New Class of Anti-E's: Estrogen Receptor Downregulators
- 07-01-2006, 02:15 PM
New Class of Anti-E's: Estrogen Receptor Downregulators
Well I wanted to look more into the agonist-like effects of Tamoxifen, since while I was digging through information on progesterone antagonists I came across the information. It appears that Faslodex (ICI 182, 780) is the advancement that they are trying to make to prevent these agonist like effects from anti-estrogen effects.
Faslodex was found to be the most potent steroidal anti-estrogen known. It is a ner class of drugs that actually downregulates the estrogen receptor. This might have implications for preventing rebound effect seen from SERMs?
Faslodex (ICI 182, 780), a novel estrogen receptor downregulator--future possibilities in breast cancer.
Nottingham City Hospital, Hucknall Road, NG5 1PB, Nottingham, UK. firstname.lastname@example.org k
Tamoxifen is an effective treatment for breast cancer; however, as well as exerting antagonistic effects on the estrogen receptor (ER), tamoxifen acts as a partial agonists in estrogen-sensitive tissues, resulting in stimulation of the endometrium and tumor growth in some patients who become resistant to treatment.ICI 182, 780 (Faslodex), a steroidal estrogen antagonist, is the first in a new class of agent-an estrogen receptor downregulator. Pre-clinical breast cancer models show that ICI 182, 780 leads to a prolonged duration of response, and that it exerts its effects via a different mode of action to tamoxifen. This was confirmed in a small clinical study involving 19 post-menopausal advanced breast cancer patients, where ICI 182, 780 was highly effective after tamoxifen failure. Definitive evidence of the differing modes of action of ICI 182, 780 and tamoxifen, were provided in a study involving post-menopausal women with primary breast cancer, where analyses of tumor samples following short-term exposure to both drugs, showed that ICI 182, 780 reduced tumor ER levels in a dose-dependent manner, and to a significantly greater extent than tamoxifen. Additionally, unlike tamoxifen, ICI 182, 780 did not promote ER-mediated progesterone receptor expression, indicating that it lacks estrogen agonist activity.Ongoing studies in post-menopausal women with advanced breast cancer are comparing ICI 182, 780 to anastrozole and tamoxifen, respectively. Future studies being considered are whether ICI 182, 780 may also be effective in breast cancer in pre-menopausal women, in early breast cancer and in ductal carcinoma in situ in the breast, in combination with other hormonals, cytotoxics and biological modifiers.
ICI 182,780 (FaslodexTM)
Development of a novel, pure antiestrogen
Anthony Howell 1 *, C. Kent Osborne, M.D. 2, Charles Morris 3, Alan E. Wakeling, Ph.D. 3
1Department of Medical Oncology, Christie Hospital National Health Service Trust, Manchester, United Kingdom
2Breast Center, Baylor College of Medicine, Houston, Texas
3Cancer Research Department, AstraZeneca, Cheshire, United Kingdom
The nonsteroidal antiestrogen tamoxifen is well established as an effective treatment for patients with breast carcinoma, both for the treatment of metastatic disease and as an adjuvant to surgery for patients with primary breast carcinoma. In addition to exerting antagonistic effects on the estrogen receptor, tamoxifen and its derivatives act as partial agonists on certain tissues. These agonistic effects, for example, endometrial stimulation and stimulation of tumor growth after previous response to tamoxifen, may limit their clinical efficacy. ICI 182,780 (FaslodexTM) from AstraZeneca (Cheshire, United Kingdom) is a novel, steroidal estrogen antagonist that was designed to be devoid of estrogen agonist activity in preclinical models.
ICI 182,780 was tested in a large number of in vitro and in vivo preclinical models, and its value was assessed clinically when administered before surgery for breast carcinoma and hysterectomy for benign conditions and after failure of tamoxifen in patients with advanced breast carcinoma.
All data indicated that ICI 182,780 is devoid of agonist activity in preclinical models and in clinical trials. It inhibits growth of the breast and endometrium. In animal models, it does not cross the blood-brain barrier and appears to be neutral with respect to lipids and bone. ICI 182,780 down-regulates the estrogen receptor and is active in tamoxifen-resistant breast carcinoma. In a small, Phase II study, durable responses were seen: Phase III clinical trials are in progress comparing ICI 182,780 with anastrozole and tamoxifen in the treatment of patients with advanced breast carcinoma.
ICI 182,780 specifically down-regulates the estrogen receptor and, thus, represents the first of a new class of therapeutic agents. In this report, the authors present the current evidence that distinguishes ICI 182,780 from tamoxifen and related nonsteroidal compounds and establishes ICI 182,780 as the first in a new class of therapeutic agents. Cancer 2000;89:817-25. © 2000 American Cancer Society.PharmD
- 07-01-2006, 02:22 PM
- 07-01-2006, 02:37 PM
if these new drugs were put into effect on our pet gerbils we would probably have to watch out for more pronounced estrogen-deficit related side effects. perhaps downregulating ALL estrogen receptors is a bad idea. namely in regards to bone density, immune system, and joint lubrication.
Raloxifene (estrogen receptor agonist in skeletal ER's) could be used to prevent bone deterioration but as for immune system and joint lubrication i really couldnt say.
also, what type of effect would result from more long term downregulation of the estrogen receptors on the hypothalmus? the thought gives me the chills.
07-01-2006, 02:52 PM
Originally Posted by jomi822
Well it doesn't cross the blood brain barrier i don't believe. I could have sworn I read that somewhere.
Not only that but the point isn't to completely eliminate ER's as that would be basically impossible. Smaller dosages could be used, however, to effectively be used in PCT and possibly to prevent the estrogen rebound seen by SERM's
07-01-2006, 05:10 PM
It may be fine for a one time dose at the beginning of PCT, but it's not suitable for long term use. In male rats, a loss of spermatozoa from the seminiferous tubules was observed after a 6 month study and degenerative changes were seen in the epididymides with seminiferous tube atrophy. These changes were still present even 20 wks after cessation of treatment! That's what scares me. The drug is not discriminate enough and is strictly designed for all out war on estrogen dependent tumor growth. Unless you're fighting cancer, you really wouldn't wanna do that to yourself.
07-01-2006, 05:15 PM
07-01-2006, 05:35 PM
A one time treatment would definitely be interesting.Originally Posted by DR.D
It is in phase III of FDA testing so we know it has been well documented in humans.
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