Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Methoxyestradiol, once considered an inacitve end-metabolite of estradiol, has recently emerged as a very promising agent for cancer treatment. It is orally active in a wide range of tumor models, and inhibits tumor growth at doses showing no clinical signs of toxicity. 2ME2 targets both the tumor cell and endothelial cell compartments by inducing apoptosis in rapidly proliferating cells and inhibiting blood vessel formation at several stages in the angiogenic cascade. Moreover, the ability of 2ME2 to inhibit metastatic spread in several models adds to its therapeutic value for cancer treatment at various stages of the disease. Though the mechanism of action is still undefined, several potential molecular targets and pathways of activation have been suggested.
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PMID:2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate. 1119 Oct 57

2-Methoxyestradiol (2-ME) is a physiological metabolite of estrogen, which is excreted with the urine. In contrast to most estrogens, tumor growth-inhibiting effects were observed. Further studies have revealed that it may be an effective anticancer compound for many tumor types. Several different mechanisms have been attributed to 2-ME. Besides a strong antiangiogenic effect on endothelial cells and tumors, there is a tubulin-inhibiting mechanism, causing cells to arrest in the G2/ M phase of the cell cycle. In other tumors, p53-dependent and p53-independent mechanisms with induction of apoptosis have been shown. The number of different tumors examined for a growth-inhibiting effect is increasing, and new mechanisms are continuously described. In vivo studies in mice, rats, and dogs show no or very little toxicity, even at high doses. Here, we discuss the antitumor activity and their mechanisms. 2-ME appears to be a new anti-tumor compound with strong potential for clinical application.
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PMID:The physiological estrogen metabolite 2-methoxyestradiol reduces tumor growth and induces apoptosis in human solid tumors. 1146 76

2-Methoxyestradiol (2ME(2)) is an endogenous metabolite of 17beta-estradiol (E(2)) that arises from the hydroxylation and subsequent methylation at the 2-position. In vitro 2ME(2) inhibits a large variety of tumor and nontumor cell lines from diverse origins, as well as several stages of the angiogenic cascade. In vivo it has been shown to be a very effective inhibitor of tumor growth and angiogenesis in numerous models. Although various molecular targets have been proposed for this compound, the mechanism of action is still uncertain. As this molecule emerges as a drug candidate it is important to assess the estrogen receptors (ERs) as molecular targets for 2ME(2). The purpose of this study was to investigate whether 2ME(2) is able to engage ERs as an agonist and whether its antiproliferative activities are mediated through ERs. We confirm that 2ME(2) has a lower binding affinity for ERalpha as compared with E(2) and other E(2) metabolites and antagonists, and we demonstrate that the affinity of 2ME(2) for ERbeta is even lower. When assessed in the presence of galangin, a cytochrome P450 enzyme inhibitor, at concentrations at which 2ME(2) interacts with ERalpha in an in vitro binding assay, it does not stimulate the proliferation of an estrogen-dependent breast carcinoma cell line. Similar IC(50) values for inhibition of proliferation and induction of apoptosis are obtained in estrogen-dependent and estrogen-independent human breast cancer cell lines, irrespective of the expression of ERalpha and ERbeta. Moreover, the estrogen antagonist ICI 182,780 does not inhibit the antiproliferative activity of 2ME(2). In E(2)-responsive cells such as MCF-7 and human umbilical vascular endothelial cells, high levels of E(2) inhibit the antiproliferative activity of ICI 182,780 but not of 2ME(2). Collectively, these results suggest that 2ME(2) is distinct among estradiol metabolites because of its inability to engage ERs as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of ERalpha and ERbeta.
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PMID:2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta. 1209 76

2-Methoxyestradiol (2ME2), a natural metabolite of estradiol, is a potent antitumor and antiangiogenic agent. In vitro, 2ME2 inhibits the proliferation of a wide variety of cell lines and primary cultures, and in numerous models in vivo, it has been shown to be an effective inhibitor of tumor growth and angiogenesis. 2ME2 is currently in several Phase I and Phase II clinical trials under the name Panzem. Although various molecular targets have been proposed for this compound, the mechanism by which 2ME2 exerts its effects is still uncertain. This study shows that 2ME2 uses the extrinsic pathway for induction of apoptosis. 2ME2 treatment results in up-regulation of death receptor 5 (DR5) protein expression in vitro and in vivo and renders cells more sensitive to the cytotoxic activities of the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). 2ME2-induced apoptosis requires caspase activation and kinetic studies show the sequential activation of caspase-8, caspase-9, and caspase-3. Blockage of death receptor signaling by expression of dominant-negative Fas-associated death domain severely attenuates the ability of 2ME2 to induce apoptosis. Because 2ME2 administration has not manifested dose-limiting toxicity in the clinic, DR5 expression may serve as a surrogate marker for biological response.
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PMID:2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway. 1254 4

Estrogens occurring naturally in the body are metabolized to catecholestrogens (2- and 4-hydroxyestradiol) by the cytochrome P450 enzymes. 2-Hydroxy catecholestrogens are further metabolized by catechol-O-methyltransferase to 2-methoxyestradiol, which is known to be protective against tumor formation. 2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine-binding site, have been reported. The exact mechanism of action of 2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor alpha compared with that of estradiol, and its affinity for estrogen receptor beta is even lower than that of estrogen receptor alpha, thus it has minimal estrogenic activity. 2-Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors alpha and beta. A phase I clinical trial of 2-methoxyestradiol 200, 400, 600, 800, and 1,000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2-methoxyestradiol 200-1,000 mg/day in combination with docetaxel 35 mg/m2/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug-related adverse effects. A phase II randomized, double-blind trial of 2-methoxyestradiol 400 and 1,200 mg/day in 33 patients with hormone-refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1,000 mg/day.
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PMID:2-Methoxyestradiol, a promising anticancer agent. 1258 5

2-Methoxyestradiol (2ME(2)), a metabolite of 17-beta-estradiol, inhibits angiogenesis and has additional antitumor activities. We have analyzed the tumor stage-specific effects of 2ME(2) in the C3(1)/Tag transgenic mouse model for breast cancer, which spontaneously develops estrogen receptor-negative mammary tumors following a predictable progression of lesion formation. When given either as a therapeutic agent in established tumors (late intervention study) or in mice with pre-invasive mammary lesions (early intervention study), tumor growth was reduced by 60% compared with untreated controls and was associated with an induction of apoptosis. In a prevention study, a significant reduction in mammary intraepithelial neoplasia (MIN) lesions was observed in animals beginning treatment at 6 weeks of age, before the appearance of histopathologic abnormalities. However, although 2ME(2) reduced the number of MIN lesions in the prevention study, a paradoxical increase in tumor multiplicity and growth rate was observed. This was associated with unusual cystic tumor formation, in which significant central necrosis was observed, surrounded by an outer region of proliferative tumor cell growth. The characteristics of the cystic tumor formation in mice treated with 2ME(2) at early ages are consistent with an impaired angiogenic response as observed in mice deficient for inhibitor of differentiation (Id-1). We further show that Id-1 expression is negatively regulated by 2ME(2), which may be an additional mechanism for the antiangiogenic effect of 2ME(2). Although 2ME(2) significantly reduced tumor growth at late stages, these results also suggest that altered tumor morphology and accelerated tumor growth may occur if 2ME(2) is administered in a prevention setting for prolonged periods.
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PMID:Distinct tumor stage-specific inhibitory effects of 2-methoxyestradiol in a breast cancer mouse model associated with Id-1 expression. 1658 73

2-Methoxyestradiol is a physiologic metabolite of 17beta-estradiol. This orally active compound can inhibit tumor growth or metastasis in tumor models without inducing any clinical sign of toxicity. Our previous studies indicated that 2-methoxyestradiol-mediated apoptosis involves the disappearance of intact 21-kDa Bid protein, cytochrome c release, and predominant procaspase-3 cleavage. Here, using MIA PaCa-2 cells as a model, we investigated whether this estrogen metabolite induces apoptosis by converging two major pathways: the death receptor-mediated extrinsic and the mitochondrial intrinsic pathway. Exogenous expression of dominant-negative caspase-8 or dominant-negative FADD reverts the effect of 2-methoxyestradiol-mediated cell death. In parallel with this observation, Z-IETD-FMK, a cell permeable irreversible inhibitor of caspase-8, can render significant protection against 2-methoxyestradiol-induced apoptosis. RNase protection assay and cell surface receptor analysis by flow cytometry show the up-regulation of members of death receptor family in 2-methoxyestradiol-exposed pancreatic cancer cells. Our mechanistic studies also implicate that oxidative stress precedes 2-methoxyestradiol-mediated c-Jun NH2-terminal kinase activation, leading to elevated Fas level. Because 2-methoxyestradiol is able to trigger death receptor signaling, we were interested in examining the effects of 2-methoxyestradiol and Fas ligand (FasL)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) together on pancreatic cancer cell death. Interestingly, the endogenous angiogenesis inhibitor 2-methoxyestradiol augments FasL/TRAIL-induced apoptosis in these cells. Moreover, the combination of 2-methoxyestradiol and TRAIL reduces the tumor burden in vivo in MIA PaCa-2 tumor xenograft model by caspase-3 activation.
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PMID:Crosstalk between extrinsic and intrinsic cell death pathways in pancreatic cancer: synergistic action of estrogen metabolite and ligands of death receptor family. 1661 56

2-Methoxyestradiol (2ME2) is an endogenous estradiol metabolite that inhibits microtubule polymerization, tumor growth, and angiogenesis. Because prostate cancer is often treated with radiotherapy, and 2ME2 has shown efficacy as a single agent against human prostate carcinoma, we evaluated 2ME2 as a potential radiosensitizer in prostate cancer models. A dose-dependent decrease in mitogen-activated protein kinase phosphorylation was observed in human PC3 prostate cancer cells treated with 2ME2 for 18 h. This decrease correlated with in vitro radiosensitization measured by clonogenic assays, and these effects were blocked by the expression of constitutively active MEK. Male nude mice with subcutaneous PC3 xenografts in the hind leg were treated with 2ME2 (75 mg/kg) p.o. for 5 days, and 2 Gy radiation fractions were delivered each day at 4 h after drug treatment. A statistically significant super-additive effect between radiation and 2ME2 was observed in this subcutaneous model, using analysis of within-animal slopes. A PC-3M orthotopic model was also used, with bioluminescence imaging as an end point. PC-3M cells stably expressing the luciferase gene were surgically implanted into the prostates of male nude mice. Mice were given oral doses of 2ME2 (75 mg/kg), with radiation fractions (3 Gy) delivered 4 h later. Mice were then imaged weekly for 4 to 5 weeks with a Xenogen system. A significant super-additive effect was also observed in the orthotopic model. These data show that 2ME2 is an effective radiosensitizing agent against human prostate cancer xenografts, and that the mechanism may involve a decrease in mitogen-activated protein kinase phosphorylation by 2ME2.
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PMID:Radiosensitization and modulation of p44/42 mitogen-activated protein kinase by 2-Methoxyestradiol in prostate cancer models. 1780 47

2-Methoxyestradiol (2ME(2)), a physiologic metabolite of 17beta-estradiol (estrogen), has emerged as a promising cancer therapy because of its potent growth-inhibitory and proapoptotic effects on both endothelial and tumor cells. 2ME(2) also suppresses osteoclast differentiation and induces apoptosis of mature osteoclasts, and has been shown to effectively repress bone loss in an animal model of postmenopausal osteoporosis. Given these observations, we have examined whether 2ME(2) could effectively target metastasis to bone, osteolytic tumors, and soft tissue tumors. A 4T1 murine metastatic breast cancer cell line was generated that stably expressed Far Red fluorescence protein (4T1/Red) to visualize tumor development and metastasis to bone. In an intervention study, 4T1/Red cells were injected into bone marrow of the left femur and the mammary pad. In the latter study, 2ME(2) (10, 25, and 50 mg/kg/d) treatment began on the same day as surgery and was continued for the 16-day duration of study. Tumor cell growth and metastasis to bone were monitored and bone volume was determined by micro-computed tomography. 2ME(2) inhibited tumor growth in soft tissue, metastasis to bone, osteolysis, and tumor growth in bone, with maximum effects at 50 mg/kg/d. Furthermore, tumor-induced osteolysis was significantly reduced in mice receiving 2ME(2). In vitro, 2ME(2) repressed osteoclast number by inducing apoptosis of osteoclast precursors as well as mature osteoclasts. Our data support the conclusion that 2ME(2) could be an important new therapy in the arsenal to fight metastatic breast cancer.
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PMID:2-Methoxyestradiol suppresses osteolytic breast cancer tumor progression in vivo. 1797 50

C2- and C4-position 17beta-estradiol metabolites play an important role in breast carcinogenesis. 2-Hydroxyestradiol and 4-hydroxyestradiol are implicated in tumorigenesis via two pathways. These pathways entail increased cell proliferation and the formation of reactive oxygen species that trigger an increase in the likelihood of deoxyribonucleic acid mutations. 2-Methoxyestradiol, a 17beta-estradiol metabolite, however, causes induction of apoptosis in transformed and tumor cells; thus exhibiting an antiproliferative effect on tumor growth. The 4-hydroxyestradiol:2-methoxyestradiol and 2-hydroxyestradiol:2-methoxyestradiol ratios therefore ought to be taken into account as possible indicators of carcinogenesis.
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PMID:C2- and C4-position 17beta-estradiol metabolites and their relation to breast cancer. 2006 28


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