Combined effects of epirubicin and tamoxifen on the cell-cycle phases in estrogen-receptor-negative Ehrlich ascites tumor cells
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New tamoxifen analogues were tested for their antiproliferative activity both in vitro and in vivo. Binding studies showed that both 4-iodotamoxifen and pyrrolidino-4-iodotamoxifen and 2.5-fold higher affinities for the estrogen receptor compared with tamoxifen. Pyrrolidino-4-iodotamoxifen was also 1.5-fold more effective in causing inhibition of estrogen-induced growth of MCF-7 cells compared with tamoxifen at 10(-6) M. The 4-iodotamoxifen analogue was similar to tamoxifen in its inhibitory action at 10(-6) M. Antiproliferative activities of these drugs were tested using the nitrosomethylurea-induced rat mammary tumor model. Pyrrolidino-4-iodotamoxifen caused regression in 92% of rats, whereas tamoxifen caused regression in 75% of rats. The agonist activity of the analogues was determined using the immature rat and mouse uterotrophic assays. Both tamoxifen and 4-iodotamoxifen had similar partial agonist activity, and this was greater than that seen with pyrrolidino-4-iodotamoxifen. Furthermore, pyrrolidino-4-iodotamoxifen caused a dose-dependent inhibition of estrogen-induced vaginal cornification, whereas tamoxifen and 4-iodotamoxifen did not. These studies demonstrate that pyrrolidino-4-iodotamoxifen is more effective than tamoxifen in inhibiting tumor regression and that its reduced uterotrophic activity and increased estrogen receptor binding may give it significant clinical advantages over the parent compound.
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Fifty-nine postmenopausal women with advanced breast cancer were treated with tamoxifen (antiestrogen), 20 mg orally twice a day for at least 2 months. They had been previously treated with other types of hormonal therapy or intensive chemotherapies, or both. Nineteen of the 59 patients (32%) had either a complete response (seven patients) or partial response (12 patients). The median duration of response was 9 + months. Tumors containing estrogen receptors and those that responded to previous hormonal manipulation tended to respond to tamoxifen (60% and 69%, respectively). Patients with receptor-negative tumor or with a history of failure of previous hormonal treatments did not respond to tamoxifen therapy. Tamoxifen is effective against advanced breast cancer. Side effects of the treatment were mild.
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Tamoxifen (20-40 mg/day) has been widely used for the treatment of breast cancer and is recognized as a useful antiestrogen. A 40 mg/day dose of toremifene showed comparable efficacy, safety and usefulness to a 20 mg/day dose of tamoxifen in the double-blind comparative study with tamoxifen. Furthermore, high-dose toremifene (120 mg/day) was effective on the tamoxifen-failed breast cancer patients. Although droloxifene (3-hydroxytamoxifen) showed efficacy and safety in phase I and phase II studies, this trial has regretably been ineffective in Japan. In phase I and early phase II trials in Japan, the safety and efficacy of TAT-59 was demonstrated and a 20 mg/day dose was moderate. Tamoxifen analogues including their metabolites are expected to act effectively on tamoxifen-resistant, low estrogen receptor levels or estrogen receptor-negative tumors by mechanisms of action different from tamoxifen.
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6 patients with breast cancer were treated for 4 weeks with the antiestrogen Tamoxifen, and for another 4 weeks with a combination of Tamoxifen and levodopa. Blood samples were examined every four days during the whole period of treatment to determine secretion of prolactin. Levels of serum prolactin was not sensibly modified during treatment with Tamoxifen, while there was a significant decrease in prolactinemia during treatment with Tamoxifen and levodopa. The small number of cases observed does not allow a sufficient evaluation of the clinical effectiveness of the treatment.
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Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth.Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naïve tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands.Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naïve breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naïve endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice.GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naïve endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.
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