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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of action of tamoxifen and of 4-hydroxytamoxifen is reviewed at the cellular and molecular level, through the current view of the authors. Synthetic antiestrogens are mainly acting directly on breast cancer cells by interacting with the estrogen receptor (RE). They prevent estrogen action by competing with estrogens on the cytosol RE. The resulting complex is partially activated, leading to its nuclear localisation and a partial and dissociated stimulation of the expression of estrogen responsive genes. A defective and partial activation of RE induced by antiestrogen is shown in vitro by several alterations of the RE concerning the dissociation rate of ligands and the affinity for double-stranded DNA and for a monoclonal antibody against the RE. The explanation of the inhibition of tumor growth is more controversial, since the proliferation of estrogen responsive cells is not only regulated by estrogens but also by other hormones and factors. We present evidence of a direct effect of antiestrogen mediated by the RE, and discuss the mechanism of resistance to antiestrogen in RE positive breast cancer cells.
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PMID:Cellular and molecular mechanism of action of antiestrogens. 688 74

Antiestrogens (Tamoxifen) are used for the treatment of breast cancer. However these compounds are also weak estrogens that may stimulate tumor growth. Cytotoxic-linked estrogens (Estradiol Mustard, Estracyt) are devoid of major therapeutic activity. This led to search for new antiestrogens devoid of estrogenicity and for active cytotoxic-estrogens. Hydroxylation of C-4 of triphenylethylene antiestrogens (tamoxifen, CI 628 and U 23,469) largely increases their binding affinity for the estrogen receptor (ER). Hydroxylation also increases the in vitro antitumor activity of the drugs as shown by their higher ability to inhibit the growth of the ER-positive cell line MCF-7. Triphenylethylene antiestrogens contain an aminoethoxy side chain which appears essential for their physiological activity. Removal of the chain of tamoxifen suppresses its antiestrogenicity and antitumor activity. The grafting of side chains on a weak estrogen of the gem-diphenylethylene category produces "symmetrical" antiestrogens devoid of estrogenic activity. This observation raises the question of the role played by the third phenyl ring of the triphenylethylenes since the trans-isomers of the latter display antiestrogenicity and the cis-isomers estrogenicity. Comparison of the binding affinity for ER and antitumor activity of di- and triphenylethylene antiestrogens suggests that this third phenyl ring increases the interaction with ER of the 4-phenolic group of the drugs and/or their aminoethoxy side chain. An analogue of this chain is without any biological activity suggesting that the di-(tri)pheny-lalkene structure is required for promoting the interaction of the chain with ER. New chemical structures yielding antiestrogens with antitumor activity are also reviewed. New cytotoxic estrogens designed for producing lethal damage of DNA show a low binding affinity for ER. Moreover, there is no evidence suggesting specific antitumor activity. Such activity may be more easily obtained with estrogens bearing reagents for proteins rather than DNA. The biological properties of a 2-mesylate derivative of estrone irreversibly interacting with ER supports the concept. On MCF-7 cells, the drug displays a strong antitumor activity which can only be suppressed by high, equimolar, concentrations of estradiol. It is devoid of cytotoxic activity on the ER-negative cell line Evsa-T suggesting that ER is involved in its action.
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PMID:Guide-lines in the design of new antiestrogens and cytotoxic-linked estrogens for the treatment of breast cancer. 688 75

To understand how estradiol-17 beta (E2) influences MtTW15 rat pituitary tumor function, we have evaluated the cytosolic E2 binding properties of tumors derived from control and steroid treated host animals. Specific E2 binding (approximately 3 pmoles/g tumor) was observed in all groups and was steroid responsive. The E2 binding macromolecule migrated to 7S following sucrose density gradient sedimentation and was specific for estrogenic steroids. Saturation analysis of E2 binding revealed a high affinity interaction (Kd = 5.5 +/- 0.5 x 10(-10) M). Furthermore, E2 binding was temperature-sensitive and degraded by trypsin. Thus, the MtTW15 tumor contains an estrogen receptor. Accordingly, the effects of 4 antiestrogenic drugs on tumor estrogen-receptor levels, tumor growth and hormone production were evaluated. In general, these drugs reduced cytosolic estrogen receptor levels, promoted tumor growth and increased tumor growth-hormone production. It is suggested that these compounds can exert both estrogen agonist and antagonist properties in MtTW15 tumors.
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PMID:Estrogen receptor-like macromolecule in MtTW15 rat pituitary tumors: effects of antiestrogens. 728 85

The functionality of the estrogen receptor as determined by the effect of estrogen on progesterone receptor levels and the effect of tamoxifen on tumor growth has been examined in the R3327 Dunning rat prostate adenocarcinoma. The progesterone receptor was absent in 78% of prostate tumors grown in male Copenhagen X Fischer F1 rats but was induced in tumors taken from rats given injections of 25 microgram estradiol benzoate per kg for 10 days. This result suggested that the tumor might be sensitive to the antiestrogen tamoxifen, and it was subsequently shown that treatment of rats with tamoxifen (0.5 mg/kg) 5 times/week for 2 to 7 months resulted in marked suppression of tumor growth in 91% of the tumors examined. In vitro binding analysis demonstrated that tamoxifen competed for the estrogen receptor in the tumor but not for the androgen receptor. These data suggest that tamoxifen might be acting directly on the tumor, although an indirect effect cannot be ruled out, since plasma testosterone levels were reduced as a result of tamoxifen treatment. Regulation of androgen and estrogen receptors was also observed in this tumor system. Thus, administration of estradiol benzoate for 10 days resulted in increased levels of androgen receptor with no change in estrogen receptor. Long-term tamoxifen treatment had a similar effect. Short-term castration, which appeared to induce the progesterone receptor, also resulted in increased levels of both androgen and estrogen receptors. This latter observation suggests that tamoxifen might be even more effective in castrated rats.
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PMID:Functionality of estrogen receptor and tamoxifen treatment of R3327 Dunning rat prostate adenocarcinoma. 738 87

The effect of the antiestrogen tamoxifen on growth of the transplantable autonomous mammary tumor MTW-9B was compared with its effects on progesterone and estrogen receptor levels. Growth of the tumor was similar in intact rats, ovariectomized rats, or ovariectomized rats given estradiol, in both the presence and the absence of tamoxifen. Progesterone receptor levels, however, were reduced by ovariectomy and restored by estrogen administration. Tamoxifen antagonized this effect of estrogen, although when administered by itself to ovariectomized rats it acted as an agonist, since progesterone receptor levels were induced. Cytosol estrogen receptor was depleted by tamoxifen in both intact and ovariectomized rats. In uterus from the same animals, tamoxifen also showed both antagonist and agonist properties, although here too there was an apparent dissociation between effects on growth and progesterone receptor levels. We conclude from these experiments that: (a) the estrogen receptor complex may be acting at more than one site on the genome; and (b) regulation of progesterone receptor levels by estrogen (or tamoxifen) does not necessarily predict sensitivity of tumor growth to antiestrogens.
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PMID:Dichotomous effects of tamoxifen on a transplantable rat mammary tumor. 745 86

Angiogenesis is essential for tumor growth and metastases. Studies in breast carcinomas suggest that microvessel quantitation as a measure of angiogenesis might be one of the most powerful prognostic tools available. Node negative breast cancer is a particular group for which better prognostic markers would be helpful. We therefore measured microvessel density in a series of well characterised node negative breast carcinomas to evaluate angiogenesis as a prognostic marker and assess its relationship to epidermal growth factor receptor (EGFR) and estrogen receptor (ER), which have previously been reported to be of value. 109 patients with a mean age of 55 years and a median follow-up of 25 months were examined. Vessels were immunohistochemically highlighted using an antibody to platelet endothelial cell adhesion molecule CD31, and microvessel density was quantified using a Chalkley point eyepiece graticule. No significant correlation was observed with patient age, tumor size, grade, ER, or EGFR expression. In a univariate analysis of survival, whereas ER expression was not a significant indicator of either relapse-free (RFS) or overall survival (OS), vascular count (VC) predicted both early RFS and OS (p = 0.01) and p = 0.028 respectively). Furthermore, in patients with ER positive tumors, a subgroup usually considered to have a good prognosis, there was a significant reduction in RFS and OS if tumors had high VCs (p = 0.05 and p = 0.002 respectively). A further statistically significant reduction in RFS (p = 0.05) was observed for EGFR positive highly vascular tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor angiogenesis in node-negative breast carcinomas--relationship with epidermal growth factor receptor, estrogen receptor, and survival. 751 21

A regulatory role for estrogen in the growth of salivary gland tumors has been hypothesized. In the current study we attempted to establish whether or not benign and malignant parotid tumor cells express estrogen receptors. Immunohistochemical studies were performed with samples of tissue from 72 patients with benign tumors and 26 patients with malignant tumors originating in the parotid gland. Replicate tissue sections were stained with two sets of reagents specific for the receptors. There was no immunohistochemical evidence for the presence of estrogen receptors in any specimen examined. In contrast, cells in tissue sections from a breast cancer control were consistently positive for estrogen receptor using the same techniques. These observations show that the estrogen receptor concentration in parotid tumors is below the level required for visualization by immunohistochemical techniques. Thus, it is unlikely that this receptor plays a major role in regulating parotid tumor growth.
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PMID:Estrogen receptors in parotid tumors. 758 32

The effect of obesity and fat distribution on survival of breast cancer patients was studied prospectively in 241 women with a natural menopause who participated in a breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Mean follow-up time was 9.1 years and endpoint of interest was death from breast cancer. Fat distribution was assessed by contrasting groups of subscapular and triceps skinfold thickness. No significant differences in survival time between more obese (Quetelet's index > or = 26 kg/m2) and leaner (Quetelet's index < 26 kg/m2) patients or between patients with central fat distribution and patients with peripheral fat distribution were observed. Analyses were stratified by axillary node status, estrogen receptor status, and way of detection (by first screening or afterwards). Results of the stratified analyses were suggestive of a modifying effect of these factors. The absence of an association between obesity and survival time might be explained by two counteracting mechanisms. On the one hand obesity might be related to impaired survival, due to a tumor growth promoting effect of extra-ovarian estrogens. On the other hand obesity might be related to improved survival in a screened population, because obese patients profit more from screening by earlier detection of tumors than leaner counterparts.
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PMID:Obesity and subcutaneous fat patterning in relation to survival of postmenopausal breast cancer patients participating in the DOM-project. 764 30

Estrogen withdrawal versus tamoxifen (TAM) treatment was compared in two human breast cancer xenografts, the estrogen-dependent ZR75-1 and its estrogen-independent subline ZR75/LCC-3. The following parameters were determined: tumor growth, NTP:P(i) by 31P magnetic resonance spectroscopy, apoptotic index, and creatine kinase (CK) activity. Tumors of each line were grown in ovariectomized nude mice during stimulation from a s.c. 17 beta-estradiol pellet. At a tumor size of approximately 350 mm3, the pellet was removed from one-half of the animals. The remaining one-half served as controls. In parallel experiments, injections of TAM were initiated instead of estrogen withdrawal. Estrogen withdrawal as well as TAM induced growth inhibition of ZR75-1 tumors, whereas ZR75/LCC-3 was resistant to both types of therapy. Growth inhibition of ZR75-1 by estrogen withdrawal, but not by TAM, was accompanied by an 80% increase of the NTP:P(i) ratio (P < 0.01) and a significantly decreased cytosolic CK activity (P < 0.01). No significant change in pH was observed. These changes seemed not to be related to changes in apoptotic index. None of the described changes occurred in ZR75/LCC-3. The present data indicate: (a) ZR75-1 and ZR75/LCC-3 xenografts respond differently to estrogen withdrawal and TAM with regard to growth inhibition, 31P magnetic resonance spectroscopy, and CK activity; (b) estrogen withdrawal, but not TAM, induced a decrease in the CK activity of estrogen-dependent tumor tissue, and (c) increased apoptosis did not explain the growth inhibition and the increase in NTP:P(i) induced by estrogen withdrawal. The results indicate other growth inhibitory mechanisms of TAM in addition to competitive inhibition of the estrogen receptor.
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PMID:Growth inhibition in response to estrogen withdrawal and tamoxifen therapy of human breast cancer xenografts evaluated by in vivo 31P magnetic resonance spectroscopy, creatine kinase activity, and apoptotic index. 766 92

Quantitative imbalance in chromosomal material relative to the normal diploid situation is the most conspicuous genetic change in breast tumors, affecting virtually all chromosomes in varying frequencies. This imbalance is reflected by deviant DNA stemlines observed in DNA flow cytometry analysis, by numerical chromosome abnormalities in karyotype analysis and by loss of heterozygosity in DNA polymorphism studies. Gene amplification might be caused by the same genetic mechanisms that cause these chromosomal abnormalities [134]. The number of known genes for which there is now good evidence for their role in the development of breast cancer is still limited, and basically restricted to TP53 and ERBB2. Clearly, the estrogen receptor, not discussed here, can be conjectured to be of importance in breast cancer development, yet the significance of the reported sequence variants [157] for hormone-independent growth is presently undetermined [158]. For many others, such as MYC, CCND1, EMS1, EGF, RB1, NME, DCC and prohibitin, the evidence is still largely circumstantial, or obtained only by in vitro studies on breast cancer cell lines. In many cases of chromosomal imbalance and certainly those affecting whole chromosomes or chromosome arms, it is unclear what their effect on tumor growth will be, because multiple potential candidate genes are located in the affected region. In addition, it is obvious that multiple chromosomes are affected simultaneously in a single tumor, but that the total set of chromosome changes varies in different tumors. This intra- and intertumor heterogeneity of chromosome involvement suggests that an unknown number of the observed abnormalities are not important for tumor development, but merely result from genetic instability. On the other hand, there is accumulating evidence, particularly from flow cytometry and allelotype studies reviewed here, to suggest that the genetic evolution associated with tumor development and progression does reach a stage of equilibrium despite the presence of extensive tumor heterogeneity. The number of genetic events found per tumor raises the question whether each event of heterozygosity loss represents the second step in the inactivation of a tumor suppressor gene. Also, LOH observed with polymorphic markers can sometimes be interpreted as allelic copy number gain instead of loss. Possibly, some of these allelic imbalances contribute to the tumorigenic process simply because they create a dosage effect in certain gene products [2]. This supposes that the sole presence of allelic imbalance at certain chromosomes is sufficient to provide selective growth advantage in certain cases.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Somatic genetic changes in human breast cancer. 781 70


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