Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic administration of the catecholestrogens 2-OH-estrone (2-OH1) and 2-OH-estradiol (2-OHE2), of tamoxifen and its metabolites and of high concentrations of estradiol have been previously shown to inhibit the growth of the estrogen/progesterone receptor-positive transplantable prolactin (PRL)-secreting rat pituitary tumor 7315a. The mechanism of action of these inhibitory effects on tumor growth is unknown. In the present study we investigated the direct effects of these compounds on PRL release by a tumor cell clone derived from the 7315a tumor. E2 stimulated PRL release in FCSABS (10% estrogen-stripped fetal calf serum)-cultured tumor cells in a biphasic manner: at low concentrations (0.1-100 nM) there was a dose-dependent stimulation of PRL release, which decreased in response to 1 microM E2 and which was greatly inhibited by 10 microM E2. Both 2-OHE2 (100 nM and 1 microM) and 2-OHE2 (1 microM) inhibited PRL release by FCS-cultured tumor cells. In FCSABS-cultured tumor cells, 0.1-10 nM 2-OHE1 and 1 microM 2-OHE2 inhibited PRL release, but 1-100 nM 2-OHE2 stimulated PRL release. Tamoxifen (TMX) and its metabolites dihydroxy (di-OH-TMX) and 4-hydroxytamoxifen (4-OH-TMX) inhibited PRL in a dose-dependent manner. The PRL release inhibiting effect of 4-OH-TMX was 100 times more potent that those of TMX and di-OH-TMX, which were similar in their effect. The inhibitory effects of micromolar concentrations of the catecholestrogens on PRL release could be overcome by estradiol, while the inhibitory effects of high concentrations of tamoxifen were not prevented by estradiol. Both "endogenous" (catecholestrogens) and "exogenous" (tamoxifen and its metabolites) antiestrogens and very high concentrations of estradiol directly inhibit PRL secretion by cultured pituitary tumor cells. The mechanism of their anti-tumor effects, however, seems to differ. The catecholestrogens have direct anti-estrogenic effects on cultured tumor cells, which can be antagonized by estradiol. The final effect of their mixed antagonistic/agonistic action depends on the presence or absence of estrogens in the culture medium. Tamoxifen also affects tumor growth probably mainly via a direct effect, partly involving anti-estrogenic and partly direct toxic effects.
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PMID:Differences in the mechanism of the inhibitory actions of catecholestrogens, tamoxifen and high concentrations of estrogens on prolactin release by cultured rat pituitary tumor cells. 282 Jul 46

The athymic nude mouse has been used as an in vivo model for pharmacologic studies of the antiestrogen, tamoxifen. Serum and tumor tamoxifen and metabolite concentrations were examined during and after 100 and 1000 micrograms/day doses injected s.c. Tamoxifen and tamoxifen metabolites were quantitated by high-performance liquid chromatography. Tamoxifen was detected in tumors after a dose of 100 micrograms/day, although serum concentrations were not detected. At a dose of 1000 micrograms/day, tumor tamoxifen and its active metabolites were detected in high concentrations ranging up to greater than 6 mmol/g tissue. Serum tamoxifen metabolites were not detected at either dose. In summary, high doses of tamoxifen were required in the nude mouse to obtain clinically relevant serum concentrations, and significant tumor levels were achieved at doses that resulted in undetectable serum levels. The relationship between serum tamoxifen concentrations, tumor tamoxifen levels, and the biologic activity of the drug requires further study.
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PMID:Tumor and serum tamoxifen concentrations in the athymic nude mouse. 291 May 13

In a rat mammary adenocarcinoma model, prolonged exposure to the antiestrogen Tamoxifen results in a Tamoxifen-tolerant tumor cell line which is readily transplantable and grows under continuous oral intake of the drug. The solid tumor contains steroid receptors; however, the level of Tamoxifen needed for effective displacement of diethylstilbestrol cannot be achieved with therapeutical doses; resistance to Tamoxifen is not the result of diminished or absent estrogen receptors.
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PMID:Tamoxifen tolerance and steroid receptors in a tumor model. 297 47

Tamoxifen binding sites (TBS) were measured using 3H-tamoxifen, the objective being to evaluate the relationships among TBS and hormone receptors and/or clinical and pathological characteristics in malignant tissues from 60 patients with mammary cancer. TBS were detected in most (96.7 per cent) cancers in the breast tissues, and the mean content and affinity were 569 fmol/mg X protein with Kd: 1.98 nM. There was no significant correlation between TBS and the estrogen receptor and/or progesterone receptor, with respect to positivity or content. However, there was a significant correlation between TBS and histological grading, thereby indicating the differentiation and the proliferative activity in this tissue. The content of TBS was significantly higher in the group with a high grade of malignancy. The TBS content significantly increased in parallel with the degree of malignancy, as related to tubule formation, nuclear pleomorphism and mitotic activity. On the other hand, there was no significant correlation between TBS and age, tumor size, lymph node status or clinical stage. These results suggest the possibility that TBS may be associated with differentiation and cell-proliferation in breast cancer tissues.
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PMID:Tamoxifen binding sites in human mammary cancers. 302 94

The modified therapeutic approach to metastatic breast cancer has been influenced by the realization that it cannot be cured even with the most aggressive chemotherapy. Consequently, quality of life and duration of remission have become more important parameters than judging therapeutic success only by rate of remission. The discovery of hormone receptors and of potent drugs with few side effects, which replaced ablative procedures, has led to an increased significance of endocrine therapy. Improved understanding of the endocrine mechanisms regulating malignant growth and their relationship to growth factors and tumor associated proteolysis have concurrently stimulated clinical research. Endocrine manipulation of malignant growth is based on competitive (antihormones), inhibitive (aromatase inhibitors, LHRH agonists), additive (gestagens) and ablative (ovarectomy) mechanisms. The knowledge of the optimal sequence and modality is mandatory for an individualized treatment, leading to significant advantages for the majority of patients. Premature induction of cytotoxic polychemotherapy may even cause disadvantages for subgroups of patients and should only be used as primary therapy in those situations, where urgent remission is mandatory. Only after all endocrine therapies have been tried and evaluated, one should turn to chemotherapy, whereby a trend towards "soft" chemotherapy, often as monotherapy, is favoured. The development of new substances, such as long acting LHRH analogues, "pure" antiestrogens with high receptor affinity, highly potent selective aromatase inhibitors and also the discovery of anti-progestins lead to further improvement of endocrine therapy in relation to efficacy as well as reduction of side effects. Adjuvant endocrine therapy with Tamoxifen correlates positively with the course of the disease and the survival rate in postmenopausal women. Unfortunately no effective adjuvant hormone therapy in premenopausal women exists to date.
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PMID:[Endocrine therapy of breast cancer. Status and perspectives]. 306 56

This study examined the influence of high dietary fat intake on the development of ovarian-independent mammary tumors in both vehicle-treated controls and rats made deficient in estrogen and prolactin during tumor induction. The majority of 7,12-dimethylbenz(a) anthracene (DMBA)-induced mammary tumors in rats are dependent on estrogen and prolactin for growth, and suppression of prolactin and estrogen at the time of tumor initiation causes a reduction in tumor incidence and increase in tumor latency. However, the majority of mammary tumors which do develop in these animals exhibit ovarian-independent growth. Sprague-Dawley rats were given 7.5 mg DMBA p.o. at 57 days of age. Starting 1 day prior to and continuing for 7 days after DMBA administration, rats were given daily injection of vehicle or the combination of tamoxifen (20 micrograms/rat) plus bromocryptine (5 mg/kg). At the end of drug treatment, rats in each treatment group were equally divided and placed on normal fat (5% corn oil) or high fat (20% corn oil) diets for the duration of the experiment. Vehicle-treated rats were ovariectomized 27 wk and drug-treated rats 47 wk after DMBA administration to determine tumor ovarian dependency. Vehicle-treated rats fed high fat diets showed significant increases in mammary tumor incidence and number as compared to similarly treated rats fed a normal fat diet, with approximately 80% of the tumors in each group being ovarian dependent. Likewise, tamoxifen-bromocryptine-treated rats fed a high fat diet showed a significant enhancement in mammary tumor number, although not incidence, as compared to similarly treated rats fed a normal diet. Tumors in these drug-treated groups displayed essentially the same incidence of ovarian dependence (23%). Tamoxifen-bromocryptine-treated groups displayed a 2-fold increase in latency of tumor appearance as compared to vehicle-treated controls; however, this long latency was not reduced when these rats were fed a high fat diet. These results demonstrate that high dietary fat stimulates ovarian-dependent and -independent mammary tumorigenesis in rats but does not influence the hormonal responsiveness of these tumors.
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PMID:Effects of high dietary fat on the growth and development of ovarian-independent carcinogen-induced mammary tumors in rats. 307 69

The effect of combined treatment with D,L-2-difluoromethylornithine (DFMO) and tamoxifen on the growth status, ornithine decarboxylase (ODC) activity and polyamine content of established 1-methyl-1-nitrosourea (MNU)-induced mammary tumors was investigated. DFMO treatment, a 0.125% solution provided as drinking water, inhibited the rate of tumor occurrence and reduced the number of mammary tumors induced by a high dose of MNU (50 mg/kg body weight) during the first 120 days post-carcinogen treatment. Tamoxifen was administered daily via s.c. injection (25 micrograms/100 g body weight) to tumor-bearing rats in both treatment groups, i.e. control and DFMO-treated, for a 30-day period beginning 120 days after carcinogen. Tamoxifen treatment induced tumor regression but the percentage of regressing, static or growing tumors was no different in the presence or absence of DFMO. Whereas the mammary tumors of DFMO-treated rats had reduced ODC activity and lower polyamine concentrations in comparison to the tumors of untreated animals, tamoxifen had no effect on these parameters independent of its effect on tumor growth status. DFMO did not increase the efficacy of tamoxifen in inducing tumor regression.
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PMID:Effect of tamoxifen and D,L-2-difluoromethylornithine on the growth, ornithine decarboxylase activity and polyamine content of mammary carcinomas induced by 1-methyl-1-nitrosourea. 308 21

With the aim of clarifying the nature of the synergistic action of LNT with endocrine therapy for mammary tumor, the effect of LNT post-treatment was investigated in rats with DMBA-induced mammary tumors and also in patients with recurrent breast cancer. LNT injection following surgical therapy (Ax + Ox) resulted in a much greater regression of tumor growth than that obtained by surgery alone, but not after medical therapy (Tamoxifen). Image analysis using an immunohistochemical technique revealed that LNT-surgical therapy resulted in marked atrophy of tumors and as well as intense infiltration of T cells, B cells and macrophages into the stroma around the tumor. Blood prolactin level was greatly reduced by LNT injection. A clinical randomized controlled study demonstrated the efficacy and safety of LNT post-treatment with surgical therapy in 33 patients with recurrent breast cancer. The mode of the synergistic action of LNT in combination with endocrine therapy on hormone-dependent tumors was discussed.
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PMID:[Synergistic action of lentinan (LNT) with endocrine therapy of breast cancer in rats and humans]. 310 9

Transferrin receptors on proliferating and malignant cells are well documented. Faulk et al. demonstrated transferrin receptors in breast carcinoma by immunofluorescence. Malignant cells requiring more iron modulate a transferrin receptor and the iron transporting protein transferrin delivers iron to the cell. We have developed a physiologically active platinum transferrin complex that has been tested on several cell lines in culture, a tumor model in the Fischer rat, and five human patients with advanced breast carcinoma. The complex slowed the rate of growth of feline lymphoma cells to one-half that of controls and killed human HeLa cell cultures in 7 days. Growth of the rat tumor was slightly impaired, but treated rats never got systemic disease and controls died. Two patients had dramatic responses to treatment. One had systemic disease and the other advanced locoregional disease. Both patients were on Tamoxifen, as receptors were positive for estrogen. Disease was progressing in the former with little improvement in the latter. After treatment both had a marked response. We postulate that MPTC-63 may work synergistically with Tamoxifen and be an effective nontoxic antitumor agent. More studies are indicated.
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PMID:Preliminary evaluation of platinum transferrin (MPTC-63) as a potential nontoxic treatment for breast cancer. 318 Jan 41

Physiochemical properties of an estrogen binding protein were characterized in three human melanoma cell lines, UISO-MEL-1, UISO-MEL-2, and UISO-MEL-4. Estrogen binding to melanoma cytosol was saturable, specific for estrogens, and represented by a single class of high-affinity, limited-capacity binding sites (Kd 5.5 x 10(-10) M, 2.7 +/- 0.5 fmol/mg of cytosol protein, UISO-MEL-2; 2.2 x 10(-10) M, 7.8 +/- 3.3, UISO-MEL-4) (SEM). UISO-MEL-1 cytosols did not bind estradiol. The binding protein in UISO-MEL-2 and -4 sedimented at 8.5S and 9.2S, respectively, in the presence of 10 mM sodium molybdate. Solid-phase radioimmunoassay with a monoclonal antibody specific for human estrogen receptor (H222 sp lambda) showed good correlation (r = 0.84) with a hydroxyapatite biochemical assay of identical melanoma cytosols. Exposure of UISO-MEL-2 to estradiol produced a time- and temperature-dependent increase in total nuclear receptor for estrogen in vitro. Estradiol treatment of athymic mice also significantly increased cytosol progesterone receptor content in UISO-MEL-2 and UISO-MEL-4 xenografts. Estradiol had no effect on the plating efficiency or growth of any melanoma cell line or normal melanocytes in vitro. Tamoxifen also had no effect on melanoma growth in vitro. In contrast, chronic exposure of athymic mice carrying estrogen receptor-positive UISO-MEL-2 to estradiol resulted in a sex-dependent increase in tumor latency and overall inhibition of tumor growth. Taken together, these observations suggest that a subset of human melanomas contains limited amounts of an estrogen binding protein similar to that observed in other estrogen-responsive tissues. The lack of effect of estradiol on melanocyte and melanoma growth in vitro, coupled with a decrease in tumor growth in athymic mice, suggests that, while inhibition may be receptor mediated, possible indirect actions of estradiol must also be considered.
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PMID:Effect of 17 beta-estradiol on the growth of estrogen receptor-positive human melanoma in vitro and in athymic mice. 319 86


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