HER2 Support Group Forums - View Single Post - 1000% increase in chemotherapy efficiency with prozac!

Rich66 · 01-29-2010, 09:15 PM

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."

01-29-2010, 09:15 PM	#28
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: 1000% increase in chemotherapy efficiency with prozac! 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." __________________ Mom's treatment history (link)