Cancer Chemotherapy and Pharmacology

, Volume 37, Issue 1–2, pp 7–13 | Cite as

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

  • Toshiyuki Toko
  • Jiro Shibata
  • Yoshikazu Sugimoto
  • Hidetoshi Yamaya
  • Masahiko Yoshida
  • Kazuo Ogawa
  • Eiji Matsushima
Original Article TAT-59, Pharmacodynamics, Anti-Estrogenic Activity, DMBA-Induced Mammary Tumor


TAT-59 suppressed the growth fo 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.

Key words

TAT-59 Pharmacodynamics Anti-estrogenic activity DMBA-induced mammary tumor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Asao T, Toko T, Sugimoto Y, Takeda S, Yamada Y, Ogawa K, Yasumoto M (1989) Synthesis and structure-activity relationships of 4-hydroxytamoxifen derivatives. 16th International Congress of Chemotherapy, Jerusalem. Abstract 281, E. Lewin-Epstein LTD., Offset PrintersGoogle Scholar
  2. 2.
    Brown RR, Bain R, Jordan VC (1983) Determination of tamoxifen and metabolites in human serum by high-performance liquid chromatography with post-column fluorescence activation. J Chromatogr 272: 351Google Scholar
  3. 3.
    Daniel P, Gaskell SJ, Bishop H, Campbell C, Nicholson RI (1981) Determination of tamoxifen and biologically active metabolites in human breast tumours and plasma. Eur J Cancer 17: 1183Google Scholar
  4. 4.
    Daniel P, Gaskell SJ, Nicholson RI (1984) The measurement of tamoxifen and metabolites in the rat and relationship to the response of DMBA-induced mammary tumors. Eur J Clin Oncol 20: 137Google Scholar
  5. 5.
    Etienne MC, Milano G, Fishel JL, Frenay M, Francois E, Formento JL, Gioanni J, Namer M (1989) Tamoxifen metabolism: pharmacokinetic and in vitro study. Br J Cancer 60: 30Google Scholar
  6. 6.
    Formaon JM, Pearson S, Bramah S (1973) The metabolites of tamoxifen (I.C.I46474). Part 1: In laboratory animals. Xenobiotica 3: 693Google Scholar
  7. 7.
    Furr BJA, Jordan VC (1984) The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25: 127Google Scholar
  8. 8.
    Gulino A, Barrera G, Vacca A, Farina A, Ferretti C, Screpanti I, Dianzani MU, Frati L (1986) Calmodulin antagonism and growthinhibiting activity of triphenylethylene antiestrogens in MCF-7 human breast cancer cells. Cancer Res 46: 6274Google Scholar
  9. 9.
    Huggins C, Grand LC, Brillantes P (1961) Mammary cancer induced by a single feeding of hydrocarbons and its suppression. Nature 198: 204Google Scholar
  10. 10.
    Jordan VC (1976) Antiestrogenic and anti-tumor properties of tamoxifen in laboratory animals. Cancer Treat Rep 60: 1409Google Scholar
  11. 11.
    Jordan VC, Allen KE (1980) Evaluation of the anti-tumor activity of non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16: 239Google Scholar
  12. 12.
    Jordan VC, Collins MM, Rowsby L, Prestwich G (1977) A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75: 305Google Scholar
  13. 13.
    Lien EA, Solheim E, Lea OA, Lundgren S, Kvinnsland S, Ueland PM (1989) Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 49: 2175Google Scholar
  14. 14.
    O'Brian CA, Liskamp RM, Solomon DH, Weinstein IB (1985) Inhibition of protein kinase C by tamoxifen. Cancer Res 45: 2462Google Scholar
  15. 15.
    Ogawa K, Matsushita Y, Yamawaki I, Kaneda M, Shibata J, Toko T, Asao T (1991) Synthesis and antiestrogenic activity of the compounds related to the metabolites of (Z)-4-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-(4-isopropylphenyl)-1-butenyl]pheny] monophosphate (TAT-59). Chem Pharm Bull 39: 911Google Scholar
  16. 16.
    Osborne KC, Wiebe VJ, McGuire WL, Ciocca DR, DeGregorio MW (1992) Tamoxifen and the isomers of 4-hydroxytamoxifen in tamoxifen-resistant tumors from breast cancer patients. J Clin Oncol 10: 304Google Scholar
  17. 17.
    Ramu A, Glaubiger D, Fuks Z (1984) Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by tamoxifen and triparanol analogues. Cancer Res 44: 4392Google Scholar
  18. 18.
    Robinson SP, Jordan VC (1988) Metabolism of steroid-modifing anticancer agents. Pharmacol Ther 36: 41Google Scholar
  19. 19.
    Scatchard G (1949) The attraction of proteins for small molecules and ions. Ann N Y Acad Sci 51: 660Google Scholar
  20. 20.
    Sutherland RL, Murphy LC, Foo MS, Green MD, Whybourne AM, Krozowski ZS (1980) High-affinity anti-oestrogen binding site distinct from the oestrogen receptor. Nature 288: 273Google Scholar
  21. 21.
    Toko T, Sugimoto Y, Matsuo K, Yamasaki R, Takeda S, Wierzba K, Asao T, Yamada Y (1990) TAT-59, a new triphenylethylene derivative with anti-tumor activity against hormone dependent tumors. Eur J Cancer 26: 397Google Scholar
  22. 22.
    Toko T, Matsuo K, Shibata J, Wierzba K, Takeda S, Yamada Y, Asao A, Hirose T, Sato B (1992) Interaction of DP-TAT-59, an active metabolite of new triphenylethylene derivative (TAT-59), with estrogen receptors. J Steroid Biochem Mol Biol 43: 507Google Scholar
  23. 23.
    Wakeling AE, Slater SR (1980) Estrogen-receptor binding and biologic activity of tamoxifen and its metabolites. Cancer Treat Rep 64: 741Google Scholar
  24. 24.
    Wiebe VJ, Bens CC, Shemano I, Cadman TB, DeGregorio MW (1990) Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer. Cancer Chemother Pharmacol 25: 247Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Toshiyuki Toko
    • 1
  • Jiro Shibata
    • 1
  • Yoshikazu Sugimoto
    • 1
  • Hidetoshi Yamaya
    • 1
  • Masahiko Yoshida
    • 1
  • Kazuo Ogawa
    • 1
  • Eiji Matsushima
    • 1
  1. 1.Tokushima Research CenterTaiho Pharmaceutical Co., Ltd.TokushimaJapan

Personalised recommendations