1000% increase in chemotherapy efficiency with prozac!

[DianneS]

I think that's why it's important to get tested with the CPY2D6 metabolizer test to see if you metabolize Tamoxifen poorly, intermediate, normal or hypermetabolize. The dosing for Tamoxifen would be individualized based upon how you metabolize the drug. Genelex can do the test as well as Mayo. Genelex charges $295 which may be covered under some insurance.

Dianne

[fullofbeans]

Well my 2 cents..

Why would there be a multimillion pound trials for a product that is already approved with many generic one available..it would not be cost efficient for any pharmaceutical company to undertake me think.

As I said chemo is just active for few minutes/hours at bestafter IV so really I think it would just be a matter of taking prozac perhaps just few days before or perhaps just during chemo treatments, what ever you feel may be appropriate.

I would not venture into trying other forms that the one we have data for, what would be the point. As to interaction with tamoxifen well as explained before it would not be taken for long. And as a matter of fact there is a debate as to whether one should take inhibitors during chemos..

As I said before I am not advising simply putting the info and my thoughts out there..

[Rich66]

Sure about the short active time-frame of chemo? Intuitively, it would seem much longer given that nadir is usually a week out or so for typical chemos. And the recent Dox followed by Zometa info suggests at least 24 hours separation for benefit.
Regardless, however it works, seems like benefits of this combo should be pursued. To start with, how about everyone ask their oncs about it?

[fullofbeans]

Pretty sure (but will try to find out where I read this to confirm). I remember thinking the same as you did when reading the info and being surprised too. But no it is broken down quickly by the body (defending itself) and the weeks that follow chemo is used to deal with the cellular damages and metabolites created (which we associate with chemo action but it is in fact chemo effects).

Well indeed 24h separation is not long in any case..

And indeed again if you in the USA have onconlogists that are ready to sit down and take the time to read this and are open to suggestions and progressive then yes it would be great to ask!

And there is no counter indication for you to use it then it seems that there is little to be lost..IMHO

[Rich66]

HDACs, thought to help defeat cancer stem cells, compared to Fluoxetine.

A recent paper in the Journal of
Neuroscience has shown that inhibitors
of histone deacetylases (HDACs)
— enzymes that affect the acetylation
status of histones and regulate the
remodelling of chromatin — have
antidepressant actions.
Although currently used antidepressants
rapidly modulate
mono aminergic systems in the
brain, the emergence of their moodelevating
effects requires several
weeks of administration, which
suggests that altered gene expression
is involved in antidepressant action.
So, compounds that modulate
the epigenetic regulation of gene
expression, such as HDAC inhibitors,
might have antidepressant actions.
Nestler and colleagues used a
mouse model of chronic social defeat
to investigate histone acetylation in
depression and the effect of HDAC
inhibitors in the nucleus accumbens,
which is a brain region implicated in
the development of depression and
antidepressant action.
Immunohistochemical analysis
showed that, although acetylation
levels of histone H3 at lysine
residue 14 (acH3K14) decreased
transiently by ~50% 1 hour after
the final stress event, there was an
increase at 24 hours and 10 days.
Expression levels of HDAC2, but
not of HDAC1 or HDAC3, were
decreased 24 hours and 10 days after
the final stress event, suggesting that
this could mediate the increase in
acH3K14 levels. A similar increase
in acH3K14 levels, accompanied
by a decrease in HDAC2 levels,
was present in postmortem
samples
of the nucleus accumbens from
depressed humans.
Infusion of the HDAC inhibitors
vorinostat (a class I and II HDAC
inhibitor) or MS275
(a class I
HDAC inhibitor) into the nucleus
accumbens of mice that were
subjected to chronic socialdefeat
stress reversed stressinduced
social
avoidance and increased the amount
of time that the mice spent socially
interacting. In forcedswim
tests,
which are often used as an acute
screen for antidepressants, both
inhibitors showed antidepressantlike
effects but had no effect on anxietylike
behaviour.
As chronic socialdefeat
stress
leads to distinctive patterns of gene
expression in the nucleus acumbens,
which can almost be normalized by
fluoxetine treatment, the authors
tested the effects of MS275
on gene
expression using microarray analysis.
Like fluoxetine, MS275
mostly
reversed stressinduced
genomic
changes, and both fluoxetine and
MS275
treatment caused similar
changes in the expression patterns
of many genes. The regulation of
certain genes by chronic stress
was reversed by MS275
but not
fluoxetine, which might reveal new
targets for antidepressant action.
These included genes encoding gap
junction membrane channel protein
α5 (which is involved in gap junction
formation), discs largeassociated
protein 1 (which assembles postsynaptic
density complexes) and
the α1αadrenergic
receptor.
So, although selectivity and
delivery issues remain to be resolved,
HDAC inhibitors, which are in
clinical trials for cancer indications,
might also have therapeutic potential
in depression.
Charlotte Harrison
ORIGINAL RESEARCH PAPER
Covington, H. E. et al. Antidepressant actions of
histone deacetylase inhibitors. J. Neurosci. 29,
11451–11460 (2009)
FuRtHER REAdING Kazantsev, A. G. &
Thompson, L. M. Therapeutic application of
histone deacetylase inhibitors for central
nervous system disorders. Nature Rev. Drug
Discov. 7, 854–868 (2008)
MOOd dISORdERS
Antidepressant action
through gene regulation
ReseaRch highlights
NATurE rEvIEwS | Drug Discovery voLuME 8 | NovEMbEr 2009
© 2009 Macmillan Publishers Limited. All rights reserved

[jones7676]

I've been real depressed lately, I wonder if I should give it a whirl? Maybe I will talk to the Doc next Thursday.

[v-ness]

rich66 - i am curious about what you wrote on this subject about valproic acid (depakote). i happen to be on it and would like to know what effect, if any, it has on chemo. thank you. valerie

[Rich66]

On this thread..still waiting to for Dr. Peer to release more helpful data regarding Prozac/Chemo synergy.

On Valproic acid and chemo,
Possibly quite helpful.

I posted some abstracts on HDAC inhibitors and benefit against presumed cancer stem cells. HDACs may also reduce resistance to endocrine therapy. It very well may depend on the exact combinations used. But these would be good items to mention to your onc:


Histone deacetylase inhibitors as a new weapon in the arsenal of differentiation therapies of cancer.

Botrugno OA, Santoro F, Minucci S.
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Absent or altered differentiation is one of the major features of cancer cells. Histone deacetylases (HDACs) play a central role in the epigenetic regulation of gene expression. Aberrant activity of HDACs has been documented in several types of cancers, leading to the development of HDAC inhibitors (HDACi) as anti-tumor drugs. In vitro and in vivo experimental evidences show that HDACi are able to resume the process of maturation in undifferentiated cancer cells, justifying their introduction as differentiating agents in several clinical trials. Modulation of cell fate by HDACi is observed at several levels, including the stem cell compartment: HDACi can act both on cancer stem cells, and with the rest of the tumor cell mass, leading to complex biological outputs. As a note of caution, when used as single agent, HDACi show only a moderate and limited biological response, which is augmented in combinatorial therapies with drugs designed against other epigenetic targets. The optimal employment of these molecules may be therefore in combination with other epigenetic drugs acting against the set of enzymes responsible for the set-up and maintenance of epigenetic information.
PMID: 19345000

1: Clin Cancer Res. 2009 Apr 1;15(7):2488-96. Epub 2009 Mar 24. Links
Clinical and biological effects of valproic acid as a histone deacetylase inhibitor on tumor and surrogate tissues: phase I/II trial of valproic acid and epirubicin/FEC.

Munster P, Marchion D, Bicaku E, Lacevic M, Kim J, Centeno B, Daud A, Neuger A, Minton S, Sullivan D.
Division of Hematology Oncology, University of California, San Francisco, Divisadero, San Francisco, California 94143-1711, USA. pmunster@medicine.ucsf.edu
PURPOSE: The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies. EXPERIMENTAL DESIGN: A phase I dose escalation of valproic acid given on days 1 to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets. RESULTS: Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid-associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression. CONCLUSION: Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.
PMID: 19318486

J Mammary Gland Biol Neoplasia. 2009 Mar;14(1):45-54. Epub 2009 Feb 28.
Resistance to endocrine therapy: are breast cancer stem cells the culprits?

O'Brien CS, Howell SJ, Farnie G, Clarke RB.

"A common theme of many investigations into CSCs is that they have inherent resistance to chemo and radiotherapy. This is proposed to be due to mechanisms such as more efficient DNA damage checkpoints and survival pathways compared to more differentiated tumor
cell populations."

"Enhanced interaction between estrogen receptor signalling and growth factor tyrosine kinase pathways such as EGFR, HER2/erbB2 and IGFR mediates resistance to endocrine therapy"

"HDAC inhibitors are being used in a number of on going clinical trials including a phase II trial evaluating vorinostat in ER positive patients with metastatic breast cancer who failed prior aromatase inhibitor therapy and up to three chemotherapy regimes [95]. A report of preliminary findings presented at ASCO 2008 showed that out of the 17 enrolled patients 21% had a partial response and 29% had stable disease after treatment with vorinostat 400 mg daily for 3 of 4 weeks and tamoxifen 20 mg daily,
continuously. These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have failed prior aromatase inhibitors or adjuvant tamoxifen may restore hormone sensitivity."

[v-ness]

hm. they're experimenting with only 120 mgs.... i take 1250! maybe i have some valproic acid whammo to back up my chemo! wouldn't *that* be nice. i already loved the fact that it just happens to also stop migraines, which i had before and which have now disappeared. a triple bennie med. thank you for the information. valerie

[Rich66]

120 mg/kg/day is a weight based dose equation, not actual dose. 1kg = 2.2 lbs. So they were administering roughly 60mg for each pound of patient presenting. You are either very petite or getting lower dose http://acronyms.thefreedictionary.com/MG%2FKG%2FDAY

[fullofbeans]

Just updating this thread with more (good) news on prozac.

http://www.dailymail.co.uk/health/ar...ht-cancer.html

I want to work out a bit more on which chemo prozac has been found to sensitise the cancer cell.. has anyone looked at that already?

[fullofbeans]

And more:

Please note that I have looked at the article unrelated to tamoxifen & prozac since I am ER negative but there seem to be some issues with that.

Fluoxetine induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats.

http://www.ncbi.nlm.nih.gov/pubmed/21554931


Abstract

Fluoxetine (FLX) is a drug commonly used as antidepressant. However, its effects on tumorigenesis remain controversial. Aiming to evaluate the effects of FLX treatment on early malignant changes, we analyzed serotonin (5-HT) metabolism and recognition, aberrant crypt foci (ACF), proliferative process, microvessels, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) expression in colon tissue. Male Wistar rats received a daily FLX-gavage (30mgkg(-1)) and, a single dose of 1,2 dimethylhydrazine (DMH; i.p., 125mgkg(-1)). After 6 weeks of FLX-treatment, our results revealed that FLX and nor-fluoxetine (N-FLX) are present in colon tissue, which was related to significant increase in serotonin (5-HT) levels (P<0.05) possibly through a blockade in SERT mRNA (serotonin reuptake transporter; P<0.05) resulting in lower 5-hydroxyindoleacetic acid (5-HIAA) levels (P<0.01) and, 5-HT2C receptor mRNA expressions. FLX-treatment decreased dysplastic ACF development (P<0.01) and proliferative process (P<0.001) in epithelia. We observed a significant decrease in the development of malignant microvessels (P<0.05), VEGF (P<0.001), and COX-2 expression (P<0.01). These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue, probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events





http://www.ncbi.nlm.nih.gov/pubmed/21497159
Oral administration of fluoxetine alters the proliferation/apoptosis balance of lymphoma cells and up-regulates T cell immunity in tumor-bearing mice.


Abstract

Antidepressants have a controversial role with regard to their influence on cancer and immunity. Recently, we showed that fluoxetine administration induces an enhancement of the T-cell mediated immunity in naïve mice, resulting in the inhibition of tumor growth. Here we studied the effects of fluoxetine on lymphoma proliferation/apoptosis and immunity in tumor bearing-mice. We found an increase of apoptotic cells (active Caspase-3(+)) and a decrease of proliferative cells (PCNA(+)) in tumors growing in fluoxetine-treated animals. In addition, differential gene expressions of cell cycle and death markers were observed. Cyclins D3, E and B were reduced in tumors from animals treated with fluoxetine, whereas the tumor suppressor p53 and the cell cycle inhibitors p15/INK4B, p16/INK4A and p27/Kip1 were increased. Besides, the expression of the antiapoptotic factor Bcl-2 and the proapoptotic factor Bad were lower and higher respectively in these animals. These changes were accompanied by increased IFN-γ and TNF-α levels as well as augmented circulating CD8(+) T lymphocytes in tumor-bearing mice treated with the antidepressant. Therefore, we propose that the up-regulation of T-cell mediated antitumor immunity may be contributing to the alterations of tumor cell proliferation and apoptosis thus resulting in the inhibition of tumor



Development of stealth liposome coencapsulating doxorubicin and fluoxetine.



Abstract

Stealth liposomes form an important subset of liposomes, demonstrating prolonged circulation half-life and improved safety in vivo. Caelyx(®) (liposomal doxorubicin; Merck & Co., Whitehouse Station, New Jersey, USA) is a successful example of the application of stealth liposomes in anticancer treatment. However, multidrug resistance (MDR) to chemotherapy still remains a critical problem, accounting for more than 90% of treatment failure in patients with advanced cancer. To circumvent MDR, fluoxetine and doxorubicin were tested in combination for synergistic activity in MCF-7 (human breast carcinoma) and MCF-7/adr (doxorubicin-resistant human breast carcinoma) cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell-viability assay. Coencapsulation of doxorubicin and fluoxetine, using an ammonium sulphate gradient, was investigated, and a factorial experiment was designed to determine the optimal drug-to-lipid (D/L) ratio for coencapsulation. Drug release from Dox-Flu-SL (stealth liposome coencapsulating doxorubicin and fluoxetine) under both in vitro and in vivo conditions was determined. In MCF-7 cells, synergism was demonstrated at specific doxorubicin:fluoxetine ratios of between 0.09 and 0.5 (molar ratio), while MCF/7/adr cells demonstrated synergism across all drug ratios. Coencapsulation of doxorubicin and fluoxetine (Dox-Flu-SL) was successfully achieved (optimal doxorubicin:fluoxetine:lipid molar ratio of 0.02:0.05:1), obtaining a mean concentration of 257 ± 12.1 and 513 ± 29.3 µM for doxorubicin and fluoxetine, respectively. Most important, Dox-Flu-SL demonstrated drug release in synergistic ratios in cell-culture media, accounting for the improved cytotoxicity of Dox-Flu-SL over liposomal doxorubicin (LD) in both MCF-7 and MCF-7/adr cells. Pharmacokinetic studies also revealed that Dox-Flu-SL effectively prolonged drug-circulation time and reduced tissue biodistribution. Dox-Flu-SL presents a promising anticancer formulation, capable of effective reversal of drug resistance, and may constitute a novel approach for cancer therapy.