional studies, but we pooled the results from this study with those from a previously conducted case-control study using the DerSimonian-Laird random effects method. RESULTS: We observed a non-significant risk reduction in the highest tertile of 2-OHE1 (OR 0.72, 95% CI 0.25-2.10). Conversely, the odds in the highest tertile of 16alpha-OHE1 showed a non-significant risk increase (OR 1.76 95% CI 0.62-4.98). There was a suggestion of reduced Pca risk for men in the highest tertile of 2-OHE1 to 16alpha-OHE1 ratio (OR 0.56, 95% CI 0.19-1.68). The pooled estimates confirmed the association between an increased Pca risk and higher urinary levels of 16alpha-OHE1 (third vs. first tertile: OR 1.82, 95% CI 1.09-3.05) and the protective effect of a higher 2-OHE 1 to 16alpha-OHE1 ratio (third vs. first tertile: OR 0.53, 95% CI 0.31-0.90). CONCLUSION: Our study and the pooled results provide evidence for a differential role of the estrogen hydroxylation pathway in Pca development and encourage further study.

Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer.

PURPOSE: Physically active women have a reduced risk of breast cancer, but the dose of activity necessary and the role of energy balance and other potential mechanisms have not been fully explored in animal models. We examined treadmill and wheel running effects on mammary tumorigenesis and biomarkers in p53-deficient (p53(+/-)):MMTV-Wnt-1 transgenic mice. METHODS: Female mice (9 wk old) were randomly assigned to the following groups in experiment 1: treadmill exercise 5 d x wk(-1), 45 min x d(-1), 5% grade at 20 m x min(-1), approximately 0.90 km x d(-1) (TREX1, n = 20) or at 24 m x min(-1), approximately 1.08 km x d(-1) (TREX2, n = 21); or a nonexercise control (CON-TREX, n = 22). In experiment 2, mice were randomly assigned to voluntary wheel running (WHL, n = 21, 2.46 +/- 1.11 km x d(-1) (mean +/- SD)) or to a nonexercise control (CON-WHL, n = 22). Body composition was measured at approximately 9 wk and serum insulin-like growth factor 1 (IGF-1) at two to three monthly time points beginning at approximately 9 wk on study. Mice were sacrificed when tumors reached 1.5 cm, mice became moribund, or there was only one mouse per treatment group remaining. RESULTS: TREX1 (24 wk) and TREX2 (21 wk) had shorter median survival times than CON-TREX (34 wk; P < 0.01), whereas those of WHL and CON-WHL were similar (23 vs 24 wk; P = 0.32). TREX2 had increased multiplicity of mammary gland carcinomas compared with CON-TREX; WHL had a higher tumor incidence than CON-WHL. All exercising animals were lighter than their respective controls, and WHL had lower body fat than CON-WHL (P < 0.01). There was no difference in IGF-1 between groups (P > 0.05). CONCLUSIONS: Despite beneficial or no effects on body weight, body fat, or IGF-1, exercise had detrimental effects on tumorigenesis in this p53-deficient mouse model of spontaneous mammary cancer.

Ethnicity, body size, and estrogen levels in postmenopausal Hispanic and non-Hispanic white women.

BACKGROUND: Hispanic women are at lower risk for incident breast cancer, but the reasons for this lower risk are unknown. Among postmenopausal women, breast cancer risk is inversely associated with circulating levels of 2-hydroxyestrone but directly associated with levels of 16alpha-hydroxyestrone, according to most studies. Likewise, according to most research, the ratio of 2-hydroxyestrone/16alpha-hydroxyestrone is, therefore, inversely associated with breast cancer risk. METHODS: We measured levels of these two circulating estrones as well as estradiol in 40 Hispanic women and 40 non-Hispanic white women who were all postmenopausal and not taking hormones. RESULTS: Compared with non-Hispanic white women, Hispanic women had 69% higher circulating levels of 2-hydroxyestrone (p = 0.04), and 10% lower levels of 16alpha-hydroxyestrone (p = 0.09). Consequentially, Hispanic women had more favorable estrogen profiles than non-Hispanic white women, with an 89% higher 2:16 ratio (p = 0.01). This finding was not substantially affected by adjustment for other breast cancer risk factors, including matching on body mass index (BMI). CONCLUSIONS: This ethnic difference in estrogen profile requires further research to establish whether there is a causal relationship to breast cancer risk that may, at least partially, explain why postmenopausal Hispanic women have a lower incidence of breast cancer.

Associations between endogenous sex hormone levels and mammographic and bone densities in premenopausal women.

PURPOSE: Mammographic breast and bone mineral densities (BMD) have been associated with luteal phase hormone concentrations in premenopausal women. We assessed the associations of breast and bone densities with follicular phase hormones and sex hormone binding globulin (SHBG) in premenopausal women, given that follicular phase hormones have been shown to be positively associated with premenopausal breast cancer risk. METHODS: One hundred and ninety-two 40-45-year-old women provided a spot urine and/or blood sample during the follicular phase. Hormone and SHBG concentrations, and bone density were measured and routine mammograms were accessed and digitized to obtain breast density measures. Regression models were fit to assess the associations between hormones and SHBG, and breast and bone densities. RESULTS: Positive associations were observed between percent breast density and SHBG (p trend = 0.02), as well as estradiol (p trend = 0.08), after controlling for body mass index (BMI), number of pregnancies, and breast feeding history. In addition, a statistically significant inverse association was observed between total testosterone and head BMD (p trend = 0.01), after controlling for BMI. CONCLUSIONS: Associations were observed between breast and bone densities, and serum hormone concentrations during the follicular phase of the menstrual cycle.

Daidzein-metabolizing phenotypes in relation to mammographic breast density among premenopausal women in the United States.

BACKGROUND: Mammographic breast density is an established marker of breast cancer risk, and is hormonally sensitive. Studies suggest that production of the daidzein metabolites equol and O-Desmethylangolensin (ODMA) may be associated with hormones and hormonally mediated factors, but few studies have assessed relationships between the capacity to produce these metabolites and breast density. OBJECTIVE: To evaluate the relationship between equol- and ODMA-producer phenotypes and breast density in premenopausal women in the United States. DESIGN: Two hundred and three women attended a clinic visit and 200 provided a urine sample following a 3 day soy challenge. Samples were analyzed for isoflavones by GC-MS to determine daidzein-metabolizing phenotypes. Percent density on recent (<14 month prior to their clinic visit) mammograms was assessed by one reader using a computer-assisted method. Multiple regression analysis was used to assess relationships between the production of equol and ODMA and breast density. Results 55(27.5%) and 182(91%) women were classed as equol- and ODMA-producers (>87.5 ng/ml urine), respectively. In unadjusted and adjusted analyses, there were no differences in breast density between producers and non-producers of either equol or ODMA (P > 0.05). CONCLUSION: In this population of low-soy consuming premenopausal women, there were no associations between daidzein-metabolizing phenotypes and breast density, suggesting that these phenotypes per se do not influence premenopausal breast density.

Daidzein-metabolizing phenotypes in relation to serum hormones and sex hormone binding globulin, and urinary estrogen metabolites in premenopausal women in the United States.

OBJECTIVE: Blood and urine concentrations of hormones are implicated in the etiology of some cancers. Small studies have assessed relationships between production of the daidzein metabolites equol and O-desmethylangolensin (ODMA) and hormones, but findings are unclear. We evaluated relationships between daidzein-metabolizing phenotypes and follicular phase concentrations of estrogens, androgens, sex hormone binding globulin (SHBG), and urinary estrogen metabolites in premenopausal women. METHODS: Two-hundred women collected a first-void urine sample after a 3-day soy challenge, and 191 and 193 provided fasting blood and spot urine samples, respectively, during days 5-9 of their menstrual cycle. Soy challenge urines were analyzed for isoflavones; serum was analyzed for estrogens, androgens, and SHBG; spot urines were analyzed for 2-hydroxyestrone and 16alpha-hydroxyestrone. Data were log-transformed and multiple regression analyses were conducted to assess relationships between daidzein-metabolizing phenotypes and hormones and SHBG. Data from 187 and 189 women were included in analyses of serum and urine hormones, respectively. RESULTS: 55 (27.5%) and 182 (91%) of the 200 women who provided a soy challenge urine sample were equol- and ODMA-producers (>87.5 ng/ml urine), respectively. In unadjusted analyses, equol-producers (n = 52) had lower free testosterone than equol non-producers (n = 137, p = 0.02). In adjusted analyses, there were no differences between producers and non-producers of either daidzein metabolite. CONCLUSIONS: In the absence of a soy intervention, we found no difference in serum or urine hormone concentrations between producers and non-producers of equol or ODMA.

Effect of energy deficiency on estrogen metabolism in premenopausal women.

PURPOSE: Physical activity has been associated with decreased breast cancer risk, potentially through changes in estrogen metabolism. Two-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1) have different biological properties, and the ratio of these metabolites (2/16) has been proposed to predict breast cancer risk. Diet and exercise have been found to influence estrogen metabolism, particularly when a state of negative energy balance is achieved. We sought to determine whether 4 months of moderate-intensity exercise coupled with calorie restriction would result in changes in urinary 2-OHE1, 16alpha-OHE1, or 2/16 in sedentary, premenopausal, eumenorrheic women. METHODS: Average age was 31.5 yr, average body fat was 31.6%, and average BMI was 23.7. Urinary estrogen metabolites were measured in 24 women during the baseline and for four intervention months in the midfollicular and midluteal phases. RESULTS: The intervention produced a significant drop in body fat (4.5%) and body weight (3.7 kg). Aerobic fitness increased significantly (26%; P < 0.001). Overall, there were no significant effects of the diet and exercise intervention on 2-OHE1, 16alpha-OHE1, or 2/16. However, when divided into tertiles according to baseline 2/16, the intervention resulted in significant increases in 2/16 in women in the lowest tertile. Women in the lowest tertile (average 2/16 = 0.91) did not differ from the other tertiles in baseline estradiol concentrations, body fat, weight, fitness, or changes in these variables with the intervention. CONCLUSION: The data suggest that women at higher risk for developing breast cancer because of low 2/16 may reduce their risk by participating in lifestyle interventions such as exercise/calorie restriction.

Effects of aerobic exercise training on estrogen metabolism in premenopausal women: a randomized controlled trial.

BACKGROUND: Regular physical activity may alter estrogen metabolism, a proposed biomarker of breast cancer risk, by shifting metabolism to favor production of 2-hydroxyestrone (2-OHE1). Few studies, however, have examined this question using a randomized controlled trial. PURPOSE: To examine the effects of 12 weeks of aerobic exercise training on 2-OHE1 and 16alpha-hydroxyestrone (16alpha-OHE1) in premenopausal women. METHODS: Participants were healthy, regularly menstruating, Caucasian women, 20 to 35 years, body mass index of 18 to 29.9, not using pharmacologic contraceptives, with average or below average fitness [maximal oxygen consumption (VO(2max)), <40 mL/kg/min]. Following a baseline menstrual cycle, participants (N = 32) were randomly assigned to a 12-week aerobic exercise training intervention (n = 17) or usual lifestyle (n = 15). Height, body mass, body composition by dual-energy X-ray absorptiometry, and VO(2max) were measured at baseline and following the intervention. Urine samples were collected in the luteal phase of four consecutive menstrual cycles. RESULTS: The exercise group increased VO(2max) by 14% and had significant, although modest, improvements in fat and lean body mass. No significant between-group differences were observed, however, for the changes in 2-OHE1 (P = 0.944), 16alpha-OHE1 (P = 0.411), or the ratio of 2-OHE1 to 16alpha-OHE1 (P = 0.317). At baseline, there was an inverse association between body fat and 2-OHE1 to 16alpha-OHE1 ratio (r = -0.40; P = 0.044); however, it was the change in lean body mass over the intervention that was positively associated with a change in 2-OHE1 to 16alpha-OHE1 ratio (r = 0.43; P = 0.015). CONCLUSIONS: A 12-week aerobic exercise training intervention significantly improved aerobic fitness and body composition but did not alter estrogen metabolism in premenopausal women. Interestingly, an increase in lean body mass was associated with a favorable change in 2-OHE1 to 16alpha-OHE1 ratio.

Resistance exercise training attenuates alcohol-induced cardiac oxidative stress.

BACKGROUND: Myocardial oxidative stress is believed to play an important role in the pathogenesis of alcoholic cardiomyopathy. Strenuous physical exercise has been shown to increase or decrease myocardial oxidative stress depending on the mode and duration of the exercise intervention. Given the possibility of individuals to engage in both alcohol consumption and weight-training exercise, we have examined the effect of resistance exercise training and chronic alcohol consumption on myocardial oxidative stress in rats. METHODS: Forty Sprague-Dawley rats were randomly assigned to one of four experimental groups: sedentary, sedentary plus alcohol treatment, resistance training, or resistance training plus alcohol treatment. Rats in the alcohol groups received a liquid diet containing alcohol (35% of kilocalorie intake) for 6 weeks. Non-alcohol groups were pair-fed the same liquid diet supplemented with a maltose dextrin caloric substitute. Rats in the resistance training groups were trained to rise onto their hind limbs while wearing lead-weighted vests 30 times per training session, 3 days per week during the 6 week experimental period. RESULTS: Alcohol treatment in the sedentary animals resulted in greater levels of cardiac malondialdehyde, a marker of lipid peroxidation, and a depressed index of myocardial antioxidant potential compared with all other groups (P<0.05). Hearts from the resistance training plus alcohol animals exhibited malondialdehyde and antioxidant levels similar to sedentary controls, suggesting that resistance training protected against the alcohol-induced myocardial stress. CONCLUSION: These results suggest that resistance training may attenuate the damaging effects of alcohol on the heart and preserve myocardial antioxidant capacity.

Chronic alcohol intake, resistance training, and muscle androgen receptor content.

INTRODUCTION: Chronic alcohol intake and resistance training (RT) have opposite effects on muscle physiology. PURPOSE: This study examined the effect of chronic alcohol intake on androgen receptor (AR) content in skeletal muscle to determine whether this effect was influenced by RT. METHODS: A total of 48 male Sprague Dawley(R) rats (mass = 456 +/- 1 g; mean +/- SE) were divided into five groups: baseline (N = 8), sedentary + alcohol (Sed-Al) (N = 8), sedentary + normal diet (Sed-Nml) (N = 8), exercise + alcohol (Ex-Al) (N = 12), and exercise + normal diet (Ex-Nml) (N = 12). Exercise groups completed a 6 1/3-wk "squat" RT protocol; alcohol groups received an ethanol-rich (35% caloric content of alcohol) diet throughout the 6 1/3-wk period. Baseline animals were killed at the onset of the 6 1/3-wk training period. RESULTS: Western blot analysis showed no effect of alcohol or RT on the AR of the extensor digitorum longus. Alcohol significantly reduced AR content of the rectus femoris (P < 0.05) and prevented RT-induced increases in AR content of the soleus. CONCLUSION: Chronic alcohol intake appeared to reduce the AR content of the type IIB fiber-predominant rectus femoris, and this reduction was not affected by RT. In the type I-predominant soleus, chronic alcohol intake alone had no effect but seemed to prevent RT-induced increases in AR content.

The relationship between physical activity and 2-hydroxyestrone, 16alpha-hydroxyestrone, and the 2/16 ratio in premenopausal women (United States).

OBJECTIVES: Estrogen is metabolized in the body through two mutually exclusive pathways yielding metabolites with different biological activities: the low estrogenic 2-hydroxyestrone (2-OHE1) and the highly estrogenic 16alpha-hydroxyestrone (16alpha-OHE1). The ratio of these metabolites (2/16) may be predictive of risk for developing breast cancer. Early evidence has demonstrated that exercise may alter estrogen metabolism to favor the weak estrogen, 2-OHE1. METHODS: Seventy-seven eumenorrheic females completed physical activity logs for two weeks prior to providing a luteal phase urine sample. Concentrations of 2-OHE1 and 16alpha-OHE1 were measured and the 2/16 ratio computed. Hierarchical regression, controlling for age and body mass index (BMI), was used to determine relationships between estrogen metabolites and daily physical activity. RESULTS: Regression analyses indicated significant positive relationships between physical activity and 2-OHE1 and the 2/16 ratio (p < 0.05) that appears to be independent of BMI. 16alpha-OHE1 was not significantly related to physical activity. CONCLUSION: These results indicate that physical activity may modulate estrogen metabolism to favor the weak estrogen, 2-OHE1, thus producing a higher 2/16 ratio. This alteration in estrogen metabolism may represent one of the mechanisms by which increased physical activity reduces breast cancer risk.

Associations between aerobic fitness and estrogen metabolites in premenopausal women.

UNLABELLED: Chronic physical activity may alter estrogen metabolism, a proposed biomarker of breast cancer risk, by causing a shift toward higher 2-OHE1 and lower 16alpha-OHE1 levels. PURPOSE: To investigate the association between an objective indicator of chronic exercise, aerobic fitness, and 2-OHE1 and 16alpha-OHE1 in premenopausal women. METHODS: Women with high aerobic fitness (N=17; VO2max>or=48 mL.kg.min-1) were compared with women with average aerobic fitness (N=13; VO2max

Training enhances vascular relaxation after chemotherapy-induced vasoconstriction.

PURPOSE: Although evidence is accumulating that suggests regular moderate physical activity improves physiological and psychological well-being of cancer patients undergoing chemotherapy, the mechanisms involved remain unclear. Therefore, the purpose of this study was to determine if exercise training improves endothelium-dependent vasodilation after exposure to the chemotherapeutic agent 5-fluorouracil (5-FU). METHODS: Rats were injected with N-methyl-N-nitrosourea (MNU) and assigned to either exercise (EX; treadmill running, 20-25 m.min(-1) grade, 30 min.d(-1), 5 d.wk(-1) for 8 wk) or sedentary (SED) groups. After the exercise training period, aortic rings were obtained and used to assess contractile and relaxation characteristics. In addition, endothelial nitric oxide synthase (eNOS) protein content and eNOS enzyme activity was determined. RESULTS: Exercise training resulted in increased maximal endothelium-dependent vasorelaxation to acetylcholine (ACh, 1 x 10(-5) M) (SED, 56 +/- 3%; exercise, 71 +/- 5%; P < 0.05) after norepinephrine-induced (1 x 10(-7) M) vasoconstriction. Exposure of aortic rings from each group to increasing concentrations of 5-FU (7 x 10(-5) x 10 M(-3)) resulted in vasoconstriction. Rings obtained from exercise-trained animals demonstrated enhanced vasorelaxation to ACh (1 x 10(-5) M) after 5-FU-induced vasoconstriction compared with rings obtained from SED animals (P < 0.05). In addition, exercise training enhanced eNOS protein content and eNOS activity. CONCLUSION: Exercise training enhances endothelium-dependent vasorelaxation after 5-FU-induced vasoconstriction, and this may be due, at least in part, to an increase in aortic eNOS protein content and activity. Such exercise-induced adaptations may help alleviate chemotherapy-related fatigue observed in cancer patients.

Physical activity and cancer prevention--mechanisms.

PURPOSE: This paper presents potential mechanisms by which exercise or physical activity may affect cancer development. METHODS: Analysis of published and unpublished experimental and epidemiological data from the cancer-activity literature and from other fields of study are compiled to provide a summary of potential mechanisms by which exercise may mediate cancer development. RESULTS: Exercise appears to have a beneficial effect relative to cancer development, and the reader is referred to other sections of this symposium. To date however, the mechanism(s) remains unknown. Potential mechanisms influenced by exercise include alterations in steroid hormones or insulin/insulin-like growth factors, immune modulation, alterations in free radical generation, changes in body composition or weight, and direct effects on the tumor. Cancer is a complex process. It is clear that multiple mechanisms may be operative and that the characteristics of the individual, type of exercise, as well as type of cancer and stage of carcinogenesis will affect which mechanisms may affect the disease. More experimental research in both animal models and in human clinical studies is needed to understand the basic biological mechanisms underlying the effect of physical activity on cancer. CONCLUSION: In general, physical activity is associated with reduced risk of cancer development, yet to date, the mechanisms remain unknown.

Attenuation of homocysteine-induced endothelial dysfunction by exercise training.

Hyperhomocysteinemia is an independent risk factor for the development of cardiovascular disease. Exposure of endothelial cells to elevated levels of homocysteine (HCY) results in decreased availability of nitric oxide (NO) and impaired vascular function, both of which are early events in atherogenesis. Exercise training improves vascular function by increasing endothelial NO production secondary to an increase in the enzyme responsible for its synthesis, endothelial nitric oxide synthase (eNOS). We hypothesized that exercise training would increase endothelial NO production, which would attenuate the endothelial dysfunction associated with HCY exposure. Rats were randomly assigned to either sedentary (SED) or exercise (EX) groups. The exercise regimen consisted of treadmill running at 20-25 m/min, 15% grade, 30 min/day, 5 day/week for 6 weeks. Aortic rings obtained from SED and EX trained rats were incubated with 2 mM HCY for 120 min, then exposed to norepinephrine (NE 100 nM) to induce vasoconstriction. Once a stable contraction plateau was achieved, rings were exposed to increasing concentrations of the receptor-mediated endothelium-dependent vasodilator acetylcholine (ACh; 0.1, 1, 10, 100 nM). This procedure was repeated with the non-receptor-mediated endothelium-dependent vasodilator A-23187 (0.1, 1, 10, 100 nM), and the endothelium-independent vasodilator, NaNO(2) (0.1, 1, 10, 100 muM). In addition, eNOS protein content and eNOS enzyme activity were determined. Aortic rings obtained from exercise trained rats demonstrated significantly (P<0.05) greater relaxation to both ACh and A-23187 in comparison to aortic rings obtained from SED rats following exposure to HCY. Additionally, exercise training increased aortic eNOS protein content and activity. Our data demonstrate that exercise training improves endothelium-dependent vasorelaxation following HCY exposure and this may be due, at least in part, to elevated levels of eNOS protein and an increase in eNOS activity. These results suggest the possible role exercise may play in attenuating the endothelial dysfunction associated with hyperhomocysteinemia.