Biomedical subjects

S D Hursting

Publications and source records attributed to S D Hursting.

32 records · Page 2Linked to original sources

PubMed1997

Calorie restriction induces a p53-independent delay of spontaneous carcinogenesis in p53-deficient and wild-type mice.

We reported previously that calorie restriction (CR) delays spontaneous carcinogenesis in p53-deficient (p53-/-) mice, suggesting that CR modulates carcinogenesis by p53-independent mechanisms. To further evaluate the role of p53, we monitored tumor development in p53-/- and wild-type (p53+/+) mice fed ad libitum (AL) or a CR regimen (60% of AL calorie intake). CR delayed tumor mortality in p53-/- and p53+/+ mice (mean time to death, 169 and 648 days, respectively) relative to AL feeding (104 and 470 days). The estimated age-specific cancer death rate AL:CR ratios were 4.3 for p53-/- mice and 4.4 for p53+/+ mice. Thus, despite the accelerated onset of carcinogenesis in p53-/- mice, the tumor-delaying effect of CR was similar in the two genotypes.

Animals↗

PubMed1997

Effects of dehydroepiandrosterone and calorie restriction on the Bcl-2/Bax-mediated apoptotic pathway in p53-deficient mice.

Modulation of apoptosis through altered expression of Bcl-2 and/or Bax may be a mechanism by which dehydroepiandrosterone (DHEA) administration and calorie restriction (CR) exert their chemopreventive effects in p53-deficient (p53-/-) mice. Using immunohistochemical detection we found that treatment with both DHEA and CR resulted in decreased expression of the PCNA proliferation marker in the thymus. In addition, treatment with DHEA also increased the rate of apoptosis in the thymus, resulting in marked thymic atrophy. Thus, both DHEA and CR appear to shift cell number homeostasis by favoring apoptosis. To further understand the molecular mechanisms by which DHEA and CR exert their effects, we examined two components of the apoptotic pathway, Bcl-2 and Bax. We found that p53-/- mice have much higher levels of Bcl-2 mRNA in the thymus than wild-type (p53+/+) mice. Treatment of p53-/- animals with DHEA resulted in decreased Bcl-2 but not Bax mRNA levels in the thymus. In contrast, CR did not change either Bcl-2 or Bax mRNA expression. The present study provides molecular evidence that DHEA and CR may modulate tumorigenesis through alterations in the apoptotic and/or proliferative pathways.

Animals↗

PubMed1997

Case-control assessment of diet and lung cancer risk in African Americans and Mexican Americans.

In this case-control study we determined whether dietary differences underlie some of the ethnic and sex differences in US lung cancer rates. We examined the relationship between diet and lung cancer development in 137 lung cancer cases (93 African Americans and 44 Mexican Americans) and 187 controls (78 African Americans and 109 Mexican Americans). Cases reported a higher daily mean total fat intake (p < 0.001), whereas controls had a higher daily mean intake of dietary fiber (p < 0.001) and fruits (p = 0.02). Ethnic differences in diet were also observed: Mexican Americans consumed less total fat (p < 0.02) and more fiber (p < 0.001) and vegetables (p = 0.08) than African Americans. Additionally, men consumed more total fat (p = 0.08) and less fiber (p = 0.001), fruits (p < 0.001), and vegetables (p = 0.002) than women. Multivariable analysis, after adjustment for the effects of pack-years of smoking, age, total energy intake, sex, and ethnicity, demonstrated a positive association between high total fat consumption and lung cancer risk (p < 0.01) and an inverse association between high fruit consumption and lung cancer risk (p = 0.05). In conclusion, our findings support the hypothesis that diet, particularly high fat consumption and low fruit and vegetable consumption, contributes (independent of cigarette smoking) to the excess lung cancer risk in African-American men, who have the highest lung cancer rates in the United States.

Black or African American↗

PubMed1997

Chemoprevention of spontaneous tumorigenesis in nullizygous p53-deficient mice by dehydroepiandrosterone and its analog 16alpha-fluoro-5-androsten-17-one.

Transgenic mice with both alleles of the p53 tumor suppressor gene product 'knocked out' by gene targeting are susceptible to early development of tumors, chiefly lymphomas and sarcomas. Compared with the control group, administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to male p53-deficient mice extended their lifespan by delaying death due to neoplasms (from 105 to 166 days on study, P = 0.002), primarily by suppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P = 0.010). Treatment with a synthetic DHEA analog, 16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet also increased lifespan, to 140 days for mice that developed tumors (P = 0.037). The effects of these steroids on lifespan and tumor development did not appear to be strongly related to inhibition of food consumption and weight gain, in that a group pair-fed with control diet to the reduced food consumption of the DHEA-treated group developed and died of the same types of neoplasms at the same rate as the controls fed ad libitum. The chemopreventive effect of these steroids has been proposed to be due to suppression of DNA synthesis by inhibition of glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway. Although DHEA and its analog are strong non-competitive inhibitors of this enzyme in vitro, treatment with DHEA did not deplete cellular nucleotide pools in the liver, as would have been predicted. The chemopreventive effect of DHEA in this model may be due to steroid-induced thymic atrophy and suppression of T cell lymphoma, permitting these mice to survive long enough to develop tumors with longer latency.

Androstenes↗

PubMed1997

Experimental models of gene-environment interaction for cancer chemoprevention studies.

The recent development of mouse strains with cancer-related genes overexpressed or inactivated has provided investigators with new models for testing chemoprevention strategies to offset specific genetic susceptibilities to cancer. This review focuses on the three genetically altered mouse models that have been the most widely used in chemoprevention studies: Min mice, which carry a mutation in the adenomatous polyposis coli (APC) gene; APC-knockout mice; and p53-knockout mice. Studies with the Min and APC-knockout mice provide the strongest evidence to date that the enzyme cyclooxygenase-2 plays a major role in colon carcinogenesis, and that nonsteroidal anti-inflammatory drugs that target cyclooxygenase-2 have great potential as colon cancer chemopreventive agents. In addition, chemoprevention studies in mice deficient of the p53 tumor-suppressor gene, the most commonly altered gene in human cancer, suggest that the increased susceptibility to cancer resulting from the loss of p53 function may be offset by preventive approaches. Other recently developed transgenic and knockout models of potential interest for chemoprevention studies will also be discussed.

Animals↗

PubMed1995

Chemoprevention of spontaneous tumorigenesis in p53-knockout mice.

Spontaneous tumorigenesis was evaluated in male p53-knockout (p53-/-) mice treated with dehydroepiandrosterone (DHEA), quercetin, d-limonene, or all-trans retinoic acid to determine whether tumor development in these mice can be modulated by cancer-chemopreventive agents. DHEA-treated mice experienced a delay in tumorigenesis (particularly lymphomas) and subsequent mortality (P < 0.01) relative to untreated control mice. Quercetin, d-limonene, and all-trans retinoic acid each had no effect on spontaneous tumor development in p53-/- mice. These data demonstrate that tumor development in p53-/- mice can be delayed by DHEA and suggest that p53-/- mice provide a useful model for evaluating strategies to offset the increased risk of tumorigenesis resulting from loss of p53 tumor suppressor function.

Animals↗

PubMed1995

The association between alcohol and breast cancer: popular press coverage of research.

OBJECTIVES: This study was undertaken to examine popular press reports of the association between alcohol and breast cancer. METHODS: Articles from scientific journals and stories from newspapers and magazines published from January 1, 1985, to July 1, 1992, were retrieved from six on-line databases. Lay press stories were analyzed to determine which medical articles were publicized and what information was reported. RESULTS: Fifty-eight scientific articles on the relationship of alcohol and breast cancer were found, and 64 newspaper and 23 magazine stories were retrieved. The press cited 11 studies, 19% of those published during the study period. Three studies were featured in 77% of popular press stories. No scientific review articles were reported. Behavioral recommendations were given to the public in 63% of stories. CONCLUSIONS: The vast majority of scientific studies on alcohol and breast cancer were ignored in press reports. We encourage researchers and the popular press to give the public a broader understanding of public health issues.

Alcohol Drinking↗

PubMed1994

Calorie restriction delays spontaneous tumorigenesis in p53-knockout transgenic mice.

Transgenic mice with both alleles of the p53 tumor suppressor gene (frequently mutated in human tumors) knocked out by gene targeting provide a potentially useful tumorigenesis model because these mice rapidly develop spontaneous tumors. To determine whether tumorigenesis in p53-knockout mice is sensitive to experimental manipulation, tumor development in response to calorie restriction (CR; a potent inhibitor of rodent tumors) was evaluated. Tumor development was monitored for 48 weeks in male nullizygous p53-knockout and wild-type littermate mice (28-30 per treatment group) fed ad libitum (AL) or restricted to 60% of AL carbohydrate calorie intake. CR:p53-knockout mice (median survival = 25 weeks) experienced a delay in tumor onset and subsequent mortality (P = 0.0002) relative to AL:p53-knockout mice (median survival = 16 weeks). Tumor development and mortality in wild-type littermates on either diet treatment were < 4% through 48 weeks. Cell cycle analyses were performed on splenocytes from p53-knockout mice and wild-type littermates after 4 weeks of AL feeding or CR (5 per group). The percentage of splenocytes in S phase of the cell cycle was 3-fold higher for p53-knockout mice than wild-type mice (P < 0.001), and CR reduced the percentage of S-phase splenocytes in both p53-knockout and wild-type mice (P = 0.012). These data demonstrate that tumor development in p53-knockout mice genetically predisposed to tumors can be delayed by CR (possibly via cell cycle modulation) and suggest that these mice provide a very useful model of spontaneous tumorigenesis.

Alleles↗

PubMed1994

Inhibition of rat mononuclear cell leukemia by corn oil gavage: in vivo, in situ and immune competence studies.

Corn oil administered by oral gavage decreases the spontaneous incidence of mononuclear cell leukemia (MNCL) in male Fischer rats used as vehicle controls in long-term carcinogenesis experiments. We used an MNCL transplant model, an in situ MNCL cell proliferation assay and immune competence assays to explore mechanism(s) underlying the effects of corn oil gavage on MNCL development in male rats. Relative to non-gavaged or water-gavaged rats, corn oil-gavaged rats had approximately 25% lower MNCL incidence as well as longer MNCL latency and increased survival. There were no differences in body weight or caloric intake between treatment groups, as corn oil-gavaged rats compensated for calories supplied by the gavaged oil by consuming less food. These data indicate that transplanted MNCL cells grew slower in corn oil-gavaged rats than in non-gavaged or water-gavaged rats and suggest that corn oil gavage may exert its effects through a decrease in protein or other nutrients. Five-day proliferation rates of cultured MNCL cells in diffusion chambers implanted in male corn oil-gavaged rats were 40% less than in water-gavaged rats, suggesting nutrition-sensitive endogenous factors mediate the suppression of MNCL cell proliferation in corn oil-gavaged rats. Corn oil-gavaged rats had 54% lower serum growth hormone (GH) levels, and replacement of GH into corn oil-gavaged rats by osmotic minipump infusion increased in situ MNCL cell proliferation to rates observed in water-gavaged animals. Corn oil-gavaged rats also showed enhanced cellular immune competence as measured by mitogen stimulation, natural cytotoxicity and immunofluorescence assays. Taken together, these findings suggest corn oil administered by oral gavage may decrease MNCL development by slowing MNCL cell proliferation, mediated at least in part by altered levels of diffusible factors such as GH, and/or by enhancing immune competence.

Administration, Oral↗

PubMed1993

The growth hormone: insulin-like growth factor 1 axis is a mediator of diet restriction-induced inhibition of mononuclear cell leukemia in Fischer rats.

A leukemia cell transplant model and both in situ and in vitro bioassays were used to assess the roles of endogenous factors in mediating diet restriction (DR)-induced inhibition of mononuclear cell leukemia (MNCL) in Fischer 344 rats. DR-treated male rats (n = 35), which were fed 75% of ad libitum (AL) intake of NIH-07 open formula diet, had lower transplanted MNCL incidence (54 versus 77%; P = 0.039) with longer latency (P = 0.015) and decreased severity (P = 0.01) than AL-treated rats 12 weeks after inoculation with MNCL cells. Five-day proliferation rates of cultured MNCL (CRNK-16) cells in diffusion chambers implanted in DR-treated rats were 22% less than in AL-treated rats (P = 0.03), indicating that DR-dependent diffusible factor(s) modulate in situ MNCL cell growth. Serum from DR-treated rats supported lower in vitro CRNK-16 cell proliferation rates relative to serum from AL-treated rats. Serum levels of both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) were over 50% lower in DR- versus AL-treated rats. An evaluation of the in vitro cell proliferative activity of a panel of purified factors showed that GH and IGF-1, but not 15 other growth factors, stimulated thymidine incorporation in CRNK-16 cells. Infusion of either GH or IGF-1 via osmotic minipumps restored in situ and in vitro CRNK-16 cell proliferation in DR-treated rats up to rates measured in AL-treated rats. Splenocytes from DR-treated rats, relative to AL-treated rats, were more sensitive to mitogen stimulation, displayed increased cell surface expression of receptors for class 1 and 2 major histocompatibility complex molecules, and were more cytotoxic to target tumor cells. Infusion of either GH or IGF-1 in DR-treated rats further enhanced mitogen responsiveness and natural cytotoxicity but reversed the DR-induced increase in major histocompatibility complex receptors. We conclude that DR modulates MNCL progression in Fischer 344 rats through both its influence on MNCL cell proliferation via suppression of the GH:IGF-1 axis and its enhancement of host defenses against tumor cells.

Adrenocorticotropic Hormone↗

PubMed1993

Diet and human leukemia: an analysis of international data.

BACKGROUND: There has been little direct exploration of the relationships between dietary factors and human leukemia; however, a number of literature reports from animal studies and correlation analyses between countries suggest that diet can influence leukemia risk. METHODS: Statistical analyses of international food supply data and leukemia incidence data were performed to define better the diet-human leukemia relationship. Incidence data for lymphoid, myeloid, and total leukemia (all leukemia subtypes combined) from 24 countries with reliable cancer registry data were regressed with estimates of per capita disappearance of macronutrients and alcohol, as well as gross national product and average height. RESULTS: Simple correlation analyses showed that the dietary variables were associated with leukemia in a gender- and site-specific fashion. Males consistently had higher correlations than females. The strongest correlations were found between total calorie intake and both lymphoid and total leukemia incidence, especially among males. Myeloid leukemia in either gender was most strongly associated with gross national product. To control for potential confounding, multiple regression analyses were performed, with all regression models adjusted for gross national product, height, and dietary covariates. Total calorie supply was the only significant explanatory variable for the international variation in lymphoid and total leukemia in these analyses. The calorie-leukemia association was stronger among males than among females. No significant association was observed between myeloid leukemia and any of the dietary variables studied, after adjusting for height and gross national product. CONCLUSION: The findings from this rigorous analysis of international data strengthen and expand the hypothesis based on previous simple correlation analyses and animal experiments that an underlying biological relationship exists between diet, particularly energy intake, and international variations in the incidence of certain types of human leukemia. Possible mechanisms for the calorie-leukemia associations are discussed.

Adult↗

PubMed1990

Types of dietary fat and the incidence of cancer at five sites.

The specificity of a statistical association increases the likelihood that it represents a causal relationship. In exploring the relationship between dietary fat and cancer, specificity applies both to cancer sites (outcome) and to component fats (exposure). In this study, Armstrong-Doll criteria were used to select female cancer incidence data for breast, cervix, lung, and colon, and male incidence data for lung, colon, and prostate for 1973-1977 from 20 countries with reliable registry data. Truncated age-standardized rates were correlated with estimates of per capita disappearance of total fat and of saturated, monounsaturated, and polyunsaturated (total, fish omega-3, omega-6) fats in 1975-1977. Multiple regression analyses were standardized for estimated total calorie intakes and used to assess the association between each fat and incidence at each cancer site. Estimates of per capita dietary and crude fiber intakes were also included in the analysis. Total calorie intake was not associated with cancer at any site when controlled for total fat intake, whereas total fat intake was strongly associated with cancers of the breast, colon, and prostate even after adjustment for total calorie intake. Cancers of the lung and cervix were not correlated with dietary fat intake. Monounsaturated fat had no positive association with cancer at any site. Saturated fat was positively associated with incidence of cancers of the breast, colon, and prostate and polyunsaturated fat was associated with incidence of breast and prostate cancers but not colon cancer. Fiber intake, when included in the analysis, affected the magnitude of the fat-cancer correlations, particularly between total fat and colon cancer. Fish omega-3 polyunsaturated fat had a nonsignificant negative association with the cancer sites studied. The findings supported hypotheses based on the results of animal experiments showing that different kinds of fatty acids have different tumor-promoting capabilities.

Adult↗

PubMedDate not supplied

Cancer prevention studies in p53-deficient mice.

Future progress in mechanism-based cancer prevention research may be facilitated by animal models displaying specific genetic susceptibilities for cancer, such as mice deficient in 1 (+/-) or both (-/-) alleles of the p53 tumor suppressor gene. We observed in p53-/- mice that calorie restriction (CR) increased the latency of spontaneous tumor development (mostly lymphomas) by approximately 75%, decreased serum insulin-like growth factor-1 (IGF-1) and leptin levels, slowed thymocyte cell cycle traverse, and induced apoptosis in immature thymocytes. In p53+/- mice, CR and a 1 d/wk fast each delayed spontaneous tumor development (a mix of lymphomas, sarcomas, and epithelial tumors) and decreased serum IGF-1 and leptin levels, even when begun late in life. In p53+/-Wnt-1 transgenic mice, a mammary tumor model, the same interventions increased mammary tumor latency and reduced mean serum IGF-1 and leptin levels to <50% of those of control mice. We capitalized on the susceptibility of p53+/- mice to chronic, low-dose aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches. These examples clearly indicate that mice with specific (and humanlike) genetic susceptibilities for cancer are powerful models for testing interventions that may inhibit carcinogenesis in humans.

Animals↗

PubMedDate not supplied

Genotoxicity and carcinogenicity studies of soy isoflavones.

The potential cancer preventive efficacy of soy isoflavones is being investigated in preclinical and phase 1 clinical studies sponsored by the U.S. National Cancer Institute. Although 90-day oral toxicity studies with PTI G-2535 (an investigational soy isoflavone drug product) in rats and dogs, as well as teratology studies, indicated no signs of toxicity, there remains a mechanistic concern associated with the ability of isoflavones (i.e., genistein) to inhibit topoisomerase, possibly leading to DNA strand breaks. The present report describes results from two in vitro genotoxicity studies, one in vivo genotoxicity study, and a single carcinogenicity study conducted in p53 knockout mice. Bacterial mutagenesis experiments using six tester strains without metabolic activation revealed no evidence that PTI G-2535 was mutagenic. In similar experiments with exogenous metabolic activation there were statistically significant increases in revertants, but less than twofold, in a single (Salmonella typhimurium TA100) tester strain. Mouse lymphoma cell mutagenesis experiments conducted with and without metabolic activation revealed statistically significant increases in mutation frequency at PTI G-2535 concentrations > or = 0.8 and 12 microg/ml, respectively; such increases were dose related and increases in the frequency of both small and large colonies were observed. A statistically significant increase in the frequency of micronucleated polychromatic erythrocytes was also seen 24 hours after treatment in male, but not female, mice who received 500 and 1000 mg/kg body weight PTI G-2535; however,such increases were small, were not dose related, and were not observed 48 hours after treatment. In contrast, dietary genistein had no effect on survival, weight gain, or the incidence or types of tumors that developed in cancer-prone rodents lacking the p53 tumor suppressor gene, p53 knockout mice. The apparent risk/benefit of isoflavone ingestion may ultimately depend on the dose and developmental timing of exposure.

Administration, Oral↗