Abstract | PURPOSE: 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.
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Authors | J Shibata, T Toko, H Saito, A E Lykkesfeldt, A Fujioka, K Sato, A Hashimoto, K Wierzba, Y Yamada |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 45
Issue 2
Pg. 133-41
( 2000)
ISSN: 0344-5704 [Print] Germany |
PMID | 10663628
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents, Hormonal
- Estrogen Antagonists
- Receptors, Estrogen
- Tamoxifen
- TAT 59
- Estradiol
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Topics |
- Animals
- Antineoplastic Agents, Hormonal
(pharmacology)
- Breast Neoplasms
(pathology)
- Cell Division
(drug effects)
- Drug Screening Assays, Antitumor
- Estradiol
(pharmacology)
- Estrogen Antagonists
(pharmacology)
- Female
- Humans
- Lipid Metabolism
- Mice
- Mice, Inbred BALB C
- Rats
- Rats, Sprague-Dawley
- Receptors, Estrogen
(physiology)
- Tamoxifen
(analogs & derivatives, pharmacology)
- Transplantation, Heterologous
- Tumor Cells, Cultured
(drug effects)
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