Epigenetic combination therapy as a tumor-selective treatment approach for hepatocellular carcinoma.

@article{citeulike:2799349, abstract = {BACKGROUND: Innovative epigenetic therapeutics comprise histone deacetylase inhibitors (HDAC-I) and demethylating agents (DA). It was recently found that HDAC-I compounds exhibit profound therapeutic activities against hepatocellular carcinoma (HCC). A comprehensive preclinical investigation was performed on the potential of a combined HDAC-I/DA epigenetic regimen for the highly chemotherapy-resistant HCC entity. METHODS: Human HCC-derived cell lines or primary human hepatocytes (PHH) were treated with HDAC-I compound suberoylanilide hydroxamic acid (SAHA) or DA compound 5-aza-2'-deoxycytidine (5-aza-dC) or both and examined for cellular damage, proliferation, histone acetylation pattern, and DNA methylation. In vivo activities were investigated in a xenograft hepatoma model. RESULTS: Monotherapeutic application of SAHA or 5-aza-dC was found to induce substantial antiproliferative effects in HCC-derived cells, strongly enhanced by combined SAHA and 5-aza-dC treatment. PHH from different human donors did not exhibit any relevant cellular damage even when applying high doses of the combination regimen, whereas HCC-derived cell lines showed a dose-dependent damage. In vivo testing demonstrated a statistical significant inhibition of hepatoma cell growth for the combined treatment regime. CONCLUSIONS: Because the combined HDAC-I/DA epigenetic approach was found to produce significant antitumor effects in HCC model systems and did not impair cellular integrity of untransformed hepatocytes, this combination therapy is now considered for further investigation in clinical trials.}, address = {Department of Internal Medicine I, Medical University Clinic, Tubingen, Germany.}, author = {Venturelli, S. and Armeanu, S. and Pathil, A. and Hsieh, C. J. and Weiss, T. S. and Vonthein, R. and Wehrmann, M. and Gregor, M. and Lauer, U. M. and Bitzer, M. }, citeulike-article-id = {2799349}, doi = {10.1002/cncr.22652}, issn = {0008-543X}, journal = {Cancer}, month = {May}, number = {10}, pages = {2132--2141}, posted-at = {2008-05-14 17:06:36}, priority = {2}, title = {Epigenetic combination therapy as a tumor-selective treatment approach for hepatocellular carcinoma.}, url = {http://dx.doi.org/10.1002/cncr.22652}, volume = {109}, year = {2007} }

TY - JOUR ID - citeulike:2799349 L3 - citeulike-article-id:2799349 TI - Epigenetic combination therapy as a tumor-selective treatment approach for hepatocellular carcinoma. JF - Cancer VL - 109 IS - 10 SP - 2132 EP - 2141 AD - Department of Internal Medicine I, Medical University Clinic, Tubingen, Germany. SN - 0008-543X N2 - BACKGROUND: Innovative epigenetic therapeutics comprise histone deacetylase inhibitors (HDAC-I) and demethylating agents (DA). It was recently found that HDAC-I compounds exhibit profound therapeutic activities against hepatocellular carcinoma (HCC). A comprehensive preclinical investigation was performed on the potential of a combined HDAC-I/DA epigenetic regimen for the highly chemotherapy-resistant HCC entity. METHODS: Human HCC-derived cell lines or primary human hepatocytes (PHH) were treated with HDAC-I compound suberoylanilide hydroxamic acid (SAHA) or DA compound 5-aza-2'-deoxycytidine (5-aza-dC) or both and examined for cellular damage, proliferation, histone acetylation pattern, and DNA methylation. In vivo activities were investigated in a xenograft hepatoma model. RESULTS: Monotherapeutic application of SAHA or 5-aza-dC was found to induce substantial antiproliferative effects in HCC-derived cells, strongly enhanced by combined SAHA and 5-aza-dC treatment. PHH from different human donors did not exhibit any relevant cellular damage even when applying high doses of the combination regimen, whereas HCC-derived cell lines showed a dose-dependent damage. In vivo testing demonstrated a statistical significant inhibition of hepatoma cell growth for the combined treatment regime. CONCLUSIONS: Because the combined HDAC-I/DA epigenetic approach was found to produce significant antitumor effects in HCC model systems and did not impair cellular integrity of untransformed hepatocytes, this combination therapy is now considered for further investigation in clinical trials. AU - Venturelli, S AU - Armeanu, S AU - Pathil, A AU - Hsieh, CJ AU - Weiss, TS AU - Vonthein, R AU - Wehrmann, M AU - Gregor, M AU - Lauer, UM AU - Bitzer, M PY - 2007/05/15/ UR - http://dx.doi.org/10.1002/cncr.22652 ER -