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J M Cline

Publications and source records attributed to J M Cline.

At least 37 records · Page 2Linked to original sources
PubMed1998

Phytochemicals for the prevention of breast and endometrial cancer.

Although there is evidence that phytochemicals decrease the incidence of breast and endometrial cancer, many observations are only phenomenologic, and much work needs to be done to explore basic mechanisms and the strategic exploitation of their interactions. The multiplicity of phytochemical actions at different sites in the process of tumorigenesis may eventually lead to the development of a multiagent strategy designed to maximize the complementary effects of different agents. A number of effects with possible relevance to cancer chemoprevention have been excluded from this review, including effects of phytochemicals on the immune response; the question of dietary restriction, which has a profound effect on tumorigenesis; the relatively low methionine levels in some phytochemicals such as soy, which may limit the synthesis of polyamines necessary for tumor growth [151]; and the fact that diets higher in plant products are usually lower in fat and result in leaner individuals with less potential for the synthesis of estradiol in adipose tissue. Also, many studies dealing solely with in vitro mutagenesis were excluded.

Amino Acid Sequence↗
PubMed1998

Coadministration of nomegestrol acetate does not diminish the beneficial effects of estradiol on coronary artery dilator responses in nonhuman primates (Macaca fascicularis).

OBJECTIVE: Our purpose was to examine the effect of coadministered nomegestrol acetate on estradiol-induced dilator responses of coronary arteries. STUDY DESIGN: In this prospective randomized trial, ovariectomized monkeys were fed a moderately atherogenic diet for 3 months while being treated with (1) no hormone replacement (control, n = 12), (2) estradiol (1.5 mg/d equivalent) added to the diet (n = 12), or (3) estradiol (1.5 mg/d equivalent) plus nomegestrol acetate (3.75 mg/d equivalent) (n = 12) added to the diet. Effects of treatment were measured with analysis of variance. Post hoc analyses were done by multiple comparison tests with Bonferroni corrections. RESULTS: Constrictor responses of epicardial coronary arteries (measured with quantitative angiography) and decreased coronary blood velocity (measured with Doppler ultrasonography) to acetylcholine (10(-6) mol/L) were less in the estradiol-treated monkeys (with or without cotreatment with nomegestrol acetate) than in the untreated monkeys (P <.05). Typical estrogenic responses were induced by estradiol in the endometrium (ie, increased proliferation [Ki-67 expression] [P <.04] and increased hormone receptor expression). These effects were antagonized by nomegestrol acetate. CONCLUSIONS: Although nomegestrol acetate has typical progestin-like effects on the uterus, it does not diminish the beneficial effects of estrogen on acetylcholine-induced dilator responses of coronary arteries.

Acetylcholine↗
PubMed1998

Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques.

The purpose of this work was to examine the mammary glands of adult, ovariectomized female cynomolgus macaques (Macaca fascicularis) in a long-term study of the effects of hormone treatments on chronic disease. Treatments included conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE+MPA, and tamoxifen. Doses were scaled from those given women. Treatments were given in the diet for three years, followed by necropsy and tissue collection. Endpoints evaluated included glandular histology, histomorphometry, and immunohistochemical detection of the proliferation marker Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in mammary epithelial cells. Major findings were as follows: CEE induced PR expression and focal to diffuse lobuloalveolar proliferation. Proliferation was increased by the addition of MPA, but was not induced by MPA alone. Tamoxifen induced ER and PR but not Ki-67 expression or glandular hyperplasia. Neoplasms were not seen. These findings indicate that progestogens may exacerbate, not antagonize mammary gland proliferation induced by estrogen replacement therapy, and that tamoxifen has both estrogen agonist and antagonist effects on sex steroid receptor expression in the normal primate breast.

Animals↗
PubMed1998

Effects of mammalian and plant estrogens on mammary glands and uteri of macaques.

Because of their possible beneficial effects on atherosclerosis and cancer risk, soy-derived isoflavone phytoestrogens may be useful as a dietary alternative or supplement to postmenopausal hormone replacement therapy. We examined this possibility in a well-characterized primate model of postmenopause. Adult, surgically postmenopausal female macaques (Macaca fascicularis) were treated continuously with either estradiol (E2), an isoflavone-rich soy protein isolate (SPI), or both (E2+SPI). Doses were equivalent on an energy basis to 1 and 148 mg/d per woman for E2 and SPI, respectively. After 6 mo, histopathologic, morphometric, and immunohistochemical measurements of the endometrium and mammary glands were taken. Increases in endometrial thickness, gland area, and epithelial proliferation were induced by E2 and E2+SPI. Morphometric changes were accompanied by increased epithelial staining of the proliferation marker Ki-67 in the E2-treated group. The effects of E2 were partially antagonized by SPI (manifested as decreased Ki-67 staining). Mammary gland proliferation was induced by E2 and E2+SPI. The effects of E2 were also antagonized by SPI in the mammary gland. Morphometric and immunohistochemical measures of proliferation were in agreement in endometrium. In this nonhuman primate model, treatment with SPI did not induce proliferation in endometrial and mammary tissue. SPI may have antiproliferative effects in the endometrium and mammary gland when given along with exogenous estrogen.

Animals↗
PubMed1998

Induction of mutations in Ki-ras and INK4a in liver tumors of mice exposed in utero to 3-methylcholanthrene.

An understanding of the basic mechanisms responsible for the pathogenesis of liver neoplasms is needed in order to develop better therapeutic strategies. The present study utilized a pharmacogenetic mouse model to assess the role of cytochrome P4501A1 (Cyp1a1) in modulating genetic damage to oncogenic and tumor suppressor loci following in utero exposure to the polycyclic aromatic hydrocarbon, 3-methylcholanthrene (MC). Analysis of the Ha-ras, Ki-ras, INK4a and p53 genes was carried out with lysates from paraffin-embedded liver tissue from transplacentally-treated mice. The lysates were subjected to DNA amplification by the PCR technique followed by allele-specific oligonucleotide hybridization screening and SSCP analysis. All of the 26 neoplasms screened (23 hepatocellular carcinomas, two hepatocellular adenomas and one sarcoma) exhibited a GGC-->CGC (GLY13-->ARG13) transversion at the Ki-ras gene locus. None of the tumors had Ki-ras mutations at codon 12 of exon 1. Approximately 12% (3/26) of the liver tumors exhibited point mutations in exon 1 of the INK4a gene, with each of the three tumors exhibiting two point mutations. Analysis of exon 2 of the INK4a gene showed the presence of a CCG-->CTG (PRO73-->LEU73) transition in two of the 26 neoplasms. No mutations were found in exons 1 or 2 of the Ha-ras gene, or in exons 5-8 of the p53 gene. Analysis of tumor RNAs showed overexpression of Ha-ras, cip1 and c-jun in approximately 38% of the liver tumor samples. The results of this study suggest that mutagenic damage to oncogenes and tumor suppressor genes may be critical factors in mediating transplacentally-induced liver tumorigenesis. The fact that Ki-ras mutations were found in all of the tumors suggests that mutation at this gene locus may be an early event in liver tumor pathogenesis, while mutation in tumor suppressor genes may occur later during tumor progression. These combined results are consistent with the pathogenesis of cancer in humans.

Animals↗
PubMed1998

Effects of dietary soybean estrogens on the reproductive tract in female rats.

The estrogenic actions of dietary phytoestrogens have raised concerns regarding the potential DES-like developmental effects on the female genital tract, but the growing evidence of cardioprotective benefits of dietary soybean estrogens provides the impetus to assess the effects of these compounds in adult female models of the menopause. We conducted an experiment in ovariectomized rats to determine the independent effects of dietary soybean estrogens (SBE) and the interactions of these agents with the commonly used pharmaceutical estrogen preparation (conjugated equine estrogens, CEE) in the vagina and uterus. We looked at the effects of SBE and CEE, alone and in combination, on uterine weight, body weight, vaginal cytology, uterine luminal epithelial height, and immunohistochemical staining for proliferating cell nuclear antigen (PCNA), lactoferrin (Ltf), and apoptosis. Ovariectomized rats were fed diets containing casein or soybean protein (SBE, low dose = 11.6 mg isoflavones/ 1800 cal; high dose = 117.8 mg/1800 cal), with no CEE, low dose CEE (0.313 mg/1800 cal), or high dose CEE (0.625 mg/1800 cal) added. In this study, SBE did not demonstrate estrogenic activity for uterine weight or vaginal cytology. We also found no estrogenic effects of these doses of SBE for PCNA, apoptosis, Ltf staining, or for LEH measurements. In addition, our results regarding the interactions of SBE and CEE do not show any evidence that the combination is additive in effect. On the contrary, the LEH response induced by low levels of CEE, was reduced by high levels of SBE. Furthermore, the Ltf response induced by CEE also was reduced by high levels of SBE. This suggests that high doses of SBE may antagonize the estrogen-agonist actions of low doses of CEE in the rat uterus. Our results in the ovariectomized rat model of menopause suggest that dietary soybean estrogens will not elicit a pattern of effects that simply recapitulates those of steroidal estrogens.

Animals↗
PubMed1998

The potential of soybean phytoestrogens for postmenopausal hormone replacement therapy.

Hormone replacement therapy for postmenopausal women greatly reduces their risk of coronary heart disease. However, current pharmaceutical regimens have a low acceptance rate among postmenopausal women. We have sought to identify an alternative treatment that would retain the beneficial health effects of current standard therapy without its negative aspects. We have concentrated our research on naturally occurring estrogens (called phytoestrogens) found in soybeans, in the belief that delivery of phytoestrogens via the diet would be more acceptable than pharmaceutical regimens. Using a well-established nonhuman primate model of postmenopausal women, we have investigated the effects of soy phytoestrogens on cardiovascular risk factors and the reproductive system. In this review, we summarize the results of our ongoing research.

Animals↗
PubMed1998

Nandrolone decanoate causes pathologic changes in the uterus of surgically postmenopausal female cynomolgus macaques.

OBJECTIVE: To determine the effects of the androgenic anabolic steroid nandrolone decanoate on uterine endometrium and myometrium and on the mammary gland of female cynomolgus macaques by using morphologic, histomorphometric, and histopathologic determinations. DESIGN: Histologic and histomorphometric measurements were performed on uteri and mammary glands that were collected at necropsy from animals that had been used in a long-term experiment to examine the effects of nandrolone decanoate on bone and coronary arteries. The animals were surgically postmenopausal cynomolgus macaques randomized into four treatment groups: (a) intact sham ovariectomized (sham; n = 12), (b) ovariectomized (OVX; n = 15), (c) ovariectomized + nandrolone decanoate for 2 years (OVX + ND; n = 14), and (d) ovariectomized + nandrolone decanoate for 1 year, beginning 1 year after ovariectomy (OVX + NDdelay; n = 11). Intramuscular injections of nandrolone decanoate (25 mg every 3 weeks) were given to the two nandrolone-treated groups of animals (OVX + ND and OVX + NDdelay): one starting 3 weeks after ovariectomy and continuing for 2 years and the other group 1 year after ovariectomy. The sham and OVX groups were given an intramuscular injection of sterile vehicle every 3 weeks. RESULTS: Nandrolone treatment was moderately uterotropic in all treated versus ovariectomized animals. Changes induced were an increase in uterine weight, endometrial thickness, and glandular area, and a high incidence of mucometra. Glandular architecture was altered by nandrolone treatment such that glands extended into the myometrium (producing an adenomyosis-like lesion). Mammary gland changes were mild and equivocal. CONCLUSION: Nandrolone induced pathologic changes in ovariectomized monkeys similar to adenomyosis in the uterus.

Anabolic Agents↗
PubMed1997

Quantification of CCI-103F labeling heterogeneity in canine solid tumors.

PURPOSE: The purposes of this study were to assess sources of variation in the distribution of nitroimidazole-labeled hypoxic cells in canine tumors and to quantify the reliability of estimating overall nitroimidazole-labeled area fraction from biopsies. METHODS AND MATERIALS: Hypoxic cells were labeled in 24 canine tumors by immunostaining of the nitroimidazole hypoxia marker CCI-103F. In tumors with a volume < 100 cm3, each cubic centimeter of tumor was examined; in larger tumors 100 randomly selected 1 cm3 samples were examined. These data were used to estimate the overall CCI-103F-labeled area fraction in the tumor. A variance components model was used to quantify intertumoral, intratumoral, and within slide (residual) sources of variation. The ability to estimate intratumoral CCI-103F-labeled area fraction based on information obtained from biopsies was assessed by randomly selecting two or four samples from the dataset for each tumor and comparing the mean CCI-103F-labeled area fraction from this limited sample to the labeled area fraction based on each cubic centimeter; this simulation process was repeated 1000 times. RESULTS: Intratumoral (27% of total) and intertumoral (30% of total) variation in CCI-103F-labeled area fraction were similar. Residual variation (variation at the microscopic level) accounted for 43% of total variation in CCI-103F labeling. Intratumoral variation in labeling decreased as the intratumoral CCI-103F mean labeled area fraction decreased. The accuracy of estimating the intratumoral CCI-103F-labeled area fraction in a tumor from limited sampling increased as the number of samples increased or the intratumoral labeled area fraction decreased. When four random samples were used to estimate overall CCI-103F-labeled area fraction in the tumor, estimates from approximately 90% of the 1000 simulations were within 0.10 of the intratumoral CCI-103F-labeled area fraction. Classifying a minimally labeled tumor as unlabeled based on limited sampling was unlikely. CONCLUSION: Despite intratumor variation, acceptable estimates of nitroimidazole-labeled cells in a tumor may be obtained from a clinically feasible number of biopsies.

Analysis of Variance↗
PubMed1997

Regional distribution of proliferating cells and hormone receptors in the mammary gland of surgically postmenopausal macaques.

OBJECTIVE: To define the relative proliferative response and hormone receptors status in ten sites in the mammary gland of surgically postmenopausal cynomolgus macaques given hormone replacement therapy. METHODS: Surgical postmenopausal cynomolgus macaques were given either no treatment (n = 4), conjugated equine estrogens (CEE, n = 4), or combined therapy with CEE and medroxyprogesterone acetate (n = 4). The drugs were administered in the diet, at doses equivalent on a caloric basis to 0.625 mg/woman/day for CEE and 2.5 mg/woman/day for medroxyprogesterone acetate. Immunostaining of mammary sections was done for estrogen receptor, progesterone receptor, and the proliferation marker Ki-67 MIB-1 (MIB). Comparisons were made between central and peripheral gland, by quadrant, left versus right, and with respect to distance from the nipple within each quadrant. RESULT: There were no significant differences in hormone receptor or MIB expression within different sites within the gland. CONCLUSIONS: In the surgically postmenopausal, hormone-treated macaque, regional differences in estrogen and progesterone receptors and MIB staining are not apparent. The assumption of homogeneity throughout the gland makes aspiration cytology and multiple biopsy studies feasible in this species.

Animals↗
PubMed1997

Combustion products from advanced composite materials.

Recent advances in armament and materials applications are beginning to outpace the development of adequate safety characterizations. To avoid unnecessary and restrictive regulations implemented to protect individuals from potential toxic consequences resulting from exposure to combustion products of advanced composite materials (ACM); this laboratory has begun an investigation of combustion characteristics. In this preliminary investigation we have assessed the production of particulate matter and the production of organic compounds contained in both the combustion vapor phase or associated with the particulate matter. The results of these investigations have revealed that a substantial fraction of the particulates appear to be in the respirable range and that a high number of organic compounds and potential toxicants are associated with particulate matter. These findings are the first to describe the production of potentially toxic atmospheres from the combustion of advanced composite materials and indicate the usefulness of further investigations to quantify the risk of exposure to humans. These and forthcoming data will be useful in determining proper protective equipment and precautions required to protect human health during exposures to products from the combustion of advanced composite materials.

Aniline Compounds↗
PubMed1997

[Effects of estrogen monotherapy on breast tissue in the primate model (Macaca fascicularis)].

Much is unknown about the effects of estrogen's on the mammary gland in postmenopausal women today. In a recent study of estrogenmonotherapy 28 adult, surgically postmenopausal female monkeys (Macaca fascicularis) were treated continuously with estradiol or were given only a diet (control group). After 6 months serum levels of estradiol and progesterone, morphometrical, histopathological and immunohistochemical measurements of the mammary gland were performed. In monkeys receiving estradiol the mammary epithel thickness and the mammary epithelial area (as percentage of total breast area) increased. Estradiol induced mammary gland hyperplasia, but we did not see any atypical hyperplasia. Estradiol and progesterone receptors staining in mammary ducts and lobuli increased (not significant). Estradiol induced a mammary gland proliferation (not significant) shown as increased staining for PCNA and Ki67.

Animals↗
PubMed1996

Radiation plus local hyperthermia versus radiation plus the combination of local and whole-body hyperthermia in canine sarcomas.

PURPOSE: The purpose of this study was to assess the effect of increasing intratumoral temperatures by the combination of local hyperthermia (LH) and whole body hyperthermia (WBH) on the radiation response of canine sarcomas. METHODS AND MATERIALS: Dogs with spontaneous soft tissue sarcomas and no evidence of metastasis were randomized to be treated with radiation combined with either LH alone or LH + WBH. Dogs were accessioned for treatment at two institutions. The radiation dose was 56.25 Gy, given in 25 2.25 Gy daily fractions. Two hyperthermia treatments were given; one during the first and one during the last week of treatment. Dogs were evaluated after treatment for local recurrence, metastasis, and complications. RESULTS: Sixty-four dogs were treated between 1989 and 1993. The use of LH+WBH resulted in statistically significant increases in the low and middle regions of the temperature distributions. The largest increase was in the low temperatures with median CEM 43 T90 values of 4 vs. 49 min for LH vs. LH + WBH, respectively (p<0.001). There was no difference in duration of local tumor control between hyperthermia groups (p = 0.59). The time to metastasis was shorter for dogs receiving LH + WBH (p = 0.02); the hazard ratio for metastatic disease for dogs in the LH + WBH group was 2.4 (95% confidence interval, 1.2-5.4) with respect to dogs in the LH group. Complications were greater in larger tumors and in tumors treated with LH + WBH, CONCLUSION: The combination of LH + WBH with radiation therapy, as described herein, was not associated with an increase in local tumor control in comparison to use of LH with radiation therapy. The combination of LH + WBH also appeared to alter the biology of the metastatic process and was associated with more complications than LH. We identified no rationale for further study of LH + WBH in combination with radiation for treatment of solid tumors.

Animals↗
PubMed1996

Pharmacokinetics and toxicity of oral and intravenous lonidamine in dogs.

Plasma lonidamine concentration and toxicity were investigated in dogs receiving 100, 200, 400, 800, 1200 mg/m2 orally twice daily for 30 days and in dogs receiving single intravenous doses of 200, 400, 800, 1200 mg/m2. Physical or laboratory signs of toxicity were not observed in dogs receiving oral lonidamine, but severe vomiting and signs of acute hepatic and pancreatic toxicity were observed in dogs receiving intravenous doses that exceeded 400 mg/m2. The area under the lonidamine concentration versus time curve (AUC) in dogs receiving 200, 400, and 800 mg/m2 of lonidamine intravenously was a 1.8-, 3.3-, and 8.7-fold higher than in dogs receiving oral lonidamine. This suggests that the bioavailability of oral lonidamine may be limited. However, centrilobular hepatocellular swelling and vacuolation were observed in dogs receiving oral lonidamine. Serum alanine aminotransferase (ALT) activity was increased in dogs receiving intra-venous lonidamine. These findings suggest that lonidamine is hepatotoxic in dogs. However, serum ALT was increased in only 1/4 dogs receiving 400 mg/m2 of lonidamine intravenously and plasma concentration were within the range capable of sensitizing hyperthermia and chemotherapy. Therefore, this dose and route appears to be a viable and controllable method for prospective quantification of lonidamine interaction with systemic chemotherapy and/or hyperthermia.

Administration, Oral↗
PubMed1996

Effects of 17 alpha-dihydroequilenin sulfate on atherosclerotic male and female rhesus monkeys.

OBJECTIVES: Our purpose was to determine the effects of 17 alpha-dihydroequilenin on plasma lipid and lipoprotein, glucose, and insulin concentrations; coronary artery vasomotor function; and reproductive organ and mammary gland proliferation in atherosclerotic male and female rhesus macaques. STUDY DESIGN: Fifty adult female and 33 adult male rhesus macaques were randomized to treatment by lifetime dietary cholesterol exposure and ratio of total plasma cholesterol to high-density lipoprotein cholesterol. The female treatment groups were intact female controls (n = 9), ovariectomized controls (n = 16), ovariectomized plus 0.3 mg/kg/day 17 alpha-dihydroequilenin (n = 17) and ovariectomized plus subcutaneous estradiol (n = 7). The male treatment groups were control (n = 16) and 1.25 mg/kg/day 17 alpha-dihydroequilenin (n = 17). Treatment lasted 5 weeks. Longitudinal assessments of plasma lipid and lipoprotein and glucose and insulin concentrations were performed. Coronary artery vasomotor function was assessed by quantitative coronary angiography 1 week after initiation of treatment. Morphologic and immunohistochemical assessments of proliferation index values of reproductive organs and mammary glands were done at necropsy. RESULTS: 17 alpha-Dihydroequilenin prevented endothelium-dependent vasoconstriction in males (p < 0.05) and ovariectomized females (p < 0.08). 17 alpha-Dihydroequilenin treatment increased plasma apolipoprotein A-1 concentrations (p < 0.05) and lowered fasting insulin concentrations (p < 0.05) without changing fasting plasma glucose concentrations in males. 17 alpha-Dihydroequilenin had no other effects on plasma lipid and lipoprotein concentrations in either males or females. It had no trophic effects on uterus, endometrium, or breast. There was no effect on either prostatic or testicular weight. CONCLUSION: 17 alpha-Dihydroequilenin may represent a single-agent hormone therapy for reduction of ischemic hear disease risk for both menopausal women and men. It has no apparent trophic effects on reproductive organs or mammary glands of female and male rhesus macaques.

Animals↗
PubMed1996

Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques.

OBJECTIVE: Our purpose was to define the proliferative response and receptor status in the mammary glands of surgically postmenopausal macaques given hormone replacement therapy, equivalent for monkeys to that given women. STUDY DESIGN: Surgically postmenopausal adult female cynomolgus macaques (Macaca fascicularis) were given either no treatment (n = 26), conjugated equine estrogens (n = 22), or combined therapy with conjugated equine estrogens and medroxyprogesterone acetate (n = 21). Drugs were administered in the diet, at doses equivalent on a caloric basis to 0.625 mg per woman per day for conjugated equine estrogens and 2.5 mg per woman per day for medroxyprogesterone acetate, for 30 months. Mammary gland proliferation was assessed subjectively and by morphometric and stereologic means. Estrogen receptor and progesterone receptor content and proliferation were studied by immunohistochemistry. RESULTS: In this model combined therapy with conjugated equine estrogens and medroxyprogesterone acetate induced greater proliferation than did conjugated equine estrogens alone. The percentage of estrogen receptor-positive cells was decreased in the conjugated equine estrogens plus medroxyprogesterone acetate group. The percentage of progesterone receptor-positive cells was increased by treatment with conjugated equine estrogens alone. CONCLUSION: These results indicate a proliferative response of mammary gland epithelium to therapy with conjugated equine estrogens plus medroxyprogesterone acetate in postmenopausal macaques. The clinical implication of this finding may be a greater risk for development of breast neoplasms in women receiving combined hormone replacement therapy.

Animals↗