tat-59 and Breast-Neoplasms

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Topics: Adult; Anastrozole; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Estrogen Antagonists; Female; Forecasting; Humans; Indoles; Letrozole; Middle Aged; Neoplasm Metastasis; Nitriles; Osteoporosis; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Triazoles

Since ER positivity in breast cancer is highest in the early stage of its natural history, hormonal treatment should be given as the initial treatment after both surgery and recurrence. Tamoxifen and medroxyprogesterone acetate have been commonly used as the standard hormonal treatment with a response rate of 20-30% and a median duration of response of 6-10 months. New agents for hormone therapy include tamoxifen analogues, LH-RH analogues and aromatase inhibitors. They are now on or have just cleared phase studies. LH-RH analogue is a unique drug that is active for premenopausal patients and should be used as the first-line therapy for them. Aromatase inhibitors lower serum estrogen levels by inhibiting conversion from andreogens to estrogens, thus inducing regression of ER-positive tumors. They are used as the second-line treatment after tamoxifen failure for postmenopausal patients. An increasing body of information has been accumulated as to how the hormonal treatments affect breast cancer at subcellular levels. New approaches controlling growth factors such as anti-angiogenesis are under way.

Topics: Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Medroxyprogesterone Acetate; Receptors, LHRH; Tamoxifen

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.

Topics: Binding, Competitive; Breast Neoplasms; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Receptors, Estrogen; Tamoxifen; Toremifene

Phase I study of TAT-59 (Miproxifen), an antiestrogen developed in Japan for breast cancer, was conducted with the collaboration of 12 hospitals. A single dose of 1.25, 5, 10, 20, 40 and 80 mg, or 5 consecutive daily doses of 1.25, 5, 10, 20 and 40 mg/day, were given orally. After single dosing, no clinical adverse effects were found. Decrease of serum Na, Cl, Ca level and increase of serum LDH level were observed in one patient after a single dose of 5 mg of TAT. An increase in the serum LDH level was also observed in one patient after a single dose in the of 10 mg of TAT. An increase in the serum LDH level and total bilirubin, increase of eosinophil, K and milky serum were also observed in one patient after a single dose of 40 mg of TAT, respectively. All of these abnormal values returned to the normal level within 26 days after final administration of TAT. No adverse clinical findings nor abnormal laboratory findings were observed after consecutive administration of TAT. After postprandial single dosing, the time to reach the maximum serum concentration (Tmax) of DP-TAT, dephosphorylated metabolite of TAT, and its demethylated metabolite, DMDP, ranged from 5.0 to 7.3 hr and from 17.0 to 42.8 hr, respectively. The maximum serum concentration (Cmax) and AUC of DP and DMDP elevated in a dose-dependent manner. T1/2 of DP and DMDP ranged from 24.2 to 41.5, and from 91.9 to 214.7 hr, respectively. There were no significant differences between pharmacokinetics of TAT before and after food intake. Based on the above results, we concluded that a Phase II study should be conducted to evaluate the efficacy, safety and optimal dose of TAT.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Estrogen Antagonists; Female; Humans; L-Lactate Dehydrogenase; Middle Aged; Tamoxifen

A dose finding early phase II study of TAT-59, a new triphenylethylene derivative, was performed in patients with advanced or recurrent breast cancer. TAT-59 was given orally for over 8 weeks at a daily dose of 10 mg, 20 mg or 40 mg/day. Thirty-six, 38 and 35 patients were eligible in the group treated with 10, 20 and 40 mg of TAT-59, respectively. The proportion of patients obtaining a complete or partial response with 10 mg/day, 20 mg/day and 40 mg/day of TAT-59 was 28.6% (10/35), 28.6% (10/35) and 25.8% (8/31) in the evaluable cases, respectively. The median duration of initial response with TAT-59 was 38.5 days, 26.5 days and 25.6 days, respectively. The frequent adverse reactions observed in all dosing groups included hot flashes, anorexia, nausea and vomiting, sweating, and abnormal values in liver function tests. In these adverse reactions, the incidence of hot flashes, which might be caused by the pharmacologic function of TAT-59 was 0.0% (0 of 35), 2.9% (1 of 35) and 10.0% (3 of 30) in the evaluable cases receiving 10 mg, 20 mg and 40 mg of TAT-59, respectively. In conclusion, it was recommended that the optimal dose in terms of efficacy and adverse reactions should be 20 mg/day.

Topics: Adult; Aged; Anorexia; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Estrogen Antagonists; Female; Hot Flashes; Humans; Middle Aged; Nausea; Neoplasm Recurrence, Local; Postmenopause; Premenopause; Tamoxifen; Vomiting

The efficacy and safety of TAT-59 (miproxifene phospate) were compared with tamoxifen citrate (TAM) in ER-positive or ER-unknown patients with advanced or recurrent breast cancer, using the double-blind method. TAT-59 and TAM were both given 20 mg/body orally for over 12 weeks in daily doses. Eligible cases were 93 in the TAT-59 group and 102 patients in the TAM group. The response rate was shown to be 30.1% (28/93) in the TAT-59 group and 26.5% (27/102) in the TAM group. Statistical equivalence between both treatments was proven at 90% confidence interval (-8.5% < or =, < or = 12.8%). Adverse reactions observed in the patients receiving TAT-59 were hot flush, nausea and vomiting, sweating, anorexia, abnormal values in liver function tests, and anemia, showing no differences from the TAM group. Leukopenia (4.9%) and thrombopenia (2.9%) reactions were found only in the TAM group. Two patients in the TAT-59 group and three in the TAM group discontinued treatment due to adverse reactions. However, these adverse reactions were reversible in both groups. In conclusion, TAT-59 was showed comparable efficacy and safety with TAM in ER-positive or ER-unknown patients with advanced or recurrent breast cancer.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Double-Blind Method; Estrogen Antagonists; Female; Humans; Neoplasm Recurrence, Local; Receptors, Estrogen; Tamoxifen

Ductal drug therapy is a novel therapeutic approach for primary breast cancers, particularly those involving ductal carcinoma in situ lesions. Total or partial mastectomy with or without radiotherapy is the standard local therapy for primary breast cancer. Here, we propose a novel drug administration method for ductal drug therapy based on a drug delivery system (DDS) for primary breast cancer. This DDS was designed to deliver miproxifen phosphate (TAT-59), an antiestrogen drug, to ductal lesions via the milk duct, where carcinomas originate, more efficiently than systemic administration, using an iontophoretic technique applied to the nipple (IP administration). Autoradiography imaging confirmed that TAT-59 was directly delivered to the milk duct using IP administration. The plasma concentrations of TAT-59 and its active metabolite DP-TAT-59 were quite low with IP administration. The area under the curve value of DP-TAT-59 in the mammary tissue was approximately 3 times higher with IP administration than with oral administration, at a 6-fold lower dose, indicating higher availability of the drug delivered via DDS than via systemic administration. The low plasma concentrations would limit adverse effects to minor ones. These characteristics show that this DDS is suitable for the delivery of active DP-TAT-59 to ductal lesions.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Dogs; Drug Delivery Systems; Estrogen Antagonists; Female; Humans; Iontophoresis; Mammary Glands, Animal; Rats; Tamoxifen

We evaluated miproxifene phosphate (TAT-59) to elucidate its efficacy in antiestrogen therapy for breast cancer patients and to assess its tissue-selective estrogenic/antiestrogenic activity.. Using DP-TAT-59, a major and active metabolite of TAT-59, an in vitro cell growth inhibition test was performed. Antitumor activity was determined using TAT-59 against human tumor xenografts of the MCF-7 and the Br-10 cell lines and MCF-7-derived tamoxifen-resistant cell lines, R-27 and FST-1. The antitumor activity of DP-TAT-59 and DM-DP-TAT-59, major metabolites of TAT-59 found in human blood following a TAT-59 dose, was also examined after intravenous administration to experimental animals. The residual estrogenic activity of TAT-59, evaluated in terms of bone and lipid metabolism in ovariectomized rats, was then compared with that of tamoxifen.. DP-TAT-59 significantly inhibited the proliferation of estrogen receptor-positive MCF-7 and T-47D tumor cells in the presence of 1 nM estradiol. TAT-59, given to mice bearing MCF-7 or Br-10 xenografts, at the dose level of 5 mg/kg, exerted a significant growth inhibitory effect that was stronger than that of tamoxifen. Moreover, R-27 and FST-1 tumors, which show a resistance to tamoxifen, responded strongly to TAT-59, suggesting that TAT-59 might be effective against tumors resistant to tamoxifen. The metabolites of TAT-59, DP-TAT-59 and DM-DP-TAT-59, showed similar antitumor activity. Both TAT-59 and tamoxifen suppressed the decrease in bone density and reduced the blood cholesterol levels in ovariectomized rats, suggesting that the estrogenic activity of TAT-59 is comparable to that of tamoxifen.. On the basis of the above results, one may expect TAT-59 to become an effective drug in patients with tumors less sensitive to tamoxifen, while its estrogenic activity as determined by bone and lipid metabolism is similar to that of tamoxifen.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Division; Drug Screening Assays, Antitumor; Estradiol; Estrogen Antagonists; Female; Humans; Lipid Metabolism; Mice; Mice, Inbred BALB C; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Tamoxifen; Transplantation, Heterologous; Tumor Cells, Cultured

DP-TAT-59, an active metabolite of miproxifene phosphate (TAT-59), showed a strong anti-proliferating activity against ER-positive human mammary carcinoma cell lines, MCF-7 and T-47D, in the presence of 1 nM of estradiol. The ED50 value of DP-TAT-59 for each cell line was 30-fold lower than that of tamoxifen. TAT-59 suppressed the growth of mammary carcinoma, MCF-7 and Br-10, xenografted into nude mouse at a dose of 5 mg/kg/day, which is equivalent to 20 mg/body of daily dose to the patients. TAT-59 inhibited the growth of tamoxifen-resistant breast cancer cell lines, R-27 and FST-1, but not tamoxifen, suggesting the possible efficacy of TAT-59 for tamoxifen-refractory patients. DP-TAT-59 and DM-DP-TAT-59, major metabolites of TAT-59 detected in blood after oral administration in the patients, exhibited equal growth-inhibitory activity against human mammary tumor xenograft, meaning the antitumor activity of TAT-59 may equally depend on these two metabolites. In uterotrophic testing using both immature mice and ovariectomized rats, while the effective dose of TAT-59 was lower than that of tamoxifen, TAT-59 showed dose-dependent estrogenic activity against their uteri, similar to tamoxifen. These results suggested that TAT-59 had a stronger antagonistic activity against estrogen-dependent mammary tumor than tamoxifen. We expect that TAT-59 will become an effective therapeutic agent for patients with high estrogen levels in their blood, such as premenopausal women, and the patients with whom the tamoxifen modality failed.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Estrogen Antagonists; Estrogens; Female; Humans; Mice; Mice, Inbred ICR; Mice, Nude; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Rats; Tamoxifen; Tumor Cells, Cultured

We gave miproxifene phosphate to six patients with recurrent breast cancer and to one patient with advanced breast cancer. This drug was orally administered at a daily dose of 20 mg in the morning, and serial blood samples were obtained just before the drug administration. Treatment was discontinued in 16 days in the patient with advanced breast cancer. Tumor response was 2 PR and 4 NC (3MR) with an efficacy rate of 29%. Adverse effects of grade 2, such as anorexia, nausea or vomiting and fatigue with grade 3 flushing and chilling were observed in the one patient with advanced breast cancer. This climacteric syndrome disappeared after cessation of administration. In one of the patients with recurrent breast cancer, a calf muscle cramp was observed. Steady plasma levels were observed in one week or two for miproxifene and in 2 to 8 weeks for desmethyl miproxifene, which were active metabolites of miproxifene phosphate. The half lives of these metabolites for disappearance were calculated in three patients. That of miproxifene was 27 to 36 hours and that of desmethyl miproxifene was 156 to 202 hours. Miproxifene phosphate is a promising drug for breast cancer, and the results of pharmacokinetics of active metabolites will suggest the time to obtain maximum efficacy and for it to disappear.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Tamoxifen

The purpose of this study was to clarify the mechanism(s) of antiestrogenic action of DP-TAT-59 ((Z)-2-(4-(1-(4-hydroxyphenyl)-2-(4-isopropyl-phenyl)- 1-butenyl)phenoxy)-N,N-dimethylethylamine), the main active metabolite of TAT-59.. Using 4-OH-tamoxifen (a hydroxylated metabolite of tamoxifen) as a reference compound, we examined the relationship between hormone-dependent tumor cells and DP-TAT-59 and characterized estrogen receptor (ER) complexes with DP-TAT-59 using ion-exchange chromatography.. DP-TAT-59 inhibited the in vitro proliferation of MCF-7 cells under serum-free conditions at a lower concentration than did 4-OH-tamoxifen. The conditioned medium (CM) obtained from the culture supernatant of MCF-7 cells in the presence of these antiestrogens suppressed the growth of ER-negative cell lines, but that from ER-negative human mammary carcinoma MX-1 cells did not. The CM from DP-TAT-59-treated cells showed a higher growth-inhibitory potency against human mammary carcinoma ZR-75-1 cells than did that from 4-OH-tamoxifen-treated cells. The growth-inhibitory potency of the CM was neutralized by the addition of the anti-TGF-beta antibody. The CM obtained from cells treated with DP-TAT-59 contained more TGF-beta and less TGF-alpha than that treated with 4-OH-tamoxifen. As the antiestrogenic activity of TAT-59 might be mediated through ER, the interaction of these antiestrogens with a cytoplasmic receptor of MCF-7 cells was examined. While the competitive binding of [3H]-estradiol with these antiestrogens to ER was similar, ER complexes with DP-TAT-59 showed a different elution profile by ion-exchange chromatography, indicating that DP-TAT-59 formed a different complex with ER from either 4-OH-tamoxifen or estradiol.. These findings suggest that at least a part of the growth suppressive ability of DP-TAT-59 against human mammary carcinoma might depend on the production of growth inhibitory factors and/or the suppression of production of growth factors from ER-positive cells, and that the production of growth inhibitory factors might be stimulated by ER complexes with antiestrogens rather than with estrogen.

Topics: Binding, Competitive; Biological Transport; Breast Neoplasms; Cell Division; Chromatography, Ion Exchange; Culture Media, Conditioned; Estradiol; Estrogen Antagonists; Female; Humans; Kinetics; Receptors, Estrogen; Tamoxifen; Transforming Growth Factor beta; Tumor Cells, Cultured

The antiestrogenic action of TAT-59 [(E)-4-[1-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4-isopropyl) phenyl-1-butenyl]phenyl monophosphate] was characterized and compared with that of Tamoxifen (TAM). Its active metabolite, 4-OH-TAT-59, had a high binding affinity to estrogen receptor (ER), present in the cytosol of the uterus of immature rat, similar to estradiol. TAT-59 and 4-OH-TAT-59 inhibited in vitro estrogen-stimulated proliferation of MCF-7 cells at a lower concentration than TAM. In the absence of estradiol, TAT-59 and 4-OH-TAT-59 were effective at a lower concentration than that of 4-OH-Tamoxifen (4-OH-TAM), the active metabolite of TAM. In uterine growth inhibition, the effective dose of TAT-59 was about 3-6-fold lower than that of TAM, in various administration schedules. The minimum effective dose of TAT-59 against in vivo MCF-7 cells was about 3-fold lower than that of TAM. In DMBA-induced rat mammary tumors, TAT-59 inhibited the growth of existing tumors at about a 10-fold lower dose than TAM. Especially in the tumors with low ER levels (10-20 fmol/mg protein), TAT-59 showed a significantly stronger inhibitory effect than TAM. These experiments showed that TAT-59 was more effective in lower doses than TAM, even against the tumors with low ER content.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Rats; Tamoxifen; Tumor Cells, Cultured