Abstract | BACKGROUND: METHODS: Effects of antiestrogens on the growth of estrogen-dependent breast tumors in vivo were determined using several mouse xenograft models (including the tamoxifen-sensitive tumors MCF7, T47D, and MV3366 and the tamoxifen-resistant tumors ZR75-1 and MCF7/TAM) and chemically induced (nitrosomethyl urea [NMU] and dimethylbenzanthracene [DMBA]) rat breast cancer models (groups of 10 animals). We determined the initial response and effects on hormone receptor levels and the time to relapse after treatment (i.e., time to reach a predetermined tumor size threshold). Estrogen receptor (ER) levels were determined by immunoassay. RESULTS:
ZK-703 (administered subcutaneously) and ZK-253 (administered orally) were more effective than tamoxifen or fulvestrant at inhibiting the growth of ER-positive breast cancer in all xenograft models. For example, MCF7 tumors relapsed (i.e., reached the size threshold) in 10 weeks in mice treated with tamoxifen but in 30 weeks in mice treated with ZK-703. ZK-703 and ZK-253 also prevented further tumor progression in tamoxifen-resistant breast cancer models to a similar extent (more than 30 weeks in mice with ZR75-1 and MCF7/TAM tumors). In the chemically induced rat breast cancer models, orally administered ZK-703 and ZK-253 caused a nearly complete (>80%) inhibition of tumor growth. ER levels were dramatically reduced in MCF7 tumors after 5 weeks of ZK-703 treatment compared with ER levels in vehicle-treated tumors; by contrast, ER levels in tamoxifen-treated tumors were higher than those in control tumors. CONCLUSION:
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Authors | Jens Hoffmann, Rolf Bohlmann, Nikolaus Heinrich, Helmut Hofmeister, Jörg Kroll, Hermann Künzer, Rosemarie B Lichtner, Yuki Nishino, Karsten Parczyk, Gerhard Sauer, Hille Gieschen, Hannes-F Ulbrich, Martin R Schneider |
Journal | Journal of the National Cancer Institute
(J Natl Cancer Inst)
Vol. 96
Issue 3
Pg. 210-8
(Feb 04 2004)
ISSN: 1460-2105 [Electronic] United States |
PMID | 14759988
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents, Hormonal
- Estrogen Receptor Modulators
- Estrogens
- Receptors, Estrogen
- Selective Estrogen Receptor Modulators
- ZK253
- ZK703
- Tamoxifen
- Estradiol
- 9,10-Dimethyl-1,2-benzanthracene
- Methylnitrosourea
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Topics |
- 9,10-Dimethyl-1,2-benzanthracene
- Administration, Oral
- Animals
- Antineoplastic Agents, Hormonal
(administration & dosage, blood, pharmacology)
- Breast Neoplasms
(chemically induced, drug therapy, metabolism)
- Disease Models, Animal
- Disease Progression
- Drug Resistance, Neoplasm
- Estradiol
(analogs & derivatives, pharmacology)
- Estrogen Receptor Modulators
(administration & dosage, blood, pharmacology)
- Estrogens
(blood)
- Female
- Humans
- Injections, Subcutaneous
- Methylnitrosourea
- Mice
- Neoplasms, Hormone-Dependent
(chemically induced, drug therapy, metabolism)
- Receptors, Estrogen
(drug effects)
- Selective Estrogen Receptor Modulators
(administration & dosage, pharmacology)
- Tamoxifen
(pharmacology)
- Transplantation, Heterologous
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