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Ito, Yoshikazu Z. ; Hiromachi, Sachiko ; Futawatari, Tamae ; Arai, Michiko
概要:
application/pdf<br />Departmental Bulletin Paper<br />The efficacies of the steroidal antiandrogens chlormadinone acetat
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e (CMA), 17 α-acetoxy-6-chloro-2-oxa-4, 6-pregnadiene-3, 20-dione (TZP), and cyproterone acetate (CypA) for retardation of the growth of androgen-dependent human prostatic adenocarcinoma transplanted into nude mice (Honda tumor) were tested. CypA inhibited the growth of these tumors, while CMA and TZP did not affect the weight of cancer tissue at the doses examined. Serum levels of human prostatic acid phosphatase (PAP) in the tumor-bearing mice were very sensitive to the administration of antiandrogens, but the levels were not dependent on the changes in tumor weight. In contrast, human prostate-specific antigen (PSA) levels in the blood of the host mice were correlated with the weight of the tumors, and were independent of treatment with antiandrogens. Castration of the cancer-bearing mice resulted in reductions in all experimental parameters tested. The validity of PSA-secreting androgen-dependent human prostate cancer xenograft as a tool for screening of efficacious antiandrogens will be discussed.
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| 2.
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Ito, Yoshikazu Z. ; Hiromachi, Sachiko ; Futawatari, Tamae ; Arai, Michiko ; Nakazato, Yoichi
概要:
application/pdf<br />Departmental Bulletin Paper<br />A tumorigenic epithelial-like cell line of rat prostate origin (PR4) was established in vitro. The cell line originated from a single cell of a previously established rat
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ventral prostate cell line, and has been serially subcultured more than 100 times over 5 years. The doubling time of the cells was 18 hours, and the saturation density was 5 x 10(6) cells/ml. Oval nuclei with dispersed chromatin and well developed cytoplasmic organelles were ultrastructural characteristics of the cells. The PR4 cells were transplanted into nude mice and the histology of the resulting tumors was neopolastic epithelial-like morphology that showed cells arranged in a sheet and cord structure with a solid pattern. Very high activities of prostatic acid phosphatase and beta-glucuronidase were observed in the cytosol of the cells. The PR4 cells did not respond to androgen. The use of the new cell line and other in vitro models of rat prostate as experimental tools for human prostatic cancer research was discussed.
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| 3.
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Ito, Yoshikazu Z. ; Kuroiwa, Syunsuke ; Hiromachi, Sachiko ; Futawatari, Tamae ; Arai, Michiko
概要:
application/pdf<br />Departmental Bulletin Paper<br />Human prostatic cancer transplanted into nude mice (HONDA) was tre
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ated with nonsteroidal antiandrogen, flutamide (FLT) or steroidal antiandrogen, chlormadinone acetate (CMA), with the doses of 50 mg and 200 mg for 28 days, and with a 5 μg daily dose of gonadotropin-releasing hormone agonist, leuprolide (LEU), for 8 weeks separately. Administration of 200 mg of FLT showed the most significant inhibition of the tumor growth followed in decreasing order by 200 mg of FLT, and 50 mg FLT. Monotherapy with 50 mg of CMA showed no effect on the growth of the tumor, suggesting that FLT is more potent antiandrogen than CMA. However, there was no reduction of the tumor weight despite the treatment with these agents. Orchiectomy markedly reduced the tumor weight. The weight of seminal vesicles and ventral prostate of the host mice were reduced significantly after the treatment with these antiandrogens, suggesting that there was substantial suppression of endogenous androgen action in these organs. Notable reduction of serum human prostatic acid phosphatase in the tumor-bearing mice was observed. Monotreatment with LEU did not inhibit the tumor growth, indicating the impairment of pituitary-gonadal axis of the nude mice. There was no changes in the content of the androgen receptor in the tumor cells regardless of the treatment. These results indicate that inhibitory effects of the antiandrogens in this experimental system is by direct cellular action. Although orchiectomy indicates the total androgen blockade in the mice, the discrepancy between the continuous tendency of the tumor growth notwithstanding antiandrogen treatment and the suppression of the endogenous androgen action suggests that growth-promoting factors other than androgens exist in the cancer family.
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| 4.
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Ito, Yoshikazu Z. ; Hiromachi, Sachiko ; Shirahama, Akiko ; Arai, Michiko ; Futawatari, Tamae ; Nakazato, Yoichi a6fda3e0d86bb4578a02926de06c4502
概要:
application/pdf<br />Departmental Bulletin Paper<br />Combination treatment with human natural interferon-alpha (IFN-alpha) and natural interferon-gamma (IFN-gamma) markedly reduced the weight of metastatic human renal cell carcinoma
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(RCC) transplanted into nude mice. Monotherapy with IFN-alpha or IFN-gamma inhibited the tumor growth without reducing the tumor weight. After combination treatment with IFN-alpha and-gamma, histological features showed notable reduction in the number of mitotic tumor cells and appreciable fibrosis in the stroma of the tumor. Infiltration of macrophages in the tumor was sparse. The results suggested that the antitumor activity of the IFNs is by direct cellular action. The general condition of tumor-bearing mice treated with IFN-alpha and-gamma was well retained, while marked emaciation was observed in the untreated tumor-bearing animals. The finding indicated that the combination treatment of RCC with IFN-alpha and-gamma may reduce the tumor burden of host mice.
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| 5.
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Ito, Yoshikazu Z. ; Mashimo, Sachiyo ; Kako, Masako ; Futawatari, Tamae ; Arai, Michiko
概要:
application/pdf<br />Departmental Bulletin Paper<br />The effect of fatty acids and delta 12 prostaglandin J2 (PGJ) on androgen ([3H]R1881) binding to human prostatic cancer cytosol was investigated with glycerol density gradient
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analysis and dextran-charcoal assay. The binding of androgen to the prostatic cancer cytosol receptor proteins was not modulated by saturated fatty acids such as palmitic acid (C16:0) or stearic acid (C18:0). Unsaturated fatty acids (UFAs) such as palmitoleic acid (C16:1), linoleic acid (C18:2) and arachidonic acid (C20:4) showed concentration dependent inhibition on androgen binding to the receptor. The inhibitory potency of UFAs did not parallel to the number of cis double bonds and carbon; however, C20:4 had a marked inhibitory effect on the binding. PGJ at a low concentration (9.0nM) stimulated androgen binding to the receptor up to 130% of the control value. At a higher PGJ concentration (30nM), the androgen binding was markedly reduced. The inhibitory effect of PGJ on the androgen binding was more potent than that of UFAs. The results suggest that modulation of steroid hormone action by UFAs is a general characteristic of steroid hormone target cells regardless of species differences or malignant transformation of the cells.
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Ito, Yoshikazu Z. ; Futawatari, Tamae ; Arai, Michiko
概要:
application/pdf<br />Departmental Bulletin Paper<br />The synthesis of protein by the prostate of immature rats cultured
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in Nutrient mixture Ham F10, was strongly inhibited by high concentrations (10^<-4>M) of testosterone. At concentrations between 10^<-6>M to 10^<-8>M, androgens increased the synthesis of protein. There was a noticeable increase of protein synthesis as measured by the incorporation of labeled leucine into the protein fraction of the organ, with the addition of 5α androstane-3 α, 17β -diol to the organ culture.
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