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Biomedical subjects

R G Mehta

Publications and source records attributed to R G Mehta.

At least 55 records · Page 3Linked to original sources
PubMed1989

Chemoprevention of experimental carcinogenesis in animals.

Retinoids are well-established chemopreventive agents for experimental carcinogenesis of many target organs including mammary glands, urinary bladder, lung, skin, liver, pancreas, colon, and esophagus. Modification of the basic retinoid structure has produced analogs with enhanced target organ specificity, increased inhibitory activity, and reduced toxicity. N-(4-hydroxyphenyl)retinamide (4-HPR) currently appears to be the most efficacious retinoid against carcinogen-induced breast, urinary bladder, and lung cancer in rodents. Retinoids are most effective when administered shortly after the carcinogen treatment; however, the treatment can be delayed significantly while maintaining its chemopreventive effect. Under various experimental conditions combining retinoid treatment with other modifiers of growth enhances its chemopreventive activity; for example retinoid plus hormonal modulation can provide better protection against mammary cancer than either treatment alone. More recently chemopreventive activity of various other classes of agents, such as thiols, phenols, antioxidants, inhibitors of prostaglandin synthesis, etc., have been investigated in experimental mammary, urinary bladder, and lung cancer models.

Animals↗
PubMed1989

Therapeutic effect of N-(4-hydroxyphenyl)retinamide on N-methyl-N-nitrosourea-induced rat mammary cancer.

Virgin Sprague--Dawley rats received a single i.v. injection of 40 mg N-methyl-N-nitrosourea (MNU)/kg body wt. at 50 days of age. After the first palpable mammary tumor reached 10 mm in size, the animals were sequentially allocated to one of 4 groups: (I) placebo diet, (II) 10 micrograms tamoxifen s.c. 3 times per week, (III) 3 mmol N-(4-hydroxyphenyl)retinamide (4-HPR)/kg diet, or (IV) both (II) and (III). Weekly measurements of initial tumors and subsequent tumors were made throughout the study. 4-HPR administration resulted in a complete regression (non-palpable state) of the first mammary tumor in 6 animals (22%) and partial regression or nonprogression in 5 others (19%). Tamoxifen alone induced only partial response in 9 animals (33%). 4-HPR and tamoxifen resulted in 19% total and 26% partial response. The data suggests therapeutic value of 4-HPR in MNU-induced rat mammary carcinoma.

Adenocarcinoma↗
PubMed1989

Suppression of rat mammary cancer development by N-(4-hydroxyphenyl)retinamide (4-HPR) following surgical removal of first palpable tumor.

A study was conducted to determine whether N-(4-hydroxyphenyl)retinamide (4-HPR) affects the development of new mammary tumors subsequent to the surgical removal of the first palpable tumor. Sprague-Dawley female rats were injected i.v. with 35 mg N-methyl-N-nitrosourea (MNU) per killogram body weight at 50 days of age. The first palpable tumor was removed when 0.3-0.5 cm in diameter, and the animals placed on diets containing either 1, 2 or 3 mmol 4-HPR/kg diet. Placebo diet without 4-HPR served as control. Some animals were killed at the time of surgical removal of the first tumor and whole mounts of the mammary glands were prepared. Moreover, five animals per group were bled at 1, 3 and 6 months after commencing the 4-HPR diet and the levels of 4-HPR and N-(4-methoxyphenyl)retinamide (4-MPR) were determined. 4-HPR decreased tumor multiplicity in a dose-related manner, but cancer formation was only inhibited at the 2 and 3 mmol levels of 4-HPR. Whole mounts of mammary glands of rats treated with MNU demonstrated the presence of nonpalpable microscopic tumors in addition to the palpable tumor which was excised. Plasma levels of 4-HPR and 4-MPR increased with increasing dietary dose levels, but a linear relationship was not evident. However, the increase in plasma 4-HPR was directly correlated with an increased survival of the tumor-bearing animals. The results indicate that 4-HPR effectively inhibits the appearance of subsequent mammary tumors following excision of the first palpable tumor, and thus may be suitable for use as a chemopreventive agent in patients at increased risk for breast disease.

Administration, Oral↗
PubMed1988

Metabolism of the chemopreventive retinoid N-(4-hydroxyphenyl)retinamide by mammary gland in organ culture.

N-(4-Hydroxyphenyl)retinamide (4-HPR) is considered to be the most effective chemopreventive retinoid for chemically induced mammary carcinogenesis in rats. However, the mechanism of 4-HPR action in mammary cells is poorly understood. In the present study we examined the metabolism of 4-HPR in the mouse mammary gland in organ culture. Mammary glands excised from BALB/c mice were incubated with 4-HPR in the presence of insulin, prolactin and steroid hormones for 6 days. The glands were extracted with chloroform/methanol (2:1, v/v), and the metabolites were separated on a reversed-phase h.p.l.c. column. Three metabolites were separated in addition to 4-HPR; one of the metabolites, M2, was co-eluted with 13-cis-4-HPR, M3 was co-eluted with N-(4-methoxyphenyl)retinamide (4-MPR) and M1 remains unidentified. There appeared to be some hormonal regulation in the distribution of metabolites in the glands. Increased levels of 4-MPR and M1 were observed in insulin-plus-prolactin-treated glands as compared with the glands incubated with steroid hormones. Furthermore, it was observed that M1 isolated from the livers of 4-HPR-treated rats competed for the cellular retinoic acid-binding protein (CRABP) sites; however, 4-HPR did not bind to CRABP. These results indicate that mouse mammary gland can metabolize 4-HPR and that the metabolites which compete for CRABP sites may have physiological significance in the retinoid inhibition of mammary carcinogenesis.

Animals↗
PubMed1986

Anticarcinogenic effects of retinoids in animals.

Retinoids are effective inhibitors of chemical carcinogenesis in the skin, mammary gland, esophagus, respiratory tract, pancreas, and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with enhanced target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Newer retinoidal benzoic acid derivatives are even more active. Combining retinoid treatment with other modulators of carcinogenesis results in a synergistic inhibition of tumor development. Retinoids in combination with hormonal manipulation are much more effective in inhibiting mammary carcinogenesis than is either treatment alone; this combination approach also inhibits mammary tumor recurrence following surgical removal of the first tumor. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment is delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods. The mechanism(s) by which retinoids inhibit carcinogenesis is unknown; however, in the mammary gland, retinoids inhibit differentiation and proliferation, DNA synthesis, and RNA polymerase activity. Cytosolic retinoid-retinoid receptor complexing is apparently a prerequisite for the nuclear interaction of retinoids, at least in mammary cells.

Animals↗
PubMed1986

Cellular retinoic acid-binding protein and its relationship to the biological activity of four synthetic retinoids in hamster tracheal organ culture.

The mechanism of action of retinoid in reversing keratinization in hamster trachea is yet unknown. The purpose of this study was to determine if cellular retinoic acid binding protein (CRABP) is present in tracheal epithelium following incubation in serum-free, vitamin A-deficient culture medium for 10 days, and if the effectiveness of a retinoid in reversing keratinization in organ culture is correlated with its ability to compete for CRABP sites. The cytosol prepared from tracheal cultures contained CRABP at a concentration of 2.61 pmoles per mg protein. Of the four retinoids with carboxyl end group selected for the study, two of the biological active retinoids competed for the CRABP sites. However, no correlation was observed between the biological activity of the inactive retinoids and their ability to associate with the CRABP sites. These results indicate that even though the action of retinoid may be mediated by retinoid binding protein, it cannot be used as a sole predicator of retinoid response in hamster trachea.

Animals↗
PubMed1986

Effects of 12-O-tetradecanoylphorbol-13-acetate on carcinogen-induced mouse mammary lesions in organ culture.

Mammary glands of young female BALB/c mice develop hyperplastic nodule-like alveolar lesions (NLAL) in response to a 24-h exposure to 7,12-dimethylbenz(a)anthracene (DMBA; 2 micrograms/ml) on Day 3 during a 24-day organ culture. Experiments were conducted to determine if 12-O-tetradecanoylphorbol-13-acetate (TPA), a known tumor promoter, can influence the development of DMBA-induced NLAL in mammary gland organ culture. Mammary glands were incubated with TPA (25 ng/ml) for various periods of time in the presence of appropriate hormone combinations. Results indicated that the presence of TPA in the medium between Days 9 to 14 of the culture period enhanced both the incidence and multiplicity of DMBA-induced NLAL; however, it was ineffective when included in the medium between Days 4 to 9 or 19 to 24 of the organ culture. Toxicity of TPA was evident when it was present during the entire culture period subsequent to DMBA treatment. Computer-assisted image analysis of NLAL in the glands determined the area covered by these lesions within the gland. It was observed that 7.8% of the area was covered by NLAL in DMBA plus TPA-treated glands as compared to 2.5% by DMBA treatment alone. These results provide a model for initiation-promotion studies of mammary carcinogenesis in vitro, as well as a modified approach for quantitative analysis of structural alterations.

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

Retinoids and mammary gland differentiation.

Certain retinoids serve as effective chemopreventive agents against breast cancer. The effective retinoids are also antiproliferative agents for the mammary gland both in vivo and in vitro. N-(4-hydroxyphenyl)retinamide (HPR) can inhibit the occurrence of hyperplastic alveolar nodules in C3H mice in vivo and 7,12-dimethylbenz[a]anthracene-induced nodule-like alveolar lesions in vitro. Moreover, HPR can also inhibit the phorbol ester-induced promotion of hyperplastic alveolar nodule development in vitro. HPR is metabolized by the mammary gland in vitro and one of the metabolites competes for the cytosolic retinoic acid-binding protein although the metabolite is not all-trans-retinoic acid.

Animals↗
PubMed1985

Cell kinetics in normal and neoplastic mammary tissues by flow cytometric analyses.

The cell cycle kinetics of normal mammary tissue and cancer mammary tissues were studied by flow cytometry to determine the effect of estrogen and progesterone and antiestrogens on proliferative activity. The proliferative activity was higher in rat mammary tissue during the estrus and pregnant stages compared to the nonestrus or lactational stages. Upon 5 days administration of estrogen and progesterone to the lactating animal, the low proliferative activity was increased to the values found in the pregnant stage. Steroidal effect on proliferative activity was also shown using organ cultures of normal rat tissues and the increase in proliferative activity can be reversed by the addition of 10(-6) M retinoic acid but not by retinyl acetate. In a human mammary tumor cell line (MCF-7), the cell kinetic activity was significantly depressed by antiestrogens (i.e., tamoxifen) as determined by both flow cytometry and tritiated thymidine uptake studies. Finally, a human tumor model system was developed with the MCF-7 cell line in estrogenized nude mice. Flow cytometry of the resulting tumor indicates a tetraploid tumor similar to the cell culture. Cell kinetic analysis of these nude mice tumor cells demonstrates the high proliferative activity of the estrogenized animals compared to the tamoxifen-treated animals. In conclusion, the use of flow cytometry to rapidly measure cell kinetic activity of mammary tissue has been demonstrated. The effects of estrogen or estrogen and progesterone hormones seem to increase the proliferative activity, while antiestrogens decrease this activity. Findings are observed in both in vivo and in vitro conditions or normal tissues, mammary cancer tissue, and cultured cells.

Animals↗
PubMed1985

Role of hormones on the induction of retinoic acid binding protein in mouse mammary gland organ culture.

Influence of various hormones on the induction of cellular retinoic acid binding protein (CRABP) was investigated in the mouse mammary gland organ cultures. Thoracic pairs of mammary glands from the BALB/c mice were cultured for seven days in the presence of various hormones in CMRL medium at 37 degrees C under 50% O2, 5% CO2 and 45% N2 atmosphere. There was a modest increase of mammary CRABP by insulin (I) + prolactin (P), however, addition of progesterone (Pg) or estrogen (E) + Pg to the medium resulted in a dramatic increase in the CRABP. Aldosterone (A) + hydrocortisone (F), in addition to I + P, which promotes differentiation to an extent similar to that of I + P + E + Pg did not have any influence on the induction of CRABP. These results indicate that prolactin and/or Pg in the medium can increase the concentration of CRABP in the mammary gland in vitro. From the results presented in this report, as well as previous work by other investigators, it is concluded that the biological response to retinoids in the mammary tissues cannot be correlated with the absolute concentration of CRABP in the cells. However, the biological response may be dependent upon both the ability of the target organ cells to metabolize the retinoid and to have minimal concentration of CRABP for binding to the active metabolite. The functional significance of hormone-induced CRABP is presently unknown.

Aldosterone↗
PubMed1984

Retinoic-acid-binding protein in normal and neoplastic human esophagus.

The concentration of cellular retinoic acid binding proteins (CRABP) was determined in the cytosol of normal esophageal tissue and in esophageal carcinomas. Unlike the reported results for human breast, colon, melanoma, or oropharynx cancers, the CRABP levels in esophageal cancers were either undetectable or contained levels of CRABP which were significantly lower than that of adjacent histologically disease-free tissue (P less than 0.005). Moreover, there was no difference between the normal mucosa of cancer or noncancer patients with regards to the CRABP concentration. The absence of CRABP in the cancer tissue was not dependent on the degree of differentiation. These results indicate that the CRABP disappears when the normal mucosa becomes malignant. If such a change is also demonstrated in known premalignant conditions of the esophagus, CRABP could serve as a diagnostic biochemical marker for early detection of this cancer.

Adenocarcinoma↗
PubMed1984

Distribution of antiestrogen-specific binding sites in normal and neoplastic mammary gland.

Recently, several investigators have demonstrated the presence of triphenylethylene antiestrogen binding sites in the cytoplasm of many tissues, which specifically bind to radioactive tamoxifen with high affinity. Although mammary gland is one of the principal target organs for antiestrogen action, the characterization of antiestrogen binding in mammary tissues has not been reported. We have studied the antiestrogen binding properties of [3H]tamoxifen in the mammary glands of virgin, pregnant and lactating rats as well as in the N-methyl-N-nitrosourea-induced mammary tumors. Tritium labeled tamoxifen bound specifically and with high affinity (Kd = 10(-9) M) to components present in 25,000 g supernatant. Unlabeled estradiol or DES did not compete for these sites, whereas unlabeled tamoxifen showed competitive inhibition. The mammary glands contained threefold higher levels of cytoplasmic binding sites as compared to the mammary tumors. Mammary glands from the pregnant rats bound tamoxifen to a greater extent than that of either virgin or lactating rats. The functional relevance of these binding sites is still unknown.

Adenocarcinoma↗
PubMed1983

Retinoids inhibit prolactin-induced development of the mammary gland in vitro.

Mouse mammary gland organ culture technique was utilized to determine the effects of retinoids on the prolactin-induced structural differentiation of the mammary gland. Thoracic glands from BALB/c mice pretreated with steroids differentiate in 6 days into alveolar structures in presence of insulin and prolactin. All-trans-retinoic acid and N-(-4-hydroxyphenyl)retinamide inhibit prolactin-induced structural changes in the glands. Retinyl acetate, which is effective against mammary carcinogenesis in the rat, but is ineffective against mouse mammary carcinogenesis, failed to inhibit such proliferation. These results were correlated with inhibition of [3H]thymidine incorporation into DNA in a dose related manner by retinoids effective in inhibiting mammary development.

Animals↗
PubMed1983

Inhibition of carcinogenesis by retinoids.

Retinoids are effective inhibitors of chemical carcinogenesis in the mammary gland and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with increased target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Combining retinoid treatment with hormonal manipulation results in a synergistic inhibition of mammary carcinogenesis; this combination approach also inhibits development of additional mammary cancers following surgical removal of the first mammary cancer. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment is delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The length of time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods.

Adenocarcinoma↗
PubMed1982

Nuclear interactions of retinoic acid-binding protein in chemically induced mammary adenocarcinoma.

Cellular retinoic acid-binding protein (CRABP) was detected in the nuclear fraction of N-methyl-N-nitrosourea-induced mammary cancers after the incubation of cytosol containing [3H]retinoic acid (RA)-bound CRABP with isolated nuclei. CRABP extracted from the nuclei in buffer containing 0.4 M-KCl sedimented as a 2 S component when subjected to sucrose-density-gradient analysis. [3H]RA-CRABP was found to be a prerequisite for the detection of nuclear binding, since the incubation of isolated nuclei or 0.4 M-KCl extract of the nuclei with [3H]RA did not result in any significant binding. Incubation of [3H]RA-CRABP at 25 or 30 degrees C before incubation with the nuclei neither altered the sedimentation coefficient nor enhanced the nuclear binding compared with 0 degrees C incubation. The tumour nuclei contained a saturable number of binding sites with a dissociation constant of 1.6 x 10(-9) M. These results indicate that the action of retinoic acid in the target organ may be mediated by its interaction with the nuclei.

Adenocarcinoma↗
PubMed1982

Temporal association between arterial cholesterol deposition, thymidine incorporation into DNA, and atherosclerosis in Japanese quail fed an atherogenic diet.

Male Japanese quail (strain SEA) rapidly develop atherosclerotic lesions in the aorta and brachiocephalic arteries when fed an atherogenic diet containing 1.0% cholesterol and 0.5% cholic acid. The present study was conducted to determine the parameters of the atherosclerotic response. Groups of 20 quail fed the atherogenic diet were killed at 0 days, 1 day, 3 days, or weekly from 1 to 12 weeks. Quail fed the atherogenic diet for 1 day showed a significant increase in serum cholesterol; a plateau was reached by 2 weeks. A significant increase in arterial cholesterol was seen after 2 weeks on the atherogenic diet, and arterial cholesterol showed a linear increase with time from 2 to 12 weeks. Increased incorporation of tritiated thymidine into the DNA of arterial cells was first seen at 2 weeks; thymidine incorporation increased to a maximum value at 9 weeks, then declined to 50-60% of the 9-week value at weeks 11 and 12. Grossly visible atherosclerotic lesions were first seen at 3 weeks, and 90% of birds showed gross atherosclerotic lesions by 8 weeks. Atherosclerosis induced in Japanese quail by feeding cholesterol and cholic acid is characterized initially by lipid deposition in the arterial wall, followed by increased incorporation of tritiated thymidine and the appearance of gross lesions.

Animals↗