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| Title: Comparison of the effects of a pure steroidal antiestrogen
with those of tamoxifen in a model of human breast cancer. |
| Title Abreviation: J Natl Cancer Inst |
Date of Pub: 1995 May 17 |
| Author: Osborne CK; Coronado-Heinsohn EB; Hilsenbeck SG; McCue BL;
Wakeling AE; McClelland RA; Manning DL; Nicholson RI; |
| Issue/Part/Supplement: 10 |
Volume Issue: 87 |
Pagination: 746-50 |
| MESH Headings: Analysis of Variance; Animal; Antineoplastic Agents
(*PD); Breast Neoplasms (*DT/*PP); Comparative Study; Disease Models, Animal;
Dose-Response Relationship, Drug; Estradiol (*AA/PD); Estrogen Antagonists (*PD);
Estrogens (AD/*PH); Female; Gene Expression Regulation, Neoplastic (*DE); Human; Mammary
Neoplasms, Experimental (DT); Mice; Mice, Nude; Neoplasm Transplantation; Support, U.S.
Gov't, P.H.S.; Tamoxifen (*PD); -RN-; |
| Journal Title Code: J9J |
Publication Type: JOURNAL ARTICLE |
| Date of Entry: 951026N |
Entry Month: 9601 |
| Country: UNITED STATES |
Index Priority: 1 |
| Language: Eng |
Unique Identifier: 96001325 |
| Unique Identifier: 96001325 |
ISSN: 0027-8874 |
| Abstract: BACKGROUND: Tamoxifen, a nonsteroidal estrogen
antagonist, is the most prescribed drug for the treatment of breast cancer. The use of
tamoxifen is limited, however, by the development of resistance to this compound in most
patients. Although tamoxifen behaves primarily as an estrogen antagonist, it has agonist
(or growth-stimulatory) activity as well. ICI 182,780 is a 7
alpha-alkylsulfinyl analogue of estradiol lacking agonist activity. The absence of agonist
activity may make this steroidal antiestrogen superior to tamoxifen in suppressing tumor
cell growth. PURPOSE: We compared the inhibitory effects of ICI 182,780,
tamoxifen, and estrogen withdrawal on the growth of established tumors and on
tumorigenesis in a model system that uses estrogen-dependent, human MCF-7 breast tumor
cells growing in athymic nude mice. We also studied the hormonal responsiveness of tumors
that became resistant to the two estrogen antagonists and the effects of these drugs on
estrogen-regulated gene expression. METHODS: MCF-7 cells were injected subcutaneously into
the flanks of castrated, female nude mice. The effects of repeated doses of tamoxifen and ICI
182,780 (500 micrograms and 5 mg, respectively) on the growth of established
tumors (8-10 mm in size) were determined after supplemental estrogen was removed. The
effects of antiestrogen treatments on the process of tumorigenesis, in the absence of
estrogen supplementation, were determined by initiating drug administration on the same
day as tumor cell inoculation. To evaluate the hormonal responsiveness of tumors resistant
to tamoxifen and ICI 182,780, 1-mm3 segments of the tumors were
transplanted onto the flanks of new recipient mice, which were then treated with estrogen
or the antiestrogens--alone or in combination. Tumor growth was monitored by measuring
tumor volumes twice a week. Expression of the estrogen-responsive genes, pLIV1 and pS2, in
the tumors of treated animals was analyzed using blots of total cellular RNA and
complementary DNA probes. RESULTS: Treatment with ICI 182,780
suppressed the growth of established tumors twice as long as treatment with tamoxifen or
estrogen withdrawal. Tumorigenesis, in the absence of supplemental estrogen, was delayed
to a greater extent in ICI 182,780-treated mice than in
tamoxifen-treated mice. ICI 182,780 was found to be more effective
than tamoxifen in reducing the expression of estrogen-regulated genes. Most tumors
eventually became resistant to ICI 182,780 and grew independently of
estrogen. CONCLUSIONS: ICI 182,780 is a more effective estrogen
antagonist than tamoxifen in the MCF-7 tumor cell/nude mouse model system. |
| Abstract By: Author |
| Address: Department of Medicine, University of Texas Health Science
Center at San Antonio 78284-7884, USA. |
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