I put leptomeningeal into the Search function above and came up with the following--
^^
07-07-2007, 10:51 AM #1
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
for those with brain mets..don't know why it took so long for them to notice!
1: J Neurooncol. 2007 Jul 5; [Epub ahead of print] Links
Capecitabine Therapy of Central Nervous System Metastases from Breast Cancer.
Ekenel M, Hormigo AM, Peak S, Deangelis LM, Abrey LE.
Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY, 10021, USA,
ekenelm@mskcc.org.
Central nervous system (CNS) metastases from breast cancer carry a poor prognosis. Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. Medical records of seven patients with brain metastases from breast cancer who received capecitabine treatment at Memorial Sloan-Kettering Cancer Center from 1994-2006 were reviewed. Treatment outcomes were analyzed retrospectively in those patients. Median time from breast cancer diagnosis to the development of CNS metastasis was 48 (18-165) months. Four patients had brain metastases alone, two patients had both leptomeningeal and brain metastases and one patient had leptomeningeal metastasis alone. Five out of seven patients had failed other treatment modalities before capecitabine. Three patients showed complete response (CR) and three patients had stable disease (SD) after capecitabine. The patient with leptomeningeal disease improved clinically, but refused repeat cerebrospinal fluid (CSF) studies. Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR and provide long-term control in patients with both leptomeningeal and parenchymal CNS metastases from breast cancer.
PMID: 17611719 [PubMed - as supplied by publisher]
^^^^
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04-06-2006, 05:52 PM #1
Lani
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Herceptin is now being tried intrathecally (injected into the brain via the CSF)
I posted this to the wrong forum--there is no clinical trial--yet.
Herceptin is now being tried intrathecally (injected into the brain via the CSF)
--CSF is the cerebral spinal fluid that bathes the brain and circulates around the parts of the brain and spinal cord
--carcinomatosis just means "widespread cancer"
leptomeningeal or meningeal involvement is different than parenchymal involvement as I explained in an earlier post (parenchymal means within the tissue of the brain itself rather than on its outside linings/covers)
Here is the abstract:
Oncol Rep. 2006 May;15(5):1373-7. Links
Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer.
Stemmler HJ, Schmitt M, Harbeck N, Willems A, Bernhard H, Lassig D, Schoenberg S, Heinemann V.
Department of Internal Medicine III, University of Munich - Klinikum Grosshadern, D-81377 Munich, Germany.
joachim.stemmler@med.uni-muenchen.de.
Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). A 39-year-old female presenting with HER2-overexpressing MBC and suffering from meningeal carcinomatosis was treated with the humanized antibody trastuzumab directed to HER2 by intrathecal administration. The patient was diagnosed with HER2-overexpressing stage III breast cancer in December 2003. In August 2004, the patient developed a singular intracerebral metastasis which was resected by neurosurgery followed by whole-brain radiotherapy. Since MRI and cerebrospinal fluid (CSF) analyses indicated meningeal carcinomatosis, the patient was commenced on trastuzumab (6 mg/kg q3w) and capecitabine (2.500 mg/m(2) d1-14, q3w). Prompted by clinical deterioration, 5 repeated doses of intrathecal methotrexate (15 mg/dose) were administered, yet without clinical improvement. There is initial evidence that trastuzumab does not reach an adequate concentration in CSF after intravenous application. Nevertheless, infiltration of trastuzumab into CSF is facilitated under conditions of an impaired blood-brain barrier, as it is known for meningeal carcinomatosis. For patients with leptomeningeal disease, intrathecal application of trastuzumab may provide an interesting therapeutical approach for patients with HER2 overexpressing metastatic breast cancer. Therefore, an Ommaya reservoir for intrathecal treatment with trastuzumab was placed surgically and intrathecal therapy was begun with escalating doses of trastuzumab (5-20 mg), which proved to be effective and well tolerated by the patient. Within 2 weeks after treatment, the patients' condition improved significantly and cell counts in CSF obtained from the Ommaya reservoir remained low for 11 months after first diagnosis of meningeal carcinomatosis when clinical symptoms and MRI indicated progression of meningeal and cerebral disease.
PMID: 16596213 [PubMed - in process]
04-06-2006, 09:11 PM #2
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
I remember a previous post asking about leptomeningeal spread of breast cancer
and found this article about experimental work in mice similar to the article above. In mice it had to be injected locally, not in the lumbar (back) region:
Clinical Cancer Research Vol. 7, 2050-2056, July 2001
© 2001 American Association for Cancer Research
Regular Articles
Treatment of Meningeal Breast Cancer Xenografts in the Rat Using an Anti-P185/HER2 Antibody1
Ira Bergman2, Mamdouha A. Barmada, Judith A. Griffin and Dennis J. Slamon
Departments of Pediatrics [I. B., J. A. G.], Neurology [I. B.], and Pathology [M. A. B.] University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; and Division of Hematology and Oncology, UCLA School of Medicine, Los Angeles, California 90024 [D. J. S.]
The metastatic spread of breast cancer to the leptomeninges (LM) is a painful, debilitating, and usually lethal condition. Current therapies are generally ineffective or extremely toxic. The current study evaluated monoclonal antibody therapy in an animal model of LM human breast cancer. Monoclonal antibody 4D5, which recognizes the extracellular domain of the HER2/neu receptor, was administered into the cerebrospinal fluid of athymic rats implanted with human breast cancer cell lines. Continuous intraventricular administration of 4D5 inhibited growth of SKBR3 cells that overexpress HER2/neu but not of MCF7 cells, which do not. Inhibition was dose-dependent, with higher doses of 4D5 producing an improved response. i.p. administration of cisplatin in addition to 4D5 did not improve results. Continuous administration of 4D5 into the lumbar, as opposed to the ventricular intrathecal space, was not therapeutically effective. Treatment with 4D5 did not result in outgrowth of cells lacking expression of the HER2/neu receptor. These results suggest that 4D5, administered regionally, may palliate LM metastases from HER2/neu-overexpressing breast carcinoma.
^^^^
ASCO abstract: most important to STAY on herceptin once have brain mets!!!
Abstract No:
11507
Citation:
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 11507
Author(s):
B. Nam, K. Lee, T. Kim, J. Ro
Abstract:
Background: Brain metastases (BM) occur in as many as one-third of patients with metastatic breast cancer (MBC). Incidences and prognoses by triple receptor subtypes in BM have not been well delineated. Methods: Retrospectively, prognoses were assessed according to clinical characteristics, triple receptor subtypes, and receipt of trastuzumab therapy by univariate and multivariate analyses. ER/PR/HER2 were tested by IHC with HER2 FISH for IHC 2+ and for all 118 consecutive primary BC. Results: Between 8/2001 and 4/2006, 138 of 805 pts (17.1%) with MBC presented with BM at NCC Korea. More pts with triple negative and HER2+ tumors developed BM (see table). The median age was 47 years. They were single (9%), multiple (80%), or leptomeningeal disease with or without multiple BM (11%). As initial therapy, 104 pts received WBRT, 8, intrathecal therapy (IT), 9, WBRT with IT, and 17 others. Of 56 HER2+ pts, 45 received trastuzumab either before (n=25) or after (n=13), or continuously before and after BM diagnosed (n=7). By 10/2006, 117 pts died with a median survival of 4.5 months. Multivariate analyses indicated age, tumor receptor subtypes,leptomeningeal presentation and number of extracranial disease sites as significant factors. Receipt of trastuzumab therapy after BM was a significant variable for survival in HER2+ diseases (3.8 vs. 13.4 mo, p=0.0000). Pts with triple negative subtype lived shortest compared with other types (p=0.0035). Conclusions: More pts with triple negative and HER2+ disease developed BM. HER2+ disease gained a significant survival benefit by trastuzumab therapy. Supported by NCC Grant 0610240 and 0510520.
Triple receptor status Brain metastasis
N (%) Metastatic breast cancer
N (%) Early breast cancer
N (%) P-value
ER or PR+/HER2- 23/126 (18.2) 254/556 (45.7) 68/118 (57.6) <0.0001
ER or PR+/HER2+ 19/126 (15.0) 73/556 (13.1) 16/118 (13.5)
ER and PR-/HER2+ 37/126 (29.4) 91/556 (16.4) 15/118 (12.7)
ER and PR-/HER2- 47/126 (37.3) 138/556 (24.9) 19/118 (16.1)
Unknown/total 12/138 111/667 0/118
^^^
from gdpawel thread:
Isolated Leptomeningeal Carcinomatosis (Carcinomatous Meningitis) after Taxane-Induced Major Remission in Patients with Advanced Breast Cancer
Christos Kosmasa, Nikolaos A. Malamosa, Nikolas B. Tsavarisc, Melina Stamatakib, Achilleas Gregorioua, Sofia Rokanaa, Maria Vartholomeoua, Minas J. Antonopoulosa
aDepartment of Medicine, Medical Oncology Unit and bDepartment of Cytopathology, Helena-Venizelou Hospital and cDepartment of Pathophysiology, Medical Oncology Unit, Laikon General Hospital, Athens University School of Medicine, Athens, Greece
Abstract
Objectives: To identify the incidence of leptomeningeal carcinomatosis (LMC), as the first site of systemic progression, in breast cancer patients after having obtained a major response (CR or near CR) to first-line taxane-based chemotherapy and compare these findings in retrospect with a matched-pair group of historical control patients from our database treated with nontaxane regimens.
Patients and Methods: Patients with histologically proven breast cancer having either metastatic disease or high-risk locoregional disease that were entered into treatment protocols with first-line taxane (paclitaxel or docetaxel) plus anthracyclines or mitoxantrone combinations and developed LMC as the first evidence of progression after major response (CR or >80% PR) were analyzed in the present study (n = 155), and compared, as regards the incidence of LMC, to a matched-pair retrospective group of 155 patients treated with nontaxane regimens in our unit.
Results: Seven patients with a median age of 54 years (range 40-70) developed LMC as their first evidence of progression after taxane-based regimens with a median interval of 6 months (range 2-18) from start of treatment to diagnosis of LMC. Five patients received intrathecal (i.t.) methotrexate treatment and whole brain radiotherapy (RT), while 1 patient received i.t. methotrexate and RT to the lumbar spine.
Two patients responded to treatment for LMC, while 2 achieved stable disease and 3 progressed. Two patients had elevated cerebrospinal fluid tumor markers (more than serum marker levels) that proved useful in monitoring response to treatment. Median survival after LMC was 3.6 months (range 1-17+) and correlated positively to the interval from the initiation of taxane-based therapy to LMC (r = 0.84, p = 0.019).
Seven out of 86 responders (8.13%) in the taxane group versus 1 out of 72 responders (1.4%) in the non-taxane-treated group developed LMC as the first sign of progression after a major response to first-line chemotherapy (p < 0.1).
Conclusions: LMC after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased, but not significantly so, when compared retrospectively to non-taxane-treated patients.
Prospective evaluation of the incidence of LMC after taxane versus non-taxane-based treatment from large randomized multi-institutional trials is warranted and identification of potential prognostic factors might help to identify patients requiring appropriate prophylactic therapy.
American Journal Clinical Oncology 2002;63:6-15
^^^^
10-27-2007, 07:12 AM #1
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
hot off the press MDAnderson review of 10 yrs' experience w bc brain mets
patients treated in earlier years did not have their her2 status studied--too bad they couldn't go back and determine their status retroactively
have included excerpts:
Cancer. 2007 Oct 25; [Epub ahead of print]
Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis.
Altundag K, Bondy ML, Mirza NQ, Kau SW, Broglio K, Hortobagyi GN, Rivera E.
Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
BACKGROUND.: Breast cancer is the second most common cause of central nervous system (CNS) metastases. Several risk factors for CNS metastases have been reported. The objective of the current study was to describe clinicopathologic characteristics and prognostic factors in breast cancer patients with CNS metastases. METHODS.: The authors retrospectively evaluated clinical data from 420 patients who had been diagnosed with breast cancer and CNS metastasis between 1994 and 2004 at the University of Texas M. D. Anderson Cancer Center. RESULTS.: The median age of the patients at the time of diagnosis of breast cancer was 45 years (range, 25-77 years). Premenopausal and postmenopausal patients were distributed equally. Most patients had invasive ductal histology (91.2%), grade 3 tumors (81.4%) (using the modified Black nuclear grading system), T2 tumor classification (40.1%), and N1 lymph node status (59.7%) diagnosis. Forty percent of patients had estrogen receptor (ER)-positive disease, and 34% had progesterone receptor-positive disease. HER-2/neu status was recorded for only 248 patients, and 39% of the patients in that group had HER-2/neu-positive disease. The most common sites of first metastasis were liver, bone, and lung. CNS metastasis was the site of first recurrence in 53 patients (12%). In total, 329 patients had received either neoadjuvant treatment (113 patients) or adjuvant chemotherapy (216 patients). The majority of those patients (74.4%) had received anthracycline-based regimens. Metastasis was solitary in 111 patients (26.4%), and 29 patients had only leptomeningeal metastases. The median time from breast cancer diagnosis to CNS metastasis was 30.9 months (range, from -5 months to 216.7 months). The median follow-up after a diagnosis of CNS metastasis was 6 months (range, 7-95.9 months). In all, 359 patients died, and the overall median survival was 6.8 months. Only age at diagnosis and ER status were associated significantly with overall survival in the multivariate analysis. CONCLUSIONS.: The current results indicated that the prognosis remains patients with breast cancer metastatic to the CNS. More effective treatment approaches are needed for patients with CNS metastases, even for those with favorable prognostic factors, such as ER-positive tumors or younger age. Cancer 2007. (c) 2007 American Cancer Society.
PMID: 17960791 [PubMed - as supplied by publisher]
^^^^^^^^^^^^^^^
Patients Who Survived for >18 Months
Eighty-two patients (19.5%) were alive at least 18 months after diagnosis of CNS metastasis. Of these 82 patients, 25 patients (30%) had HER-2-positive breast cancer. Furthermore, 18 patients (4.2%) were alive at least 60 months after this diagnosis. The median age of these relatively longer surviving patients was 42 years. Most of these patients had tumors of the ductal histologic type, tumors classified as T1 or T2, lymph node status N0 or N1, and a metastatic status of M0 at diagnosis. Approximately 50% of these patients had ER-positive or PR-positive disease, and 73% had grade 3 disease. Forty-six percent of these patients had a single CNS metastasis.
^^^^^^^^^^^^^^^^^^
Compared with the median age of all breast cancer patients, the median age of patients with CNS metastases in our series was younger. Moreover, our cohort comprised more patients with ER-negative tumors than with ER-positive tumors. These data support previous reports indicating that patients with ER-negative tumors and younger age had a greater tendency to develop CNS metastases.[1][9][10]
Authors of a previous study reported that prior lung metastases predicted brain metastases in patients with breast cancer.[21] This also was true for our study cohort, in which 84 patients had lung as the primary metastatic site. Moreover, the median time from first metastatic site to CNS metastasis was shorter for patients who had lung as the first metastatic site than for patients who had bone as the first metastatic site. This may be explained partly by the assumption that metastatic breast cancer cells lodged in lung parenchyma can go more readily to the brain than those lodged in other sites.[22] The results from our multivariate analysis indicated that age and ER status were 2 independent factors for overall survival. Patients aged <50 years are expected to have better a performance status, resulting in better tolerance to therapy and longer overall survival. Similarly, Patients with ER-negative tumors tended to have a worse prognosis than patients with ER-positive tumors.
Among 248 patients with known HER-2 status in our study, 97 patients with breast cancer (39%) had HER-2-positive disease. This information supports the broad perception that positive HER-2 status is a risk factor for CNS metastases. Furthermore, several studies have reported improved survival from the time of diagnosis of CNS metastases diagnosed in patients who had HER-2-positive disease compared with patients who had HER-2-negative disease.[23][24] In our study, patients who had HER-2/neu-positive disease also lived longer compared with patients who had HER-2/neu-negative disease (11 months vs 6 months; P = .005). Improvements in survival largely can be attributed to the control of other sites of visceral metastases by the use of trastuzumab.
Although the survival outlook for patients with breast cancer metastatic to CNS is generally poor, there were some long-term survivors. Eighty-two patients (19.5%) survived for >18 months. The median age of these patients was 42 years. Compared with an unselected series of breast cancer patients, this longer surviving population was younger and predominantly was premenopausal. This group also included a higher proportion of patients with a single metastatic lesion and with CNS as the first metastatic site. Compared with unselected breast cancer patients, these patients had a higher percentage of ER-positive tumors. Any or all of these characteristics may explain their potential for prolonged survival.
^^^^
10-27-2007, 05:35 PM #3
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
more ....from the paper
Twenty-five years ago, DiStefano et al. reported the outcome of 100 breast cancer patients with CNS metastases who were followed at MD Anderson.[18] In their analysis, the median time from first diagnosis to CNS metastases was 34 months; in our series, it was 30.6 months. It is interesting to note that, whereas the median survival after the documentation of CNS metastasis was 4 months in the former study, during the time of the current study, this interval had increased to 6.8 months. This difference has several possible explanations, including the availability of better imaging techniques in the current study, and the use of more effective treatment modalities, such as radiotherapy and/or chemotherapy. In their further analysis, DiStefano et al. observed longer survival in patients who underwent surgical resection and in those whose brain was the site of first metastasis. In our series as well, patients with CNS as the first site of metastases and those with a single metastasis that was amenable to surgery and/or radiotherapy lived longer. Furthermore, a randomized trial demonstrated that selected patients with resectable single brain metastases who were randomized to undergo resection and receive whole-brain radiotherapy survived longer than those who underwent biopsy or received whole-brain radiotherapy alone.[19] That randomized trial and a confirmatory trial[20] have established surgery and postoperative irradiation as the standard approach for such patients.
There has been substantial progress in CNS imaging, neurosurgical techniques, and radiation therapy techniques, especially gamma knife and radiosurgery. Optimal assessment of extent of disease and multidisciplinary treatment planning and implementation may improve outcomes somewhat, especially for patients with limited disease. Patients with solitary or very few metastases should be treated aggressively and with curative intent. It is intriguing that, in the current series, patients with moderate extent of metastases fared better than patients with multiple metastases but fared less well than patients with single metastases. This means that not only patients with single metastasis but also patients with moderate metastases may benefit from local interventions. Therefore, local management of CNS metastases should not be rejected in this population.
^^
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
her2+ breast cancer associated with higher risk of brain mets--but better survival
after brain mets
and it was mostly her2+er- tumors which were associated with brain mets
http://www.medicalnewstoday.com/articles/98852.php
http://breast-cancer-research.com/content/10/1/R20
Breast Cancer Research
Volume 10
Issue 1
Research article
Breast cancer subtypes and survival in patients with brain metastases
Byung-Ho Nam , Sun Young Kim , Hye-Suk Han , Youngmee Kwon , Keun Seok Lee , Tae Hyun Kim and Jungsil Ro
Breast Cancer Research 2008, 10:R20doi:10.1186/bcr1870
Published: 28 February 2008
Abstract (provisional)
Introduction
Brain metastases (BM) occur in up to one third of patients with metastatic breast cancer (MBC), whose incidences and prognoses by breast cancer subtypes in BM have not been well delineated.
Methods
Retrospective survival analyses were performed in 126 BM patients from 805 MBC patients treated at the National Cancer Center between August 2001 and April 2006, according to clinical characteristics, breast cancer subtypes, and receipt of trastuzumab. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor-2 (HER2) statuses were tested by immunohistochemical (IHC) staining, and HER2 FISH analysis conducted for IHC 2+.
Results
The proportion of HER2+/ER- (29% vs 16%) and triple-negative (37% vs 25%) tumors was higher in the 126 BM patients than those without BM. While median survival after recurrence was longer in patients with luminal A disease (median survival of luminal A vs luminal B vs HER2+/ER- vs triple-negative: p = 0.0246; 39.6 vs 27.4 vs 20.9 vs 15.5 months), survival was shorter from BM to death in luminal A and triple negatives (median survival: p = 0.0113; 4.0 vs 9.2 vs 5.0 vs 3.4 months). Receipt of trastuzumab after BM was a significant variable for survival in HER2+ patients. Multivariate analyses identified ER-negative, HER2-negative, or triple-negative, as well as older age, presence of leptomeningeal disease, and three or more extracranial disease sites, as poor prognostic factors for survival after BM.
Conclusions
MBC patients who developed BM had higher proportions of triple-negative and HER2+/ER- tumor status. Triple receptor status is a useful prognostic marker for predicting survival after BM in metastatic breast cancer patients.
I quickly put Lani brain met into the search above and found
here is info I just quickly gathered on Boswellia Serrata and intrathecal herceptin
from a 9/06 thread I started--I recently read a post from someone who thanked me for providing the info--she had used Boswellia and had a 40% decrease in the size of her brain mets and a long period of stable disease (couldn't find the post, but found these by putting Boswellia into the search function above). I also post my info on intrathecal (injected into the cerebrospinal fluid so it doesn't have to cross the blood-brain barrier) herceptin:
Here is the first post:
for those with brain mets (and those scared of developing brain metastases)
a most remarkable article--I felt it inappropriate to place it with interesting articles as only one tenth as many her2support readers view those posts and it is my impression that there are some out there who could definitely need this news, published in a very respectable journal
I was happy to see an email address attached to the abstract and have forwarded on more information...
1: J Neurooncol. 2006 Sep 26; [Epub ahead of print] Links
A lipoxygenase inhibitor in breast cancer brain metastases.
Flavin DF.
Foundation for Collaborative Medicine and Research, 24 Midwood Drive, Greenwich, CT, 06831, USA,
Dana_FK@hotmail.com.
The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwile consideration for testing in brain metastases not responding to standard therapy. Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.
PMID: 17001517 [PubMed - as supplied by publisher]
hmerch
Member
Join Date: Apr 2006
Posts: 5
I contacted Dr. Flavin for my mother who has brain mets and she said that Boswellia serrata should be used right away at 800mg 3 times a day.
My understanding from my conversation with her was that those of her patients who are using this had regression of brain mets. She also has a few patients who are met free now for a few years.
This sounds pretty great and I'm going to get this for my mom if her onc allows it, but I am curious if anyone else has used this compound and if so what has been your success?
Thanks,
Hina
10-27-2006, 03:31 PM
#15
heblaj01
Senior Member
Join Date: Apr 2006
Posts: 543
Caution: possible interaction of Boswellia with some chemo drugs
In checking the pharmacokinetics of Boswellia Serrata I found this article which describes it as an iinhibitor of P450 enzymes which are required in the liver to metabolize some chemo drugs such as Navelbine.
http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
Analysis of frankincense from various Boswellia species with inhibitory activity on human drug metabolising cytochrome P450 enzymes using liquid chromatography mass spectrometry after automated on-line extraction.
The abstract does not state if the inhibition is occuring only in he gut or in the liver or both.
If the inhibition is restricted to the gut then intravenous chemo drugs would not be affected.
If however the inhibition is in the liver the consequences could be lowered effectiveness of the chemo treatment & possibly higher level of side effects due to longer persitance of the drug in the body & higher accumulation.
I hope this will turn out to be a false alert for most of those planing to use Boswellia but it needs to be clarified by someone with the right background such as Lani.
heblaj01
Senior Member
Join Date: Apr 2006
Posts: 543
This article posted by Lani is most interesting for members of this forum since it deals with metastatic brain cancer from breast.
It appears that Boswella Serrata might also be usefull for primary brain tumors since a phase 2 clinical trial is under preparation:
http://www.clinicaltrials.gov/ct/gui/show/NCT00243022
Boswellia Serrata Combined With a Low-Fat, Vegan Diet or a Standard Diet Alone in Treating Patients Who Have Undergone Surgery and Radiation Therapy for Newly Diagnosed Glioblastoma Multiforme
from my 11/06 post:
Here are two articles on IT herceptin--the latest(hot-off-the-press) I do not yet have access to:
1: Lancet Oncol. 2006 Nov;7(11):888. Links
Care with intrathecal trastuzumab.
Siderov J.
PMID: 17081914 [PubMed - in process]
Related Links
Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer.[Oncol Rep. 2006]
Hope this helps!
PS I have very little internet access at the moment(visiting for the holidays), so sorry not to post more info on this
11-22-2006, 03:50 PM
#9
Lani
Senior Member
Join Date: Mar 2006
Posts: 1,988
got it!
The Lancet Oncology
Volume 7 • Number 11 • November 2006
Copyright © 2006 Elsevier
Reflection and Reaction
Care with intrathecal trastuzumab
Jim Siderova
a Cancer Services, Austin Health, Studley Road, Heidelberg, VIC, Australia 3084
E-mail address:
jim.siderov@austin.org.au
PII S1470-2045(06)70917-2
I read with interest the Case Report on the use of intrathecal trastuzumab published in The Lancet Oncology because it is an uncommon method of administration for a monoclonal antibody.[1] I wish to point out a potential issue with the intrathecal administration of trastuzumab.
In Australia and the UK, trastuzumab is supplied in vials of 150 mg powder,2, 3 which contains histidine, trehalose dihydrate, and polysorbate, among other excipients. Once reconstituted with water for injection, the resultant solution is free of preservatives. In the USA, trastuzumab is supplied in vials of 440 mg powder,[4] together with 20-mL bacteriostatic water for reconstitution. This bacteriostatic water contains 1·1% benzyl alcohol—a preservative.
Products that contain preservatives, particularly benzyl alcohol, should not be administered intrathecally because of the risks of anaphylaxis and potential for neurotoxicity from the preservative agent.[5] Reported events include paraparesis, fibrosis of the cauda equina, and segmental demyelination of the dorsal and ventral roots.[5]
Thus, colleagues in the USA who might consider treatment with trastuzumab intrathecally should do so without the use of the diluent provided.
Intrathecal administration is an important component of the management of malignant disease, but products injected in this way should not contain preservatives, especially benzyl alcohol. Physicians, pharmacists, and nurses involved in the preparation or administration of intrathecal treatment should ensure that preservative-free products are used.
I declare no conflicts of interest.
11-22-2006, 03:51 PM
#10
Lani
Senior Member
Join Date: Mar 2006
Posts: 1,988
references
REFERENCES:
1 Platini C, Long J, Walter S: Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol 7. 778-780.2006; Full Text
2 Roche products Pty Ltd: Herceptin (trastuzumab) Australian approved product information. Therapeutic Goods Administration approved amendment, Roche products Pty Ltd Sydney 21 April, 2006.
3 Electronic Medicines Compendium: (accessed Sept 20, 2006)
http://emc.medicines.org.uk/emc/indu...ocumentid=3567
4 In: McEvoy GK, ed. American Hospital Formulary Service (AHFS) Drug Information, American Society of Health-System Pharmacists Bethesda 2006: 1209-1215.
5 Hetherington NJ, Dooley MJ: Potential for patient harm from intrathecal administration of preserved solutions. Med J Aust 173. 141-143.2000; Abstract
01-07-2008, 06:08 PM #3
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,762
another article I just refound:
Anticancer Drugs. 2007 Jan;18(1):23-8. Links
Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier.
Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V.
Medical Department III, Ludwig-Maximilians University of Munich, Clinic Grosshadern, Munich, Germany.
Joachim.Stemmler@med.uni-muenchen.de
Patients receiving trastuzumab for HER2-overexpressing metastatic breast cancer seem to suffer from an increased risk of brain metastases, even in cases with responsive disease. To evaluate whether trastuzumab is able to penetrate the blood-brain barrier, we measured trastuzumab levels in the serum and in cerebrospinal fluid of metastatic breast cancer patients with brain metastases receiving trastuzumab for HER2-overexpressing metastatic breast cancer. In a pilot study, metastatic breast cancer patients with brain metastases and HER2-overexpressing tumors (HercepTest; Dako, Copenhagen, Denmark) were included. At different time points, trastuzumab levels in the serum and cerebrospinal fluid were measured using a newly developed immunoenzymatic test for trastuzumab. Six out of eight patients were evaluable for determination of trastuzumab level in the serum and cerebrospinal fluid. Before radiotherapy, median trastuzumab level in the serum was 52 054 ng/ml compared with 124 ng/ml in cerebrospinal fluid (ratio 420 : 1). After completion of radiotherapy, median trastuzumab level was 20 185 ng/ml in the serum and 226 ng/ml in cerebrospinal fluid, respectively (ratio 76 : 1). With concomitant meningeal carcinomatosis, trastuzumab level in the serum after radiotherapy was 17 431 and 356 ng/ml in cerebrospinal fluid (ratio 49 : 1). For the first time, we present clinical evidence that trastuzumab levels in cerebrospinal fluid are increased under conditions of an impaired blood-brain barrier such as meningeal carcinomatosis or radiotherapy. This evidence supports the concept of continuing trastuzumab therapy in patients with brain metastases treated by radiotherapy. Monitoring of trastuzumab levels in the serum and cerebrospinal fluid may enable individualized therapy strategies in metastatic breast cancer patients with brain metastases, and lead to a better understanding of trastuzumab pharmacokinetics in the cerebrospinal fluid and serum.
PMID: 17159499 [PubMed - indexed for MEDLINE]
new drug improves survival, qual of life when combined with WBR(whole brain radiation
Am J Clin Oncol. 2007 Dec;30(6):580-7.
Improved survival, quality of life, and quality-adjusted survival in breast cancer patients treated with efaproxiral (Efaproxyn) plus whole-brain radiation therapy for brain metastases.
Scott C, Suh J, Stea B, Nabid A, Hackman J.
CBS Squared, Inc., Fort Washington, Pennsylvania 19034, USA.
cbssquared@comcast.net
OBJECTIVE: To determine whether efaproxiral, an allosteric modifier of hemoglobin, improves quality of life and quality of survival in patients with primary breast cancer and brain metastases when used as an adjunct to whole-brain radiation therapy (WBRT). METHODS: Patients with brain metastases from breast cancer were randomly assigned to receive WBRT and either efaproxiral or no efaproxiral. The primary endpoint for this analysis was quality of life and quality-adjusted survival. Quality of life was assessed prior to initiation of WBRT and periodically in follow-up using the Spitzer Quality of Life Index (SQLI). RESULTS: A subgroup of 106 eligible breast cancer patients with baseline SQLI were randomized into this study and represent the target population discussed in this report. Treatment, age, and SQLI were significant predictors of survival. The addition of efaproxiral to WBRT reduced the death rate by 46% (P = 0.0086). Quality of life was improved in the WBRT + efaproxiral arm compared with the WBRT alone arm (P = 0.019). Quality-adjusted survival was statistically significantly improved by the addition of efaproxiral to WBRT (P = 0.001). CONCLUSION: Survival, quality of life, and quality-adjusted survival were all improved in breast cancer patients with brain metastases receiving efaproxiral and WBRT compared with those receiving WBRT alone.
PMID: 18091051 [PubMed - in process]
Article shows the other people involved in writing the paper were with University Cancer centers (not the drug company), that her2+ was responsible for an inordinate number of the bc brain met population due to its proclivity for the the brain, other factors.
06-12-2009, 04:40 PM #15
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
they do deliver herceptin intrathecally
All the articles agree it is very advantageous to keep herceptin going once you have brain mets-they theorize the blood brain barrier is somewhat more permeable or some indirect effect is responsible
I also came by this (not mine) in the search function:
RTA 744 in Breast Cancer Patients With Progression of Previously Irradiated Brain Met
RTA 744 in Breast Cancer Patients With Progression of Previously Irradiated Brain Mets
RTA 744 is a novel, anthracycline that has shown the ability to circumvent ATP-binding cassette transporters (Multidrug Resistance Protein 1, Breast Cancer Resistance Protein, P-glycoprotein) in vitro. This action enables RTA 744 to penetrate across the blood brain barrier. In a Phase I safety study, RTA 744 was shown to be generally well tolerated in patients with recurrent gliolastoma multiforme (GBM). Additionally, anti-tumor activity was observed. Breast cancer is known to be sensitive to anthracycline therapy. Based on the preliminary Phase I clinical results and the sensitivity of breast cancer to anthracycline therapy, this Phase II study will investigate the safety and efficacy of RTA 744 in patients with breast cancer and metastatic disease to the brain which has progressed following whole brain irradiation.
http://www.clinicaltrials.gov/ct/sho...395112?order=2
06-12-2009, 05:08 PM #16
pattyz
Senior Member
Join Date: Mar 2006
Posts: 306
Marie... can I say more than just 'hell' here??? Pretend I did, ok.
I can't think of what I sent that must be written off if it was not tried?
My onc wants to go right to Irinotecan w/my Temodar. There is an oral Irinotecan, which I like, at a dose of about 50/60mg/m2 Dx5. It is also in trial now for 'us' this way.
Besides w/Temodar, it is also used or in trial with:
*Oral etoposide aka: VePesidR
*Avastin - yes, honest for brain mets.
There is an older chemo 'Lomustine':
Lomustine Offers Effective Low Cost Treatment for Lung and Breast Cancer Brain Metastases (Doctor's Guide)
Reports results from a small study presented at the 14th International Congress on Anti-Cancer Treatment (ICACT) of the efficacy and toxicity of lomustine in patients with lung or breast cancer brain metastases. [2/03]
What this drug is used for:Treatment of brain tumors, both primary (developed in the brain) and metastatic
*And: Temodar w/Doxil -
2004 ASCO Annual Meeting
Category: Central Nervous System Tumors
Abstract No: 1576 Two CR and two PRs was recorded in the four patients with breast tumours,
Conclusions: the schedule was a well tolerated treatment (also in elder pts.) and has suggested an encouraging activity in brain metastases from breast.
*Topotecan:
Single-agent topotecan, especially in patients with SCLC or breast cancer, has demonstrated excellent response rates against brain metastases and may be safely and effectively combined with other chemotherapeutic drugs that have the ability to pass the intact blood-brain barrier....
*And these trials:
* ZK219477 in Patients With Breast Cancer and Brain Metastases
The purpose of this Phase II clinical trial is to determine the effects, both good and bad, of a new chemotherapeutic drug called ZK219477 that appears to cross the blood-brain barrier and penetrate into the brain.
* Epothilone B in Treating Patients With CNS Metastases From Breast Cancer
This phase II trial is studying how well a new experimental treatment known as epothilone B (patupilone) works in treating patients with CNS metastases from breast cancer that have recurred after whole brain radiation. Patupilone does cross the blood-brain barrier.
However, the trial Lani posted was terminated = Business decision. ?? the RTA 744
Gd, I pray you can find something for Ed to try. I'm focused on oral at the moment. IV's next... or whatever happens.
xoxopatty
06-12-2009, 05:13 PM #17
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
more references
Please see my post in the last couple of days of a new and more effective way of taking lapatinib00ie higher dose but intermittently
J Natl Cancer Inst. 2008 Aug 6;100(15):1092-103. Epub 2008 Jul 29. Links
Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain.
Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L, Liewehr DJ, Steinberg SM, Merino MJ, Rubin SD, Steeg PS.
Women's Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 37, Room 1122, MSC 4254, Bethesda, MD 20892, USA.
BACKGROUND: The brain is increasingly being recognized as a sanctuary site for metastatic tumor cells in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy, and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis. METHODS: EGFR-overexpressing MDA-MB-231-BR (231-BR) brain-seeking breast cancer cells were transfected with an expression vector that contained or lacked the HER2 cDNA and used to examine the effect of lapatinib on the activation (ie, phosphorylation) of cell signaling proteins by immunoblotting, on cell growth by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and on cell migration using a Boyden chamber assay. The outgrowth of large (ie, >50 microm(2)) and micrometastases was counted in brain sections from nude mice that had been injected into the left cardiac ventricle with 231-BR cells and, beginning 5 days later, treated by oral gavage with lapatinib or vehicle (n = 22-26 mice per treatment group). All statistical tests were two-sided. RESULTS: In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream signaling proteins; cell proliferation; and migration in 231-BR cells (both with and without HER2). Among mice injected with 231-BR-vector cells, those treated with 100 mg lapatinib/kg body weight had 54% fewer large metastases 24 days after starting treatment than those treated with vehicle (mean number of large metastases per brain section: 1.56 vs 3.36, difference = 1.80, 95% confidence interval [CI] = 0.92 to 2.68, P < .001), whereas treatment with 30 mg lapatinib/kg body weight had no effect. Among mice injected with 231-BR-HER2 cells, those treated with either dose of lapatinib had 50%-53% fewer large metastases than those treated with vehicle (mean number of large metastases per brain section, 30 mg/kg vs vehicle: 3.21 vs 6.83, difference = 3.62, 95% CI = 2.30 to 4.94, P < .001; 100 mg/kg vs vehicle: 3.44 vs 6.83, difference = 3.39, 95% CI = 2.08 to 4.70, P < .001). Immunohistochemical analysis revealed reduced phosphorylation of HER2 in 231-BR-HER2 cell-derived brain metastases from mice treated with the higher dose of lapatinib compared with 231-BR-HER2 cell-derived brain metastases from vehicle-treated mice (P < .001). CONCLUSIONS: Lapatinib is the first HER2-directed drug to be validated in a preclinical model for activity against brain metastases of breast cancer.
PMID: 18664652
06-12-2009, 05:25 PM #18
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
Patricia Steeg is at the NIH and has made bc brain mets here baileywick
here is one of her paper's abstracts:
Breast Dis. 2006-2007;26:139-47. Links
Brain metastases of breast cancer.
Palmieri D, Smith QR, Lockman PR, Bronder J, Gril B, Chambers AF, Weil RJ, Steeg PS.
Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Central nervous system or brain metastases traditionally occur in 10-16% of metastatic breast cancer patients and are associated with a dismal prognosis. The development of brain metastases has been associated with young age, and tumors that are estrogen receptor negative, Her-2+ or of the basal phenotype. Treatment typically includes whole brain irradiation, or either stereotactic radiosurgery or surgery with whole brain radiation, resulting in an approximately 20% one year survival. The blood-brain barrier is a formidable obstacle to the delivery of chemotherapeutics to the brain. Mouse experimental metastasis model systems have been developed for brain metastasis using selected sublines of human MDA-MB-231 breast carcinoma cells. Using micron sized iron particles and MRI imaging, the fate of MDA-MB-231BR cells has been mapped: Approximately 2% of injected cells form larger macroscopic metastases, while 5% of cells remain as dormant cells in the brain. New therapies with permeability for the blood-brain barrier are needed to counteract both types of tumor cells.
PMID: 17473372
Thinking out louad. To get rid of the dormant cells, the bc stem cells, Dr. Max Wicha has started a trial of gamma secretase inhibitor (a drug normally tried vs. Alzheimer's so it must get into the brain)
How about seeing if those trials allow brain mets (U of Michigan, Baylor and one or two other sites if I recall correctly)
It is 224 am in Denmark, so got to get some ZZZZ
Try the website brainmets.org that Dr. Steeg advocates at all the meetings
06-12-2009, 05:26 PM #19
WomanofSteel
Senior Member
Join Date: Nov 2007
Location: New Jersey
Posts: 820
Marie, you already know how I feel. Holding you and Ed in prayer and a great big hug to you both.
06-12-2009, 05:29 PM #20
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,812
Sagopilone ( a relative of Ixempra)
9/11/08 2:10 PM
Sagopilone crosses the blood-brain barrier in vivo...[Neuro Oncol. 2008] - PubMed Result
Page 1 of 1
http://www.ncbi.nlm.nih.gov.laneprox...ubmed_RVDocSum
1: Neuro Oncol. 2008 Sep 9. [Epub ahead of print]
PMID: 18780814 [PubMed - as supplied by publisher]
Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor
growth and metastases.
Hoffmann J, Fichtner I, Lemm M, Lienau P, Hess-Stumpp H,
Rotgeri A, Hofmann B, Klar U.
Bayer Schering Pharma AG, TRG Oncology, Müllerstrasse 172178, 13342 Berlin,
Germany.
The aim of this study was to determine the efficacy of sagopilone
(ZK-EPO), a novel epothilone, compared with other anticancer agents
in human orthotopic models of primary and secondary brain tumors.
Autoradiography and pharmacokinetic analyses were performed on
rats and mice to determine passage across the blood-brain barrier
and organ distribution of sagopilone. Mice bearing intracerebral
human tumors (U373 or U87 glioblastoma, MDA-MB-435 melanoma,
or patient-derived non-small-cell lung cancer [NSCLC]) were treated
with sagopilone 510 mg/kg, paclitaxel 812.5 mg/kg (or temozolomide
100 mg/kg), or control (vehicle only). Tumor volume was measured
to assess antitumor activity. Sagopilone crossed the blood-brain
barrier in both rat and mouse models, leading to therapeutically
relevant concentrations in the brain with a long half-life. Sagopilone
exhibited significant antitumor activity in both the U373 and U87
human glioblastoma models, while paclitaxel showed a limited effect
in the U373 model. Sagopilone significantly inhibited the growth of
tumors from CNS metastases models (MDA-MB-435 melanoma and
patient-derived Lu7187 and Lu7466 NSCLC) implanted in the brains of
nude mice, in contrast to paclitaxel or temozolomide. Sagopilone has
free access to the brain. Sagopilone demonstrated significant
antitumor activity in orthotopic models of both glioblastoma and CNS
metastases compared with paclitaxel or temozolomide, underlining the
value of further research evaluating sagopilone in the treatment of
brain tumors. Sagopilone is currently being investigated in a broad
phase II clinical trial program, including patients with glioblastoma,
NSCLC, breast cancer, and melanoma.
Fulvestrant AKA ICI 182,780 best given monthly as double dose in buttocks crosses BBB
ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology
Articles by Alfinito, P. D.
Articles by Deecher, D. C.
Endocrinology, doi:10.1210/en.2008-0532
Endocrinology Vol. 149, No. 10 5219-5226
ICI 182,780 Penetrates Brain and
Hypothalamic Tissue and Has
Functional Effects in the Brain
after Systemic Dosing
Peter D. Alfinito, Xiaohong Chen, James Atherton,
Scott Cosmi and Darlene C. Deecher
Women’s Health and Musculoskeletal Biology (P.D.A., X.C., S.C.,
D.C.D.), Drug Safety and Metabolism (J.A.), Wyeth Research,
Collegeville, Pennsylvania 19426
Address all correspondence and requests for reprints to: Darlene C.
Deecher, Ph.D., Wyeth Research, RN 3164, 500 Arcola Road,
Collegeville, Pennsylvania 19426. E-mail:
deeched@wyeth.com.
Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not
cross the blood-brain barrier (BBB). However, this hypothesis has
never been directly tested. In the present study, we tested whether
ICI crosses the BBB, penetrates into brain and hypothalamic tissues,
and affects known neuroendocrine functions in ovariectomized rats.
ICI crosses the BBB and penetrates into brain and hypothalamic
tissues
An earlier report suggested that ICI did not cross the BBB of OVX
rats because it failed to block nuclear uptake of [3H]estradiol in
hypothalamic tissue after once daily dosing at 1.0 mg/kg sc for 3 d
(2). However, the ability of ICI to cross the BBB and penetrate brain
tissues was not directly tested in these experiments. In the present study, the same dosing
paradigm was followed as reported by Wade et al. (2) (Fig. 1A), and ICI levels were
measured in plasma and brain (total brain minus hypothalamus and pituitary) and hypothalamic
tissues over time. The ICI compound was detected in all samples and at all time points tested
(Fig. 1B). The concentrations and pharmacokinetic profiles of ICI in plasma, brain, and
hypothalamus were found to be similar (Fig. 1B and Table 1 ). ICI levels were stable in
plasma and brain and hypothalamic tissues over the entire 24-h testing period, and the
concentrations of ICI in plasma and hypothalamic tissue were similar at the 24-h time point.
TABLE 1. Pharmacokinetic profile of ICI (1.0 mg/kg, sc, 3 d) in
plasma and brain and hypothalamic tissues of OVX Sprague Dawley
rats over time
The ratio of brain to plasma exposure is an indication of a compound’s ability to cross the
BBB. Based on 24-h exposure values, brain and hypothalamus to plasma ratios for ICI were
0.33 and 0.66, respectively (Table 1 ). These results demonstrate that ICI crosses the BBB, is
present in brain and hypothalamic tissues, and persists at a constant level in plasma and brain
and hypothalamic tissues for up to 24 h after systemic dosing.
ICI blocks estrogenic actions in the MD model of hot flush but showed estrogenic-like
effects when administered alone
The MD model of hot flush is based on measuring naloxone-induced increases in TST in MD
OVX rats (17, 23). Previous work indicates that estrogen’s ability to abate TST elevations in
the MD model of hot flush occurs through its actions in the brain (18). To determine whether
11/6/08 8:20 AM
ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology
P
3), these results demonstrate that ICI rapidly crosses the BBB and persists for an extended
period of time in plasma and brain and hypothalamic tissues. Consistent with its ability to
penetrate brain tissues, repeated systemic administration of ICI blocked the effects of EE on
naloxone-induced TST elevations in the MD model of hot flush and on body weight change.
Interestingly, ICI administration alone (1.0 or 3.0 mg/kg·d) demonstrated weak estrogenic-like
activity in these models. We conclude that ICI is a brain-penetrable compound that can exert
functional (antiestrogenic and estrogenic) effects in the CNS, and specifically the
hypothalamus, after systemic dosing.
Previous studies have concluded that ICI does not cross the BBB because at up to 1.0 mg/kg·d,
it failed to block uptake of [3H]estradiol into nuclei of hypothalamic cells in OVX rats (2) and
failed to mimic the effects of OVX on body weight gain and plasma gonadotropin levels in
intact female rats (1). However, it is possible that these previous studies did not use a high
enough dose to observe inhibitory effects on these endpoints. For example, despite the presence
of ICI in brain and hypothalamic tissue after systemic administration of 1.0 mg/kg·d, we found
that this dose of ICI did not inhibit the effect of EE on all functional endpoints. The 1.0
mg/kg·d dose of ICI did partially inhibit the effect of EE on TST increases in the MD model
but did not block EE’s effect on body weight change. This functional selectivity may be
explained by the fact that ICI’s inhibitory effect on different estrogen-mediated brain functions
can vary depending on the endpoint being studied. For example, Steyn et al. (28) have shown
that intracerebroventricular administration of ICI inhibited estrogen-induced GnRH pulse
frequency but did not block estrogenic effects on progesterone receptor expression in the
hypothalamus or on antepartum prolactin surges. The authors concluded that there might be a
wide range of sensitivities to ICI in the brain that could cause variable results across different
functional endpoints. Thus, it is possible that inhibition of [3H]estradiol uptake into nuclei of
hypothalamic cells or blockade of estrogen’s effect on body weight change may require higher
levels of ICI than other functional endpoints. This idea is supported by our results showing that
ICI treatment at 3.0 mg/kg·d for 8 d did partially block the effect of EE on body weight change.
Because some previous studies (1, 2) only tested ICI at up to 1.0 mg/kg·d, it is unknown if
higher doses would have inhibited [3H]estradiol uptake into nuclei of hypothalamic cells in
OVX rats, or induced body weight gain or increased plasma gonadotropin levels in intact
female rats.
Several lines of evidence suggest that estrogens regulate body weight primarily through central
mechanisms that reduce meal size (15, 16, 29, 30, 31, 32). Lesions of the ventromedial nucleus
of the hypothalamus blocked the effect of systemically administered EB on body weight change
and food intake in OVX rats (29), infusion of estradiol directly into the paraventricular nucleus
or medial preoptic nucleus of the hypothalamus reduced body weight and/or food intake in
OVX rats (30, 31), and direct administration of EB to the hindbrain just above the nucleus
11/6/08 8:20 AM
ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology
tractus solitarius reduced food intake in OVX rats (32). However, these results have not been
reproduced in all laboratories (33), and several peripheral feedback mechanisms have been
hypothesized. Therefore, it remains possible that the ability of ICI to block the effect of EE on
body weight change in the present study could occur through peripheral not central
mechanisms. However, direct involvement of peripheral mechanisms in mediating estrogens
effect on body weight is lacking. It has been shown previously that estradiol treatment does not
inhibit feeding by modulating orosensory stimuli (15, 16). Estradiol treatment can inhibit
ghrelin-induced feeding, but this effect does not occur through reduction in meal size as is well
established for estrogens (15). Estradiol does increase the satiating potency of cholecystokinin,
but this effect likely occurs through an estradiol-induced increase in neuronal activity within
the brainstem, not through regulation of signaling in the periphery (15, 16). Finally, leptin
signaling does not appear to directly mediate estrogen’s effect on body weight because estradiol
has reduced body weight and food intake in both leptin-deficient and leptin receptor-deficient
mice (34). Thus, based on current evidence, estrogenic regulation of body weight appears to be
mediated through central mechanisms, and is an appropriate endpoint for predicting whether
ICI crosses the BBB and exerts functional effects in the CNS.
The effect of ICI on body weight has been reported previously in intact cycling female rats and
OVX estrogen-treated rats (2, 24). In these studies body weight changes were unaffected by
daily ICI treatment at either 1 or 1.5 mg/kg·d (higher doses were not tested), and it was
concluded that ICI did not cross the BBB. Our results are consistent with these studies because
the ability of ICI to block EE’s effect on body weight change was not observed at the 1.0
mg/kg·d dose. However, at the higher dose (3.0 mg/kg·d), ICI treatment did block the effect of
EE on body weight change. These data suggest that in previous studies in OVX rats, ICI may
not have been administered at a high enough dose to block estrogenic effects on body weight
regulation.
The effect of ICI alone on body weight change in OVX rats has also been tested previously (2,
24). Results from these studies also suggest that body weight change is unaffected by ICI
treatment at 1.0 or 1.5 mg/kg·d. These data are in contrast to our finding that ICI had weak
estrogenic-like actions on body weight change at both 1.0 and 3.0 mg/kg·d. The discrepancy
between the current work and previous studies is difficult to reconcile. There are several
technical differences such as rat strain and vendor and total treatment length that might account
for the discrepancy. One additional possibility is that the effect of ICI on body weight may vary
depending on initial body weights. In the present work, initial body weights averaged 215 g,
whereas in both other studies, initial body weights were approximately 270–276 g. It is possible
that in heavier rats, ICI may have a greater volume of distribution, increased sequestration into
adipose tissue, and/or increased plasma clearance. These possibilities are supported by studies
showing that increased body mass can alter the pharmacokinetic properties of some drugs (35).
11/6/08 8:20 AM
ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology
Therefore, the net result of these effects could be to reduce ICI exposure in brain tissue and
limit its ability to stimulate ER signaling. Importantly, it is unlikely that rats in our study
inadvertently received EE administration because uterine weights were similar to those from
vehicle-treated rats (Fig. 4 ).
Our results suggest that ICI has relatively low clearance in plasma and brain and hypothalamic
tissues of OVX rats when administered at 1 mg/kg·d for 3 d, and can persist in all three
compartments for at least 24 h after the last dose. In fact, the concentrations of ICI for each
tissue were found to be similar at the 0.5 and 24-h time points (Fig. 1B). This relatively low
clearance suggests that ICI could accumulate, particularly in lipid compartments such as brain
and adipose tissues, after daily systemic administration. Although somewhat speculative, this
type of accumulation could alter the pharmacokinetic and pharmacodynamic properties of ICI
over time. Consistent with this idea, ICI treatment at 1 mg/kg·d for 2 d did not block the effect
of EB on lordosis, ear wiggling, or hops and darts but reduced the effect of EB on all three
parameters when administered at 1 mg/kg·d for 24 d (2). Thus, the potential functional effects
of ICI on CNS-mediated endpoints may depend on both the doses tested and the time period
over which dosing is conducted.
A question that occurs is what are the relative roles of ER and β in mediating the effects of
ICI on the endpoints measured in the current study (i.e. TST regulation in the MD model and
body weight change). Because ICI binds to both receptors with similar affinities (36) and both
receptors appear to have broad distribution in the brain, including the hypothalamus (37), the
relative roles of the and β-subtypes are not easily discerned. Regarding body weight, several
studies suggest that estrogen’s effect is ER mediated. In support of this idea, in two separate
studies, the ER agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol decreased food
intake and body weight in OVX rats, whereas the ERβ agonist 2,3-bis(4-hyroxyphenyl)-
propionitrile had no effect (38, 39). In addition, EB had no effect on body weight and food
intake in OVX ER knockout mice, suggesting that the β-subtype is insufficient to mediate the
effect of estrogen on these endpoints (40). Finally, other studies have shown that estrogenic
inhibition of feeding occurs through ER-expressing neurons located in the nucleus tractus
solitarius (32). In contrast to these results, in a single study using oligonucleotide knockdown
of ERs in the brain, only ERβ antisense probes blocked the effect of estradiol on body weight
and food intake (41). However, the ability of their probes to reduce ER expression in the brain
was not reported. Thus, based on current data, it appears that the effect of ICI on body weight
change observed in the current study is mediated through the ER receptor subtype. However,
this hypothesis will need to be confirmed in future studies.
Less is known about the respective roles of the ER and β-receptor subtypes in temperature
regulation. Both receptors have been implicated in the regulation of TST elevations in mice
ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology
regulation.
The antiestrogenic properties of ICI in the brain as well as uterine tissues have been well
established (1, 28, 43, 44). However, results from our work and others suggest that ICI may not
be a pure antiestrogen. Intrahippocampal infusion of ICI has mimicked the effect of EB on
place learning in OVX rats (43). In addition, Sibonga et al. (24) have shown that, like 17 β-
estradiol (45), ICI treatment (1.5 mg/kg·d) decreases the cancellous bone formation rate in
OVX rats. Finally, in primary hippocampal neurons, both ICI and 17 β-estradiol promoted
neuronal survival against excitotoxic- and β amyloid-induced cell death, induced rapid calcium
influxes, increased spinophilin and Bcl-2 expression, and increased phosphorylation of ERK2
and Akt (25). Thus, ICI appears to have mixed antagonist and agonist properties, and its
pharmacology now seems to be more similar to other selective ER modulators (SERMs), such
as raloxifene and tamoxifen, then initially reported. The precise mechanisms supporting the
mixed pharmacology of ICI are unknown, however, it may be related to the differential
regulation of ER dimers in the absence or presence of an estrogen. It is well known that ER
dimerization is a key step in the activation of estrogen signaling pathways. Using a yeast two-
hybrid system, Wang et al. (46) found that ICI induced ER dimerization when given alone but
destabilized ER dimers in the presence of an estrogen. Therefore, it is possible that ICI-induced
receptor dimerization could lead to activation of estrogen responsive pathways, whereas
destabilization of ER dimers in the presence of an estrogen would block signaling. In support
of this idea, ICI was found to activate a subset of estrogen-responsive genes in MCF-7 cells, a
breast cancer cell line, grown in hormone-depleted medium (47). Although this explanation
might account for the antagonist and agonist-like effects of ICI observed in the MD model and
on body weight change in the current study, it cannot be broadly applicable to all endpoints
because ICI had no detectable estrogenic-like effect on uterine tissue. Currently, it is not well
understood how the tissue-selective agonist/antagonist properties of SERMs, like ICI,
tamoxifen, and raloxifene, manifest. It has been hypothesized that agonist/antagonist activities
of SERMs result from specific ligand-induced conformational changes in ERs that alter
coactivator/corepressor protein binding, and selectively influence different genomic and/or
nongenomic signaling pathways (48). In addition, cell-specific promoter context could play a
role in determining whether a SERM will elicit estrogenic or antiestrogenic actions.
The clinical use of ICI is not likely to be altered significantly by the results from the present
work. However, our results do offer a mechanistic explanation for the occurrence of hot flushes
in premenopausal women treated with fulvestrant (8). In addition, the use of fulvestrant in
premenopausal women would be expected to induce other CNS-related menopause-like
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ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology
Psymptoms such as sleep disturbances, mood changes, loss of energy, weight gain, and
decreased libido (49). Because most of these symptoms are not life threatening, it is unlikely
that they would limit the use of fulvestrant for treating advanced breast cancer patients.
Although we found that ICI has weak estrogenic-like activity on certain CNS-mediated
functions, it is also unlikely that these results will affect the use of fulvestrant for treating breast
cancer patients. Previous work has shown that ICI inhibits human breast cancer cell
proliferation (1), and agonist-like activity would be inconsistent with the studies showing the
utility of fulvestrant in treating ER-positive breast cancer (6, 7).
In summary, we have shown that, in contrast to previous conclusions, ICI is capable of crossing
the BBB, penetrating brain and hypothalamic tissues, and exerting functional effects on
neuroendocrine endpoints after systemic administration. We have also found that ICI is not a
pure antiestrogen, and may have a mix of both agonist and antagonist activities on certain
CNS-mediated functions. Therefore, future studies should consider the potential for ICI to
influence estrogen-related functions in the CNS after systemic dosing.
06-12-2009, 05:52 PM