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Biomedical subjects

M M Juliana

Publications and source records attributed to M M Juliana.

At least 19 recordsLinked to original sources
PubMed1999

Effect of reduced body weight gain on the evaluation of chemopreventive agents in the methylnitrosourea-induced mammary cancer model.

These studies examined whether the small to moderate reductions in body weight gain (< or = 15%) affect mammary carcinogenesis. Beginning 1 week prior to methylnitrosourea (MNU) administration (experiment 1), rats received diets supplemented with 4-hydroxyphenylretinamide (4-HPR) (782 mg/kg of diet) and retinyl acetate (328 mg/kg of diet) or underwent food restrictions. Rats were administered an i.v. dose of MNU (50 mg/kg body wt) at 50 days of age. Although the final body weights were similarly depressed by 4-HPR (8%) and by retinyl acetate (11%) from rats fed ad libitum, the kinetics of inhibition were quite different. Whereas 4-HPR caused an acute decrease in body weight at the time it was administered, the effect of retinyl acetate was more chronic. At 110 days after the administration of MNU, the average number of mammary cancers per rat was 4.9 for rats fed ad libitum, 1.3 for rats fed 4-HPR, 3.1 when body weights were matched to 4-HPR-treated rats, 1.9 for retinyl acetate and 3.2 when body weights were matched to retinyl acetate. Experiment II was performed to determine the minimal degree of acute body weight gain reduction that would alter MNU-induced mammary carcinogenesis. Body weight gain depressions of 3, 6, 9, 12 and 15% were initiated at 43 days of age by dietary restrictions and MNU was administered at 50 days of age. At 120 days after MNU, the percentage decreases in mammary cancer multiplicity in the various groups were 14, 15, 41, 44 and 55%, respectively. These data demonstrate that moderate reductions (9-15%) in body weight gain, in particular when occurring during the initiation and early promotion stages can greatly affect cancer multiplicity.

Animals↗
PubMed1998

Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model.

The chemopreventive activity of the highly specific nonsteroidal aromatase inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced rat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.25 mg/kg body wt/day) were administered daily (by gavage) to female Sprague-Dawley rats starting at 43 days of age. Seven days later, the rats were given a single i.v. dose of MNU (50 mg/kg body wt). Rats were continually treated with vorozole until the end of the experiment (120 days post-MNU). Vorozole caused a dose dependent inhibition of mammary cancer multiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day) decreased cancer multiplicity by approximately 90%, and simultaneously decreased cancer incidence from 100 to 44%. The next two highest doses of vorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammary cancer multiplicity by 70-80%. Even the two lowest doses of vorozole (0.16 and 0.08 mg/kg body wt/ day) decreased cancer multiplicity -50%. Serum level determinations were performed on a variety of endpoints at either 4 or 24 h following the last dose of vorozole. Insulin-like growth factor (IGF)-1 levels were slightly, but significantly, increased by vorozole treatment. Vorozole induced striking increases in serum testosterone levels at 4 h at all the dose levels employed. Testosterone levels were significantly elevated over controls at 24 h in rats given the lower doses of vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lower than in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kg body wt/ day). This result presumably reflects the limited half-life of vorozole in rats. In a second series of experiments, the effects of limited duration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittent dosing with vorozole were determined. Treatment of rats with vorozole for limited time periods, from 3 days post-MNU administration until 30 or 60 days post-MNU treatment, resulted in significant delays in the time to appearance of palpable cancers. However, these limited treatments did not greatly affect the overall incidence or multiplicity of mammary cancers when compared with the MNU controls at the end of the study (150 days post-MNU). Finally, the effects of intermittent dosing with vorozole (2.5 mg/kg body wt/day) were examined. Rats were administered cycles of vorozole daily for a period of 3 weeks followed by treatment with the vorozole vehicle for the next 3 weeks (total of four cycles). Although this intermittent treatment did inhibit the appearance of new tumors during each of the periods that vorozole was administered, it did not cause regression of palpable cancers.

Animals↗
PubMed1997

Chemopreventive efficacy of anethole trithione, N-acetyl-L-cysteine, miconazole and phenethylisothiocyanate in the DMBA-induced rat mammary cancer model.

The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter carcinogen metabolism, was examined in the dimethylbenzanthracene (DMBA) mammary carcinogenesis model. In this protocol, animals were exposed to non-toxic doses of the chemopreventives in the diet beginning 7 days prior to DMBA administration and then continuously throughout the duration of the assay (100 days post carcinogen). Miconazole, an antifungal agent with relatively broad inhibitory activity toward a variety of cytochromes P450, increased mammary tumor latency, decreased tumor incidence at the highest dose and decreased tumor multiplicity up to 60%. Anethole trithione, a substituted dithiolthione and an analog of the relatively broad-spectrum chemopreventive oltipraz, was administered in the diet and significantly inhibited mammary cancer multiplicity but not cancer incidence. NAC, an antimucolytic agent, failed to inhibit DMBA-induced mammary tumorigenesis. Surprisingly, treatment with DMBA plus PEITC, a potent inhibitor of cytochrome P450 2E1, actually increased the multiplicity of tumors relative to that observed with DMBA alone.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Effects of viral and mycoplasmal infections, ammonia exposure, vitamin A deficiency, host age, and organism strain on adherence of Mycoplasma pulmonis in cultured rat tracheas.

Adherence to host cells is thought to be a pathogenetic mechanism in mycoplasmal diseases, thus, factors affecting adherence could affect disease expression. To determine whether factors that affect expression of Mycoplasma pulmonis respiratory disease in rats alter adherence of the organism to respiratory epithelium, we studied adherence of radiolabelled M. pulmonis in perfused whole rat tracheas. Adherence was significantly increased in tracheas from rats with sialodacryoadenitis virus infection or vitamin A deficiency (103 +/- 16% and 112 +/- 29% of control means, respectively), but Sendai virus infection, ammonia exposure, and host age (40 versus 8 weeks) were not associated with increased adherence. We also assessed the relationship between adherence and virulence of M. pulmonis strains. The virulent strain 5782C was more adherent (51 +/- 7%) than the type strain, PG34(Ash), and a polystyrene-adherent, hemadsorbing UAB CT subclone was more adherent (229 +/- 40%) than a UAB CT subclone that does not adhere to polystyrene or erythrocytes. PG34(Ash) and the UAB CT subclones caused rhinitis only; however, the adherent UAB CT subclone caused significantly more severe rhinitis than either the nonadherent subclone or PG34(Ash) as determined by scoring of histologic sections. To determine whether M. pulmonis itself induces changes in respiratory epithelium resulting in enhanced adherence, we studied adherence in tracheas from rats inoculated with M. pulmonis 3 weeks earlier. Adherence was increased 64 +/- 22%, compared with that in tracheas from control rats. Adherence in infected tracheas treated with tetracycline for 2 days was not increased, indicating that M. pulmonis-induced changes in epithelial adherence are rapidly resolved after elimination of infection.

Age Factors↗
PubMed1992

Effects of folate deficiency and supplementation on methylnitrosourea-induced rat mammary tumors.

BACKGROUND: There are metabolic and epidemiologic data consistent with the hypothesis that folate deficiency increases the likelihood of cancer. Conversely, it is also known that folate is necessary for cancer growth, but few experiments in laboratory animals have evaluated the effects of folate deficiency on the development of chemically induced cancers. PURPOSE: Our purpose was to determine the effects of nutritional folate deficiency in female Fischer 344 rats on initiation and early promotion of methylnitrosourea (MNU)-induced mammary cancer. METHODS: Rats (age, 27 days) were fed a folic acid-deficient diet (AIN-76A) supplemented with glycine and succinylsulfathiazole [FA(0)]; the FA(0) diet supplemented with 2 or 40 mg of folic acid per kilogram [FA(2) or FA(40), respectively]; or the FA(0) diet supplemented with 20 mg of folinic acid per kilogram [FL(20)]. At 57 days of age, each diet-treated group (30 rats in each group) received MNU (50 mg/kg) by intravenous injection. Immediately after MNU treatment, all animals were fed the AIN-76A complete diet containing 2 mg of folic acid per kilogram. Control groups were fed the AIN-76A complete diet throughout the entire experiment. RESULTS: After 4 weeks, folate deficiency, but not anemia or growth suppression, was documented by lower folate levels in plasma and red blood cells in the group receiving the FA(0) diet. Cancer multiplicity (i.e., number of mammary cancers per number of tumor-bearing animals) at 180 days after MNU injection was 1.32, 1.90, 2.14, and 2.73 mammary cancers per tumor-bearing animal in the FA(0), FA(2), FA(40), and FL(20) groups, respectively; the value in the FA(0) group was statistically significant compared with the values in the other groups. The time required for 50% of the rats to develop palpable mammary cancer was 170, 142, 100, and 85 days, respectively. The value of 170 days for the FA(0) group was statistically significant compared with the values of 100 and 85 days. Mammary cancer incidence was 63%, 70%, 72%, and 73%, respectively; these percentages were not significantly different. CONCLUSIONS: Folate deficiency suppresses and folate supplementation enhances initiation or early promotion of MNU-induced mammary cancer in rats, even when the folate-deficient rats do not have anemia or growth suppression. IMPLICATION: Since the rat is relatively resistant to folate deficiency anemia, other animal models should be used to test the effect of folate nutriture on carcinogenesis.

Animals↗
PubMed1991

Effect of canthaxanthin on chemically induced mammary carcinogenesis.

Canthaxanthin, a carotenoid with no vitamin A activity, was evaluated for its efficacy in the prevention of chemically induced mammary cancers. Canthaxanthin was administered in the diet at two dose levels (3,390 or 1,130 mg/kg diet). In the dimethylbenzanthracene-induced mammary cancer model, diet supplementation with canthaxanthin for 3 weeks prior to the carcinogen resulted in a 65% reduction in the number of mammary cancers. The feeding of canthaxanthin after the administration of methylnitrosourea had no significant effect on mammary carcinogenesis. These data demonstrate that canthaxanthin, at least in these models of mammary cancer, is active in preventing cancer initiation and not promotion. Analysis of tissues by high-pressure liquid chromatography revealed that canthaxanthin levels in the liver are very high when compared to those in the mammary gland. The observation that canthaxanthin is highly effective in preventing cancer initiation without toxicity suggests that carotenoids not possessing vitamin A activity should be further evaluated as chemopreventive agents.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Effect of miso (Japanese soybean paste) and NaCl on DMBA-induced rat mammary tumors.

An AIN-76A diet supplemented with miso (Japanese soybean paste) reduced the incidence (p = 0.05, Fishers exact test) and delayed the appearance (p = 0.04, log rank test) of dimethylbenz[a]anthracene (DMBA)-induced mammary adenocarcinomas in female Sprague-Dawley rats. A NaCl-supplemented AIN-76A diet (containing the same amount of NaCl as in the miso-supplemented diet) also delayed the appearance of tumors (p = 0.02, log rank test) compared with the AIN-76A control diet. The miso- and NaCl-supplemented diet treatment groups showed a trend toward a lower number of cancers per animal, a trend toward a higher number of benign tumors per animal, and a trend toward a lower growth rate of cancers compared with controls. However, no statistical differences in the total number of tumors per animal or growth rate of the cancers were observed in the miso, NaCl, and control groups. Both miso and NaCl supplementation resulted in increased water intake and urine output but no change in the growth of the animals. These data suggest that miso consumption may be a factor producing a lower breast cancer incidence in Japanese women.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Nonspecific lymphocyte responses in F344 and LEW rats: susceptibility to murine respiratory mycoplasmosis and examination of cellular basis for strain differences.

Mycoplasma pulmonis produces a mitogen which may play a role in the pathogenesis of murine respiratory mycoplasmosis in rats. Since LEW rats are more susceptible to this disease than F344 rats are, these two strains were used to examine a possible association between disease severity and the level of nonspecific lymphocyte stimulation by mitogens, including M. pulmonis membrane preparations. F344 and LEW spleen, lung, blood, and lymph node lymphocytes were exposed to various mitogens. LEW lymphocytes gave a significantly higher response to mitogenic stimulation, regardless of their anatomical source. These differences in lymphocyte responsiveness were primarily due to differences within the nonadherent cell population. Significantly higher numbers of W3/25+ (T helper) cells were found in LEW lymphoid populations, whereas no difference was found in MRC OX-8+ (T suppressor/cytotoxic) cells. These data suggest an association between disease severity and host responsiveness to nonspecific stimuli.

Animals↗
PubMed1981

Tumorigenicity of 7,12-dimethylbenz[a]anthracene, its hydroxymethylated derivatives and selected dihydrodiols in the newborn mouse.

The newborn mouse lung adenoma model has been shown to be a sensitive test for studying the tumorigenicity of bay region diol epoxides and their precursor dihydrodiols. When a total dose of 28 nmol of 7,12-dimethylbenz[a]anthracene (DMBA) or its derivatives was injected i.p. into the preweaning mice, it was found that the 3,4-dihydrodiols of both DMBA and 7-hydroxymethyl-12-methylbenz[a]anthracene caused 13.3 and 4.1 times more lung adenomas than DMBA, respectively. The mice treated with the 5,6- and 8,9-dihydrodiols of DMBA, 7-hydroxymethyl-12-methylbenz[a]anthracene and its 5,6- and 8,9- and 10,11-dihydrodiols, 7-methyl-12-hydroxymethylbenz[a]anthracene and 7,12-dihydroxymethylbenz[a]anthracene developed a level of lung adenomas/mouse less than 2-fold higher than that found in the DMSO-treated control group. Liver tumors also developed in some of the mice. The percentage of mice with liver tumors also indicated that the 3,4-dihydrodiols of both DMBA and 7-hydroxymethyl-12-methylbenz[a]anthracene were more tumorigenic than DMBA itself. These data indicate that the 3,4-dihydrodiols of both DMBA and its 7-hydroxymethyl derivative may be proximate carcinogenic metabolites of DMBA in the newborn mouse.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Anhydroretinol, a retinoid active in preventing mammary cancer induced in rats by N-methyl-N-nitrosourea.

As determined by in vitro tests, anhydroretinol, a metabolic product of retinol, was bound specifically by serum retinol-binding protein and by cellular retinol-binding protein but not by cellular retinoic acid-binding protein or the nuclear receptors, RARs and RXRs. For rats dosed with the mammary carcinogen, N-methyl-N-nitrosourea (45 mg/kg body weight) and given diets containing either the retinoid vehicle, anhydroretinol (67, 134, 268, or 536 mg/kg of diet), or retinyl acetate (328 mg/kg of diet), there were, over a 90-day observation period, no significant differences in body weights. The compound did not accumulate in liver tissue or cause an increase in hepatic levels of retinyl palmitate (potential problems observed with other retinoids). The numbers of mammary cancers were as follows: no retinoid, 4.5/rat; retinyl acetate, 2.1/rat; and increasing doses of anhydroretinol, 2.9, 3.3, 3.0, and 1.7/rat, respectively. Thus, anhydroretinol, at non-toxic levels, was effective as a preventive agent in this experimental model of breast cancer.

Animals↗
PubMedDate not supplied

Effects of acute and chronic body weight gain reductions in the evaluation of agents for efficacy in mammary cancer prevention.

Studies were performed to determine the effects of moderate decreases in body weight gain on mammary carcinogenesis. The levels of depressions in weight gain were those often observed in the evaluation of chemopreventive agents. In the first experiment, the effects of acute and chronic reductions of body weight gain when started after carcinogen treatment were examined in young rats (MNU at 50 days of age). Significant decreases (36%) in mammary cancers occurred in groups of rats that underwent a 12% acute reduction in body weight gain as compared with ad libitum controls. In contrast, chronic weight reductions of up to 12% had minimal effects on cancer multiplicities, while a 15% chronic reduction significantly decreased cancer numbers (26%). A second experiment evaluated the efficacy of toremifene (7.0 mg/kg diet), an estrogen/anti-estrogen, and the effect of toremifene-matched body weight gain reduction that occurred during the study. Toremifene caused a chronic reduction in body weight that resulted in a 10% decrease in final body weight at the end of the study. While toremifene-treated rats exhibited a 67% decrease in the number of mammary cancers, the rats which similarly exhibited a 10% decrease in final body weight showed only a 14% decrease in cancer number. Thus, the weight effects observed with toremifene, similar estrogens/anti-estrogens, and other classes of chemopreventive compounds (where chronic body weight reductions are 10% or less) imply that the body weight reduction has a limited effect on overall chemopreventive activity. A third study examined the effect of chronic body weight gain reduction on mammary cancers induced in older rats (MNU given at 100 days of age). This model more closely resembles the status of the breast tissue of mature women currently enrolled in clinical trials of chemopreventive agents. Under these conditions chronic reductions in body weight up to 15% had minimal effects on mammary carcinogenesis. These data further demonstrated that acute body weight reductions in young rats at the time of carcinogen treatment can be a concern in interpretation of the chemopreventive activity of an agent, but that moderate chronic depressions of body weight gain probably do not play a significant role.

Adenocarcinoma↗
PubMedDate not supplied

Effect of retinyl acetate and 4-hydroxyphenylretinamide on initiation of chemically-induced mammary tumors.

The anti-promotional effect of retinoids on chemically-induced mammary carcinogenesis in the rat is well established. The present studies were performed to determine the effect of long-term feeding of retinyl acetate and 4-hydroxyphenylretinamide (4-HPR) on initiation of mammary tumors induced by MNU or DMBA. Retinyl acetate (328 mg/kg of diet) or 4-HPR (782 mg/kg of diet) was added to the diet of female Sprague-Dawley rats for two months prior to the administration of the carcinogens. In the MNU model, a 50% increase in the number of mammary adenocarcinomas was observed in rats pretreated with retinyl acetate, while pretreatment with 4-HPR resulted in a 93% increase in the number of cancers. Continued treatment with 4-HPR throughout the study, however, caused a reduction in cancer number. In the DMBA mode, pretreatment with these retinoids significantly increased the number of benign mammary tumors, but not mammary cancers. These data suggest that newly synthesized retinoids should be evaluated for chemopreventive activity against mammary cancer initiation as well as for their anti promotional activity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Suppression by pregnancy of chemically induced preneoplastic cells of the rat mammary gland.

Since a previous study suggested that pregnancy either eliminated preneoplastic cells or increased their latency period in rat mammary glands, additional experiments were performed to determine the fate of these cells. Following administration of the carcinogen dimethylbenzanthracene, few mammary cancers appeared after rats completed pregnancy and lactation. Because these results are similar to those previously obtained with N-methyl-N-nitrosourea (MNU), the effect of pregnancy appears to be independent of the carcinogen used to induce cancer. For rats dosed with MNU, relatively few cancers developed either during an extended observation following pregnancy and lactation or following administration of prolactin, a growth stimulator of mammary cancers. In the latter experiment, the average number of mammary cancers per rat in the prolactin-treated virgin rats was 7.1, while prolactin-treated parous rats had only 0.8 cancers per rat; i.e., 89% fewer cancers. Thus, pregnancy appears to suppress many of the preneoplastic cells induced by carcinogens in the mammary gland of rats.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Short-term hormone treatment as a chemopreventive method against mammary cancer initiation in rats.

Because previous data had suggested that short-term treatment with pharmacological doses of estradiol and progesterone might be an effective means of preventing mammary cancer initiation, additional experiments were performed to confirm this observation and to determine if lower doses of the hormones would also have chemopreventive activity. Rats treated with the steroids for five weeks and administered the carcinogen (methylnitrosourea) three weeks later were observed for one year for the appearance of mammary cancers. Hormone pretreated rats exhibited a reduction in number of mammary cancers of approximately 90% from rats receiving the steroid vehicle. During the extended observation period, treatment with steroids did not induce gross or histological lesions in any tissues. In a separate experiment, decreasing the dose levels from 20 micrograms estradiol plus 4 mg progesterone to 5 mg estradiol plus 2 mg progesterone did not significantly alter the chemopreventive efficacy of the treatment regimen. Differentiation of the mammary gland to a secretory state with hormones apparently alters the epithelial cells so that, even after involution has occurred, the gland maintains its resistance to a carcinogenic insult.

Animals↗
PubMedDate not supplied

Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol.

Indole-3-carbinol, a component of cruciferous vegetables, was evaluated for it efficacy in the prevention of chemically-induced mammary tumors using three different protocols. Because this compound was unstable, it was administered by gavage rather than in the diet. A preliminary dose range study revealed that dose levels of 100 and 50 mg/day, 5x/week, were not toxic to female Sprague-Dawley rats. Initial studies in the DMBA model showed that administering indole-3-carbinol during the initiation and promotion phases were highly effective chemopreventive methods (91-96% reduction in cancer multiplicity). Subsequent studies showed that the administration of indole-3-carbinol only during the initiation phase (7 days prior to until 7 days post DMBA) was also highly effective as a chemopreventive agent. Determination of enzyme levels in the livers of animals treated long-term with indole-3-carbinol showed high levels of induction of various phase I and phase II drug metabolizing enzymes. Finally, indole-3-carbinol when administered both prior to and after MNU (a direct acting carcinogen) caused a significant decrease (65%) in mammary tumor multiplicity. These results support previous studies that indole-3-carbinol can prevent mammary carcinogenesis by direct and indirect acting carcinogens. Therefore, indole-3-carbinol might be a good candidate for chemoprevention of breast cancer in women.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Chemoprevention by indomethacin of N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder tumors.

The effects of indomethacin on the development of N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBn)-induced urinary bladder tumors were evaluated in male BDF mice. Preliminary feeding studies revealed that the highest non-toxic dose of indomethacin was 15 mg/kg of AIN-76A diet; thus, dose levels of 15 and 7.5 mg/kg of diet were selected to determine the chemopreventive efficacy of this agent. Diet supplementation with indomethacin was initiated when the mice were 49 days old and continued for the duration of the study. Starting one week after indomethacin treatment, OH-BBN was administered 1x/week for eight weeks. Upon termination of the study (180 days after the initial carcinogen administration), all tumors in the urinary bladder were removed and classified histologically. Mice receiving carcinogen and no indomethacin supplementation had a 24% incidence of urinary bladder tumors; mice receiving 7.5 mg/kg and 15 mg of indomethacin had a 5% and 0% incidence of urinary bladder tumors, respectively. The significant reduction of OH-BBN-induced urinary bladder tumors by indomethacin is consistent with previous suggestions that prostaglandin synthesis inhibitors are effective inhibitors of carcinogenesis.

Animals↗