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Comparison of the short-term biological effects of 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17 beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer

Robertson, J. F., Nicholson, Robert Ian, Bundred, N. J., Anderson, E., Rayter, Z., Dowsett, M., Fox, J. N., Gee, Julia Margaret Wendy, Webster, A., Wakeling, A. E., Morris, C. and Dixon, M. 2001. Comparison of the short-term biological effects of 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17 beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Research 61 (18) , pp. 6739-6746.

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Abstract

7Alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (ICI 182,780; Faslodex) is a novel steroidal antiestrogen. This partially blind, randomized, multicenter study compared the effects of single doses of long-acting ICI 182,780 with tamoxifen or placebo on estrogen receptor (ERalpha) and progesterone receptor (PgR) content, Ki67 proliferation-associated antigen labeling index (Ki67LI), and the apoptotic index in the primary breast tumors of postmenopausal women. Previously untreated patients (stages T(1)-T(3); ER-positive or -unknown) were randomized and received a single i.m. dose of ICI 182,780 50 mg (n = 39), ICI 182,780 125 mg (n = 38), or ICI 182,780 250 mg (n = 44) or oral tamoxifen 20 mg daily (n = 36) or matching tamoxifen placebo (n = 43) for 14-21 days before tumor resection surgery with curative intent. The ER and PgR H-scores, together with the Ki67LI were determined immunohistochemically in the matched pretreatment biopsy and the posttreatment surgical specimens. The apoptotic index was determined by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling on the same samples. The effects of treatment on each of these parameters were compared using analysis of covariance. ICI 182,780 produced dose-dependent reductions in ER and PgR H-scores and in the Ki67LI. The reductions in ER expression were statistically significant at all doses of ICI 182,780 compared with placebo (ICI 182,780 50 mg, P = 0.026; 125 mg, P = 0.006; 250 mg, P = 0.0001), and for ICI 182,780 250 mg compared with tamoxifen (P = 0.024). For PgR H-score, there were statistically significant reductions after treatment with ICI 182,780 125 mg (P = 0.003) and 250 mg (P = 0.0002) compared with placebo. In contrast, tamoxifen produced a significant increase in the PgR H-score relative to placebo, and consequently, all doses of ICI 182,780 produced PgR values that were significantly lower than those in the tamoxifen-treated group. All doses of ICI 182,780 significantly reduced Ki67LI values compared with placebo (ICI 182,780 50 mg, P = 0.046; 125 mg, P = 0.001; 250 mg, P = 0.0002), but there were no significant differences between any doses of ICI 182,780 and tamoxifen. ICI 182,780 did not alter the apoptotic index when compared with either placebo or tamoxifen. Short-term exposure to ICI 182,780 reduces the ERalpha in breast tumor cells in a dose-dependent manner by down-regulating ER protein concentration. The reductions in tumor PgR content by ICI 182,780 demonstrate that ICI 182,780, unlike tamoxifen, is devoid of estrogen-agonist activity. Reductions in tumor cell proliferative activity (as indicated by Ki67LI) show that ICI 182,780 is likely to have antitumor activity in the clinical setting.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Last Modified: 04 Jun 2017 03:08
URI: http://orca-mwe.cf.ac.uk/id/eprint/17176

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