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T Toko

Publications and source records attributed to T Toko.

At least 19 recordsLinked to original sources
PubMed2000

Estrogen agonistic/antagonistic effects of miproxifene phosphate (TAT-59)

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Animals↗
PubMed1999

TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) inhibits spontaneous mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma.

The anti-tumor and anti-metastatic effects of 4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid (TAC-101) were investigated using our established lung cancer model. Orthotopic implantation of Lewis lung carcinoma (LLC) cells into the lung parenchyma produced a solitary tumor nodule in the lung followed by mediastinal lymph node metastasis. Daily oral administration of TAC-101 at doses ranging from 4 to 16 mg/kg resulted in a significant inhibition of lymphatic metastasis (inhibition rate=57 to 76%), while only the dose of 16 mg/kg significantly inhibited tumor growth at the implanted sites (inhibition rate=46%). Combined treatment with cis-diamminedichloroplatinum (CDDP) and TAC-101 (8 mg/kg, p.o., daily) enhanced the anti-tumor effect of CDDP (7 mg/kg, i.v., bolus) against both the growth of implanted tumor and lymphatic metastasis. In addition, this combined treatment significantly prolonged the survival time of LLC tumor-bearing mice as compared to treatment with each agent alone. The anti-activating protein-1 (AP-1) activity of TAC-101 caused inhibition of LLC cell invasion through the repression of expression of urokinase-type plasminogen activator and its receptor. The anti-invasive activity of TAC-101 may be involved in its in vivo anti-metastatic activity. These findings suggest that TAC-101 is a novel anti-cancer agent that may improve the therapeutic modalities for lung cancer patients with metastatic disease.

Angiogenesis Inhibitors↗
PubMed1998

[Antitumor activity of miproxifene phosphate (TAT-59) against human mammary carcinoma].

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.

Animals↗
PubMed1997

Antiestrogenic activity of DP-TAT-59, an active metabolite of TAT-59 against human breast cancer.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Binding, Competitive↗
PubMed1997

In vitro inhibition of caries around a resin composite restoration containing antibacterial filler.

Class V cavities were prepared and restored with resin composite containing antibacterial filler powder (Apacider-AW, Ap-AW) using experimental restorations. The restored teeth were incubated in vitro with the cariogenic bacteria Streptococcus mutans IFO 13955. Ground sections were then prepared and examined using macrophotography. Lesions of the outer and inner wall were noted, and the depths of which the lesions penetrated were measured. We found that, in restorations containing 1-5 wt% Ap-AW, caries penetrated the marginal area, while in restorations containing 10 wt% Ap-AW the margin remained free of caries out to a distance of about 1.1 and 1.8 mm on the occlusal and gingival sides, respectively.

Biocompatible Materials↗
PubMed1997

Synthesis and biological evaluation of 7-hydroxy-3,4-diphenyl-1,2-dihydroisoquinolines as new 4-hydroxytamoxifen analogues.

A phenolic 3,4-diphenyl-1,2-dihydroisoquinoline derivative (4a) as a new 4-hydroxytamoxifen analogue and a related compound (4c) were synthesized from 3,4-diphenyl-1,2,3,4-tetrahydroisoquinolin-4-ols (5a, c), which were prepared by intramolecular Barbier reaction of N-(2-iodobenzyl)phenacylamines. Anti-proliferative activities of 4a,c and 5a,c, as well as 4b and 5b prepared previously, against human mammary carcinoma MCF-7 cell line and human nasopharyngeal carcinoma KB cell line were evaluated. The 3,4-diphenyl-1,2-dihydroisoquinoline derivatives (4a,c) and isoquinolin-4-ols (5a,b) were active against MCF-7 cells and were nearly equipotent to the corresponding nonphenolic compound (1a). The mechanism of the anti-proliferative activity of 4a-c against MCF-7 cells is discussed.

Animals↗
PubMed1995

Drug-induced apoptosis is not necessarily dependent on macromolecular synthesis or proliferation in the p53-negative human prostate cancer cell line PC-3.

The propensity of a cell to undergo apoptosis has been proposed to be a determinant for chemotherapy sensitivity that is not directly dependent on specific drug-target interactions. Androgen-independent prostate cancer is typically refractory to cytotoxic drugs, and we tested whether this is due to a loss of the ability to undergo apoptosis. Exposure of the hormone-insensitive and p53-negative human prostate carcinoma cell line PC-3 to 22 microM cisplatin, 1 microM camptothecin, 10 microM tenoposide, 135 nM vincristine, or 10 microM lovastatin for 72 h caused cell death, internucleosomal DNA fragmentation, and morphological changes typical for apoptosis. One microM cycloheximide prevented anticancer drug-induced apoptosis, whereas high concentration (1 mM) of cycloheximide alone induced apoptosis, indicating that protein synthesis was not needed for these cells to undergo apoptosis. Since cycloheximide affected DNA synthesis and proliferation of PC-3 cells, we tested whether the DNA polymerase inhibitor aphidicolin could also suppress drug-induced apoptosis. In contrast to cycloheximide, aphidicolin inhibited only vincristine-induced apoptosis. Cycloheximide prevented drug-induced changes in cell cycle distribution except for vincristine, while aphidicolin led to an accumulation of cells at the G1-S border independent of the drug used. These data indicate that macromolecular synthesis, active cell cycling, and p53 expression are not required for apoptosis to proceed in this system.

Antineoplastic Agents↗
PubMed1995

Comparative pharmacodynamic analysis of TAT-59 and tamoxifen in rats bearing DMBA-induced mammary carcinoma.

TAT-59 suppressed the growth of DMBA-induced mammary tumors in rats earlier and more strongly than tamoxifen (TAM). After oral administration of the drugs, DP-TAT-59, one of the main metabolites of TAT-59, was found in 10- to 15-fold higher concentrations in both the tumor and blood compared to 4-OH-TAM, an active metabolite of TAM. In a 3-day antiuterotrophic test, every detected metabolite of TAT-59 showed stronger antiestrogenic activity than did TAM. In a competition assay, the affinity of the metabolites for estrogen receptors ranged from that of estradiol to that of TAM. These results suggest that the superior antiestrogenic activity of TAT-59 compared to TAM was either due to its higher penetration into tumor tissue or to the stronger antiestrogenic activity of its metabolites.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

[Augmentation of chemotherapeutic efficaciousness of UFT by oral l-leucovorin--growth-inhibitory activity of combination against human tumor xenograft].

Combination chemotherapy with FUra and LV has been reported as a useful treatment for patients suffering from colon carcinoma. Usually, both FUra and LV are administered by intravenous infusion, but not orally. UFT, an anti-neoplastic agent consisting of FT and uracil, is widely used for oral administration in Japan. Using human tumor xenografts of 10 cell lines, we evaluated the efficacy of UFT combined with l-LV, which is the active form of LV, by oral administration. Combined treatment of UFT with l-LV was more effective than UFT alone on the growth suppression of colon carcinoma (KM 20 C, Col-1) and mammary carcinoma (H-31, MX-1). When 1.85 mg/kg (5.55 mg/m2) of LV was given to tumor bearing mice, the antitumor activity of UFT was augmented and at a dose of 5.56 mg/kg (16.7 mg/m2) of LV, it was significantly augmented. Among various 5-FU derivatives, such as UFT, 5'-DFUR or FUra, combined treatment using UFT with l-LV was the most effective by oral administration. l-LV did not improve the anti-tumor efficacy or toxicity of 5'-DFUR. l-LV seemed to augment the anti-tumor activity of FUra, but not significantly. These results suggest that combination chemotherapy of UFT with LV is a promising approach for the clinical treatment of human colon cancer.

Administration, Oral↗
PubMed1995

[Augmentation of chemotherapeutic efficaciousness of UFT by oral l-leucovorin--l-leucovorin factors enhancing cytotoxic activity of 5-fluorouracil].

The relationship between augmentation of cytotoxic activity of 5-fluorouracil (FUra) by l-leucovorin (l-LV) and combination schedule was investigated using human colon adenocarcinoma KM 20 C cell line. The enhancement of cytotoxic activity of FUra by l-LV or 5-CH3FH4, a main metabolite after oral administration of l-LV, was observed after 96-hr exposure to either l-LV or 5-CH3FH4 at concentrations of greater 0.001 microM or 0.3 microM, respectively. We found that 1.5 microM FUra, which has no effect on cell-growth without l-LV, could suppress strongly the proliferation if cells were co-treated with l-LV for more than 8 hr. Therefore, enhancement of cytotoxic activity of FUra by l-LV depended on the time cell exposure to l-LV. Moreover, this effect was observed even at a concentration of 0.01 microM l-LV after 48-hr exposure. Likewise, it is known that the antitumor activity of FUra correlates with the time-schedule of treatment with FUra. These results suggest that in addition to FUra derivatives which continuously release FUra, it is beneficial for the combination therapy of FUra with l-LV to consider continuous administration of l-LV as well.

Adenocarcinoma↗
PubMed1993

Shear bond strength of composite resin to unbleached and bleached human dentine.

The purpose of this study was to compare the shear bond strength of composite resin to unbleached and bleached human dentine when used in conjunction with new dentine bonding systems. One hundred extracted, caries free, permanent human molars were used in this study. An in vitro walking bleach model was developed to stimulate clinical conditions during bleaching. It was found that the mean shear bond strength of composite resin to bleached dentine attained was lower than that to unbleached dentine. The value of 6.7 MPa bond strength to bleached human dentine demonstrated by All-Bond dentine conditioner and adhesive (Technique 1B) was much higher than in previous reports.

Borates↗
PubMed1992

Interaction of DP-TAT-59, an active metabolite of new triphenylethylene-derivative (TAT-59), with estrogen receptors.

DP-TAT-59, (Z)-2-(4-(1-(4-hydroxyphenyl)-2-(4-isopropylphenyl)-1-butenyl) phenoxy)-N, N-dimethylethylamine, has been reported to inhibit estrogen-stimulated growth of MCF-7 cells as well as rat uterus at lower concentrations than the hydroxymetabolite of tamoxifen (4-OH-TAM). In the present study, the growth of mouse Leydig cell tumor, B-1F cells were also more effectively inhibited by DP-TAT-59 than 4-OH-TAM. Additionally, the expression of estrogen responsive element ligated CAT gene transfected into B-1F cells was also suppressed by DP-TAT-59. Thus, the interaction of DP-TAT-59 with estrogen receptor (ER) was characterized and compared with that of 4-OH-TAM using immature rat and bovine uteri. The dissociation constant of DP-TAT-59 to ER of immature rat uterus was 0.24 nM and was similar to that of 4-OH-TAM (Kd = 0.20 nM) and estradiol (Kd = 0.29 nM). Using sucrose density gradients, the sedimentation constant of DP-TAT-59 with bovine uterus was 4.9S, which was similar to that of estradiol (5.1S) and 4-OH-TAM (5.3S). However, the elution profile of the DP-TAT-59-ER complex from a DEAE-Sephadex column was different for both estradiol-and 4-OH-TAM-ER complexes. These results suggest that ER forms different complexes with DP-TAT-59 than estradiol or 4-OH-TAM, while the ER binding affinity of these compounds are similar to each other.

Animals↗
PubMed1992

Application of the environmental SEM in human dentin bleached with hydrogen peroxide in vitro.

The environmental SEM (E-SEM) can be used unfixed biological samples under a low vacuum and wet condition. In this study, the fractured dentin of unfixed human teeth was treated with a 30% hydrogen peroxide solution (H2O2) for the examination of tooth-bleaching prior to the E-SEM and a conventional SEM. The peritubular matrix (PM) always showed a few cracks along the long axis of a dentinal tubule, and the ends of fine fibrils rose to the smoothly changed surface of the intertubular matrix (IM). The E-SEM with non-fixation and the conventional SEM following fixation indicated that the hydrogen peroxide solution easily permeated the PM and dissolved the non-fibrillar substance including the cracks of the PM by the constriction. In the IM, the solution may partially dissolve the organic parts within mineralized fibrils as well as non-fibrillar substance between the fibrils, although these remnants might precipitate again there.

Adolescent↗
PubMed1991

Synthesis and antiestrogenic activity of the compounds related to the metabolites of (E)-4-[1-[4-[2-(dimethylamino)ethoxy]phenyl]- 2-(4-isopropylphenyl)-1-butenyl]phenyl monophosphate (TAT-59) [corrected].

The metabolites of (E) [corrected]-4-[1-[4-[2-dimethylamino)ethoxy]phenyl]- 2-(4-isopropylphenyl)-1-butenyl]phenyl monophosphate, TAT-59, (1), a potent antitumor agent for hormone-dependent tumors, and derivatives of TAT-59 were synthesized to confirm its proposed structure. The structure and the Z-configuration of the metabolites (2a-8a) were confirmed by comparison with synthesized authentic compounds. All of the metabolites and the derivatives of TAT-59 were tested for a binding affinity toward estrogenic receptors in vitro and antiuterotrophic activity in vivo. Most of the metabolites possessed remarkable binding affinity toward estrogenic receptors as well as fairly good antiuterotrophic activity.

Animals↗
PubMed1990

TAT-59, a new triphenylethylene derivative with antitumor activity against hormone-dependent tumors.

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.

Animals↗
PubMed1990

Menogaril, an anthracycline compound with a novel mechanism of action: cellular pharmacology.

Menogaril, an anthracycline compound possessing a significant antitumor activity after both po and iv administration, has been introduced into clinical trials. However, its mechanism of action has not been clarified yet. This study revealed that its cytotoxicity correlated very well with the inhibition of macromolecular synthesis, indicating the involvement of interaction with DNA. The spectrophotometric study showed a weaker binding of this compound to calf thymus DNA when compared to that of doxorubicin (adriamycin). Despite the lower binding affinity of menogaril to DNA, pronounced DNA cleavage was observed in an intact cell system, indicating that the character of the interaction with DNA is different from intercalation. In contrast to doxorubicin, menogaril is extensively localized in the cytoplasm. The cytoplasmic localization prompted us to study its effect on cytoskeleton proteins. It was found that menogaril inhibited the initial polymerization rate of tubulin, indicating a possible contribution of this process to the overall cytotoxicity of menogaril.

Animals↗
PubMed1989

Augmentation of anti-tumor immunity in low-responder mice by various biological response modifiers: analysis of effector mechanism.

In order to elucidate the role of biological response modifiers (BRMs) in anti-tumor immunotherapy, we examined their effect on the induction of anti-tumor immunity in low-responder mice which hardly exhibit anti-tumor resistance against syngeneic Rous sarcoma virus (RSV)-induced tumors, such as B10 or B10.BR mice. The anti-tumor immunity induction in the low-responder mice was 0% on immunization with mitomycin C-treated syngeneic tumor cells alone. However, if BRMs were used as an adjuvant, BCG cell wall skeleton, OK-432 or lentinan augmented the induction of anti-tumor immunity to 50%, 33% and 33%, respectively. In the low-responder mice treated with BRMs, the anti-tumor immune cells had antigen-specificity at the induction phase of in vitro restimulation but not at the effector phase of target cell lysis by the stimulated cells. When T cells were depleted from immune spleen cells just before in vitro stimulation, cytotoxicity was not induced. Furthermore, cytotoxicity was not induced if accessory cells were removed from immune spleen cells at the induction phase. However, cytotoxicity at the effector phase was not mediated by T-lymphocytes, but by non-T cells. These results suggested that the induced cytotoxicity in low-responder mice was associated with the delayed-typed hypersensitivity-like effector mechanism.

Animals↗