Biomedical subjects

D L McCormick

Publications and source records attributed to D L McCormick.

At least 19 recordsLinked to original sources

PubMed2006

Oncogenicity evaluation of resveratrol in p53(+/-) (p53 knockout) mice.

A six-month study was conducted in p53(+/-) mice to evaluate the possible oncogenicity of resveratrol (3,5,4'-trihydroxy-trans-stilbene), a cancer chemopreventive agent present in grapes and other foods. p53(+/-) mice (25/sex/group) received daily gavage exposure to vehicle only (negative control), resveratrol doses of 1000, 2000, or 4000 mg/kg/day, or p-cresidine (400 mg/kg/day; positive control). No mortality was seen in mice receiving the low dose of resveratrol. However, the mid and high doses induced mortality associated with impaction of the test article in the gastrointestinal tract. Resveratrol had no effect on body weight, food consumption, or clinical signs in surviving mice in any dose group, but induced dose-related increases in liver weight and serum cholesterol in both sexes. Mild anemia was seen in male mice at the high dose only; hematologic effects were not seen in females. Histopathology identified the kidney (hydronephrosis) and urinary bladder (epithelial hyperplasia) as target tissues for resveratrol toxicity. The incidences of both benign and malignant tumors in mice exposed to resveratrol were comparable to those in vehicle controls. By contrast, the positive control article, p-cresidine, induced urinary bladder cancer in both sexes. When administered to p53(+/-) mice at its maximum tolerated dose, resveratrol demonstrates no evidence of oncogenicity.

Administration, Oral↗

PubMed2000

Magnetic fields and mammary cancer in rodents: a critical review and evaluation of published literature.

Epidemiological data suggesting a possible increase in breast cancer risk in male electricians have raised concerns about the relationship between exposure to power-frequency magnetic fields and breast cancer. In this paper, we review the results of animal studies that are relevant to identifying possible increases in breast cancer risk resulting from exposure to 50 or 60 Hz magnetic fields. Three large-scale chronic bioassays of carcinogenesis in rats or mice exposed to magnetic fields for 2 years demonstrated no increases in the incidence of mammary cancer; it is generally accepted that power-frequency magnetic fields have little or no activity as a complete carcinogen in the rodent mammary gland. Findings from one laboratory, though inconsistent, suggest that magnetic fields may stimulate mammary neoplasia in rats treated with a chemical carcinogen. However, studies conducted in two other laboratories failed to confirm these findings; rats exposed to magnetic fields demonstrated patterns of tumor incidence, multiplicity, size and latency that were generally similar to those in sham-exposed controls. Where differences were seen, the groups exposed to magnetic fields generally had fewer mammary tumors than did sham-exposed controls. On this basis, evaluations of the activity of 50 or 60 Hz magnetic fields in models of multistage mammary cancer in rodents have generally been negative; positive findings have been reported from only one laboratory. The totality of rodent data does not support the hypothesis that power-frequency magnetic-field exposure enhances mammary cancer in rodents, nor does it provide experimental support for possible epidemiological associations between magnetic-field exposure and increased breast cancer risk.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2000

Evaluation of the developmental toxicity of 60 Hz magnetic fields and harmonic frequencies in Sprague-Dawley rats.

Experimental data suggest that exposure to the 50 and 60 Hz sinusoidal components of power-frequency magnetic fields (MFs) does not have an adverse impact on fetal development. However, the possible developmental toxicity of MF harmonics has not been investigated. This study was designed to determine whether exposure to 180 Hz MFs (third harmonic), alone or in combination with 60 Hz MFs, induces birth defects in Sprague-Dawley rats. Groups of sperm-positive dams (> or =20/group) were exposed for 18.5 h per day from gestation days 6 through 19 to (1) ambient MFs only (<0.0001 mT; sham controls); (2) 60 Hz MFs at 0.2 mT; (3) 180 Hz MFs at 0.2 mT; or (4) 60 Hz + 180 Hz MFs (10% third harmonic; total field strength = 0.2 mT). Litter size, litter weight, percentage live births, sex ratio, and number of resorption sites were determined for each dam, and gross external, visceral, cephalic and skeletal examinations were performed on all fetuses. MF exposure had no significant effects on litter size, litter weight, or fetal development. With the exception of common rib variants, the incidence of fetal anomalies was comparable in all groups. A small increase in the incidence of rib variants was seen in the group exposed to 60 Hz + 180 Hz MFs; however, the incidence of rib variants in this group was similar to that in historical controls from our laboratory. These data extend the existing database on developmental toxicity of MFs by demonstrating that exposure to 180 Hz MFs, either alone or superimposed on an underlying 60 Hz signal, does not induce biologically significant developmental toxicity. These data do not support the hypothesis that exposure to power-frequency MFs is an important risk factor for fetal development.

Animals↗

PubMed2000

Expression of cancer-related genes in human cells exposed to 60 Hz magnetic fields.

Exposure to 60 Hz magnetic fields (MFs) may be a risk factor for human cancer. One mechanism through which MFs could influence neoplastic development is through alterations in the expression of cancer-related genes. Previous molecular studies of the action of MFs have measured effects on a limited number of genes. In the present studies, arrays containing cDNAs for 588 cancer-related genes were used to approach the hypothesis that the biological activity of MFs is mediated by alterations in gene expression. Cultures of normal (HME) and transformed (HBL-100) human mammary epithelial cells and human promyelocytic leukemia (HL60) cells were exposed to MFs at field strengths of 0, 0.01 or 1.0 mT for 24 h. Several genes were identified in MF-exposed cells whose expression was increased by at least twofold or decreased by 50% or more. However, no gene was found to be differentially expressed in each of three independent exposures for any cell type, and no relationship between exposure intensity and differential gene expression was found. These studies failed to identify a plausible genetic target for the action of MFs in human cells, and they provide no support for the hypothesis that MF exposure alters the expression of genes that are involved in cancer development.

Breast↗

PubMed2000

60 Hz magnetic fields do not enhance cell killing by genotoxic chemicals in Ataxia telangiectasia and normal lymphoblastoid cells.

Ataxia telangiectasia (AT) is an inherited autosomal recessive disease characterized by increased risk of cancer, immune deficiency, and neurodegeneration. Cells cultured from AT patients are highly sensitive to genotoxic agents and are deficient in cell cycle arrest after exposure to ionizing radiation. In consideration of their sensitivity to both ionizing and nonionizing radiation, AT cells may provide a sensitive model system to study the biological activity of other components of the electromagnetic spectrum. To characterize the effects of power-frequency (60 Hz) magnetic fields (MFs) in AT cells, we compared responses of AT and normal lymphoblast cells to sinusoidal MFs at 1.0 mT, either alone or in combination with the genotoxic agents mitomycin C or streptonigrin. The MF alone had no effect on cell growth or survival in a clonogenic assay in either AT or normal cells. The MF also had no effect on induction of cell death by mitomycin C or streptonigrin in either cell type. AT cells do not demonstrate differential sensitivity to MF exposure. These results do not support the hypothesis that MFs interact with genotoxic agents to induce adverse biological effects in either normal or genetically susceptible human cells.

Antibiotics, Antineoplastic↗

PubMed2000

Modulation of natural killer cell function after exposure to 60 Hz magnetic fields: confirmation of the effect in mature B6C3F1 mice.

In a previous study, we demonstrated that subchronic exposure to pure, linearly polarized 60 Hz magnetic fields (MFs) at flux densities ranging from 0.002 to 1.0 mT induced a modest but statistically significant and reproducible suppression of NK cell activity in young adult B6C3F(1) mice. NK cell activity in mice declines with age and is known to be suboptimal in older animals. The present study was designed to determine if the same MF exposure regimens will suppress NK cell activity in mature (i.e. more than 1 year old) animals. Extending our previous findings, a modest suppressive effect of MFs on NK cell activity in B6C3F(1) mice was found when subchronic exposure was initiated in animals held in quarantine for 1 year prior to exposure. These data demonstrate that MF exposure suppresses NK cell activity in both young and mature adult B6C3F(1) mice. However, because chronic exposure to the same MF parameters used in the NK function studies does not increase the incidence of neoplasia in B6C3F(1) mice, this statistically significant inhibition of NK cell function appears to be of limited biological significance.

Aging↗

PubMed2000

Cell viability and growth in a battery of human breast cancer cell lines exposed to 60 Hz magnetic fields.

Epidemiological data suggest that exposure to power-frequency (50/60 Hz) magnetic fields (MFs) may be a risk factor for breast cancer in humans. To determine whether MFs affect human breast cancer cells, we measured viability, growth and cytotoxicity in a battery of breast cancer cell lines after in vitro MF and sham exposure. Cells of three estrogen receptor-positive human breast cancer cell lines (MCF-7, ZR-75-1 and T-47D) and one estrogen receptor-negative human breast cancer cell line (MDA-MB-231) and normal (nontransformed) human breast epithelial cells were exposed to MFs (1 mT) or sham fields (<0.0001 mT) for 72 h. Cell viability was determined using the sulforhodamine B (SRB) assay at 0 and 72 h after the MF exposure period. Cell growth was measured as the change in SRB dye uptake over 72 h after MF exposure. MF exposure had no effect on cell viability or growth in any cell type examined. Similarly, MF exposure had no effect on cytotoxicity induced by exposure to the retinoid N-(4-hydroxyphenyl)retinamide. These data do not support the hypothesis that MF exposure stimulates growth of breast cancer cells.

Apoptosis↗

PubMed1999

Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone.

Two in vivo bioassays were conducted to evaluate the efficacy of dehydroepiandrosterone (DHEA) as an inhibitor of prostate carcinogenesis in rats. Prostate adenocarcinomas were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In the first experiment, DHEA (1000 or 2000 mg/kg diet) was administered continuously to rats beginning 1 week before MNU exposure. In the second experiment, continuous administration of DHEA (2000 mg/kg diet) was begun either 1 week before, 20 weeks after, or 40 weeks after MNU exposure. Controls received basal diet without added DHEA. Studies were terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. In the first study, continuous dietary administration of DHEA beginning 1 week before MNU resulted in a dose-related inhibition of prostate cancer induction. In the second experiment, comparable reductions in prostate cancer incidence were observed in groups exposed to DHEA beginning 1 week before, 20 weeks after, and 40 weeks after carcinogen exposure. These data demonstrate that nontoxic doses of DHEA confer significant protection against prostate carcinogenesis in rats. The efficacy of delayed administration of DHEA suggests that the compound confers protection against later stages of prostate cancer induction and can suppress the progression of existing preneoplastic lesions to invasive disease.

Adenocarcinoma↗

PubMed1999

Chemoprevention of rat prostate carcinogenesis by 9-cis-retinoic acid.

A chemoprevention study was conducted to evaluate the activity of 9-cis-retinoic acid (9-cis-RA) as an inhibitor of prostate carcinogenesis in male Wistar-Unilever (HsdCpb:Wu) rats. After pretreatment with a sequential regimen of cyproterone acetate (50 mg/kg/day for 21 days) and testosterone propionate (100 mg/kg/day for 3 days), groups of 40 rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU; 30 mg/kg body weight). Beginning 2 weeks after carcinogen administration, rats received chronic exposure to testosterone administered in s.c. implanted silastic capsules. The study was terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. Continuous dietary administration of 9-cis-RA at 100 mg/kg diet or 50 mg/kg diet beginning 1 week before MNU administration reduced cancer incidence in the dorsolateral + anterior prostate from 65% in dietary controls to 18 and 20%, respectively (P < 0.001 for both comparisons). Similarly, these dose levels of 9-cis-RA reduced the incidence of cancer in all accessory sex glands from 79% in dietary controls to 48 and 33% (P < 0.01 for both comparisons), respectively. Chronic dietary administration of 9-cis-RA induced no gross or organ-specific toxicity in any animal and did not suppress group mean body weight gain. The potent anticarcinogenic activity of 9-cis-RA in the rat prostate, when considered with its apparent lack of toxicity in rodents, suggests that this and other ligands for the retinoid X receptor merit consideration for evaluation in clinical prostate cancer chemoprevention trials.

Alitretinoin↗

PubMed1999

Multigeneration reproductive toxicity assessment of 60-Hz magnetic fields using a continuous breeding protocol in rats.

Male and female reproductive functions have been proposed as possibly sensitive targets for the biological effects of 60-Hz (power frequency) magnetic fields (MF). However, experimental data relevant to this hypothesized association are very limited. In the present study, the "reproductive assessment by continuous breeding" design was used to identify possible effects of MF exposure on reproductive performance, fetal development, and early postnatal growth in rats. Groups of age-matched Sprague-Dawley rats (40 breeding pairs/group) were exposed continuously (18.5 hr per day) to linearly polarized, transient-free 60-Hz MF at field strengths of 0 Gauss (G; sham control), 0.02 G, 2.0 G, or 10.0 G. An additional group of 40 breeding pairs received intermittent (1 hr on/1 hr off) exposure to 10.0 G fields. F0 breeding pairs were exposed to MF or sham fields for 1 week prior to mating, during a 14-week period of cohabitation, and during a 3-week holding period after cohabitation. The duration of the cohabitation period was selected to be sufficient for the delivery of five litters in the sham control group. Pups from the final F1 litter from each breeding pair were exposed to MF or sham fields until sexual maturity, were cohabitated in MF or sham fields for 7 days with nonsiblings from the same exposure group, and were held in the MF or sham fields for 22 days to permit delivery of F2 pups for evaluation. No evidence of exposure-related toxicity was identified in any rat in the F0, F1, or F2 generations. Fetal viability and body weights in all litters of groups exposed to MF were comparable to those of sham controls. No significant differences between sham controls and MF-exposed groups were seen in any measure of reproductive performance (litters/breeding pair, percent fertile pairs, latency to parturition, litter size, or sex ratio) in either the F0 or F1 generation. Exposure of Sprague-Dawley rats to 60-Hz MF strengths of up to 10.0 G either during their peak reproductive period (F0) or during gestation and throughout their life span (F1) has no biologically significant effects on reproductive performance. These results do not support the hypothesis that exposure to pure, linearly polarized 60-Hz MF is a significant reproductive or developmental toxicant.

Animals↗

PubMed1999

Design, construction, and validation of a large capacity rodent magnetic field exposure laboratory.

A magnetic field exposure laboratory has been constructed to support National Toxicology Program studies for the evaluation of the toxicity and carcinogenicity of pure, linearly polarized, 60 Hz magnetic fields in rodents. This dual corridor, controlled access facility can support the simultaneous exposure of 1200 rats and 1200 mice. The facility contains fully redundant electrical and environmental control systems and was constructed using non-metallic materials to maintain low levels of background (ambient), stray, and cross-talk magnetic fields. The exposure module design provides for large uniform exposure volumes with good control of stray and cross-talk fields, while allowing the use of roll-around cage racks for simplified animal husbandry. Stray fields and cross-talk have been further reduced by the inclusion of "steering coils" in each exposure module. Ambient 60 Hz fields (less cross-talk) in all exposure rooms are <0.1 microT (1 mG), and static magnetic fields have been mapped extensively. Magnetic field strength, waveform, temperature, relative humidity, light intensity, noise level, vibration, and air flow in all animal holding areas are tightly regulated, and are monitored continuously during all studies. Field uniformity in the animal exposure volumes is better than -/+l0%; a systematic program of cage, rack, and room rotation controls for possible positional effects within the exposure system. Magnetic fields are turned on and off over multiple cycles to prevent the induction of transients associated with abrupt field level changes. Total harmonic distortion is <3% at all field strengths. The facility has been used to study magnetic field bioeffects in rodent model systems in experiments ranging in duration from 8 weeks to 2 years.

Air Movements↗

PubMed1999

Gene expression in human breast epithelial cells exposed to 60 Hz magnetic fields.

Epidemiology suggests a possible relationship between exposure to power frequency magnetic fields (EMF) and breast cancer. One mechanism through which EMF could stimulate breast cancer induction is via altered expression of oncogenes and/or tumor suppressor genes that regulate normal and neoplastic growth. To evaluate the hypothesis that EMF action in the breast is mediated by alterations in gene expression, transcript levels of c-myc and a battery of other cancer-associated genes were quantitated in human breast epithelial cells exposed to pure, linearly polarized 60 Hz EMF with low harmonic distortion. HBL-100 cells and normal (non-transformed) human mammary epithelial cells were exposed to EMF flux densities of 0.1, 1.0 and 10.0 Gauss (G) for periods ranging from 20 min to 24 h; concurrent sham controls were exposed to ambient fields (<0.001 G) only. Gene expression was quantitated using ribonuclease protection assays. EMF exposure had no statistically significant effect on basal levels of c-myc transcripts in either human breast cell model, and had no effect on alterations in c-myc expression induced by 12-O-tetradecanoylphorbol-13-acetate. Transcript levels of c-erbB-2, p53, p21, GADD45, bax, bcl-x, mcl-1, and c-fos were also unaffected by EMF exposure. These results suggest that EMF is unlikely to influence breast cancer induction through a mechanism involving altered expression of these genes.

Breast↗

PubMed1999

Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat.

The high incidence and long latent period of prostate cancer make it an ideal target for chemoprevention. We have evaluated a series of agents for chemopreventive efficacy using a model in which hormone-dependent prostate cancers are induced in the Wistar-Unilever (WU) rat by sequential treatment with antiandrogen (cyproterone acetate), androgen (testosterone propionate), and direct-acting chemical carcinogen (N-methyl-N-nitrosourea), followed by chronic androgen stimulation (testosterone). This regimen reproducibly induces prostate cancers in high incidence, with no gross toxicity and a low incidence of neoplasia in the seminal vesicle and other non-target tissues. Dehydroepiandrosterone (DHEA) and 9-cis-retinoic acid (9-cis-RA) are the most active agents identified to date. DHEA inhibits prostate cancer induction both when chronic administration is begun prior to carcinogen exposure, and when administration is delayed until preneoplastic prostate lesions are present. 9-cis-RA is the most potent inhibitor of prostate carcinogenesis identified; a study to determine the efficacy of delayed administration of 9-cis-RA is in progress. Liarozole fumarate confers modest protection against prostate carcinogenesis, while N-(4-hydroxyphenyl)retinamide (fenretinide), alpha-difluoromethylornithine, oltipraz, DL-alpha-tocopherol acetate (vitamin E), and L-selenomethionine are inactive. Chemoprevention efficacy evaluations in the WU rat will support the identification of agents that merit study for prostate cancer chemoprevention in humans.

Alitretinoin↗

PubMed1998

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats.

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.

Animals↗

PubMed1998

Exposure to 60 Hz magnetic fields and risk of lymphoma in PIM transgenic and TSG-p53 (p53 knockout) mice.

The results of a number of epidemiology studies suggest that exposure to power frequency (50 and 60 Hz) magnetic fields may be a risk factor for hematopoietic neoplasia. To generate experimental data to test this hypothesis, the influence of magnetic field exposure on lymphoma induction was determined in two strains of mice that are genetically predisposed to the disease. PIM mice, which carry the pim-1 oncogene, are highly sensitive to lymphoma induction by N-ethyl-N-nitrosourea (ENU); ENU-treated PIM mice were studied as a 'high incidence' lymphoma model. TSG-p53 (p53 knockout) mice, in which the p53 tumor suppressor gene has been deleted from the germ line, develop lymphoma as an age-related change; hemizygous TSG-p53 mice were studied as a 'low incidence' lymphoma model. Beginning 1 day after a single i.p. injection of 25 mg ENU/kg body wt, groups of 30 PIM mice/sex were exposed for 18.5 h/day to pure, linearly polarized, transient-free 60 Hz magnetic fields at field strengths of 0 (sham control), 0.02, 2.0 or 10.0 Gauss (G). An additional group of 30 PIM mice/sex was exposed intermittently (1 h on, 1 h off) to 10.0 G fields. Groups of 30 TSG-p53 mice/sex were exposed continuously to magnetic field strengths of 0 (sham control) or 10.0 G; TSG-p53 mice received no ENU. Studies were terminated after 23 weeks of magnetic field exposure. Lymphoma incidence in male PIM mice exposed continuously to 10.0 G magnetic fields was significantly reduced from that seen in sex-matched sham controls; survival, lymphoma incidence and lymphoma latency in other groups of PIM mice did not differ from sham controls. Survival and lymphoma incidence in all groups of TSG-p53 mice was 7% or less, regardless of magnetic field exposure regimen. These data do not support the hypothesis that exposure to magnetic fields is a significant risk factor for lymphoid neoplasia in mice with a genetic predisposition to the disease.

Animals↗

PubMed1997

Eight-week toxicity study of 60 Hz magnetic fields in F344 rats and B6C3F1 mice.

Toxicity studies were performed by exposing F344/N rats and B6C3F1 mice (10 animals per sex per species per group) to transient-free, linearly polarized 60 Hz magnetic fields for 8 weeks. Targeted magnetic fields strengths used were 0 gauss (G; sham control fields did not exceed 0.001 G), 0.02 G, 2 G, and 10 G. Exposure was whole-body and continuous for 18.5 hr per day, 7 days per week. An additional group of rats and mice was exposed intermittently (1 hr on/1 hr off) to 10 G fields for the same period of time. Endpoints evaluated included morbidity, mortality, gross pathology, histopathology, body/organ weights, clinical chemistry (rats only), and hematology (rats only). All mice and all male rats survived until the end of the study. One female rat (2-G exposure group) died during Week 7 of the study; the death was not attributed to magnetic field exposure. In both studies, the mean body weight gains of exposed animals were similar to those of the respective controls. There were no gross, histological, hematological, or biochemical lesions attributed to magnetic field exposure. Statistically significant increases in liver weight and liver to body weight ratio occurred in female rats of all exposure groups but only at the termination. These data suggest that, for the variables evaluated in these studies, an 8-week exposure to linear-polarized, transient-free 60 Hz magnetic fields at field intensities of up to 10 G is not associated with significant toxicity in F344/N rats and B6C3F1 mice. Furthermore, there was no toxicity observed in animals receiving intermittent (1 hr on/1 hr off) exposures to 10-G fields. A 2-year study in F344/N rats and B6C3F1 mice is nearing completion of the in-life phase without overt toxicity in any exposed group. It is premature, however, to make any prediction concerning the possible influence of exposure to 60 Hz magnetic fields on cancer rates.

Animals↗

PubMed1996

Arachidonic acid metabolism and cell proliferation in rat mammary carcinoma cells treated with indomethacin.

To determine the specificity of action of indomethacin as an inhibitor of cyclooxygenase in the mammary epithelium, cell proliferation and levels of PGE2 and LTB4 were quantitated in 13762 MAT rat mammary carcinoma cells treated with 10(-4) to 10(-10) M concentrations of drug. Suppression of proliferation of 13762 MAT cells by indomethacin was associated with reduced levels of both PGE2 and LTB4. The antiproliferative activity of indomethacin in rat mammary carcinoma cells may be modulated through inhibition of both cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism.

Animals↗

PubMed1996

Exceptional chemopreventive activity of low-dose dehydroepiandrosterone in the rat mammary gland.

To determine if the chemopreventive activity of dehydroepiandrosterone (DHEA) in the rat mammary gland can be dissociated from its toxicity, two studies were conducted in which low doses of DHEA were administered alone and in combination with other agents to rats treated with N-methyl-N-nitrosourea. Beginning 1 week prior to administration of 35 mg N-methyl-N-nitrosourea per kg body weight, groups of 20 female Sprague-Dawley rates were fed AIN-76A diet supplemented with DHEA alone (800 or 400 mg/kg diet), DHEA + tamoxifen (80 or 40 microgram/kg diet), DHEA + carbenoxolone (3500 or 1750 mg/kg diet), or DHEA + tamoxifen + carbenoxolone. When administered alone at either 800 or 400 mg/kg diet, DHEA reduced mammary cancer incidence from >70% in dietary controls to 0%; mammary cancer incidence from >70% in dietary controls to 0%; mammary cancer incidence in all DHEA combination regimens was also < or = 5%. The dose levels of DHEA used induced no toxicity or alteration in body weight gain. These results indicate that dietary supplementation with low doses of DHEA has chemopreventive efficacy greater than or equal to that of endocrine ablation. This protection may be mediated by the induction of differentiation in the mammary parenchyma.

Animals↗