Abstract | PURPOSE: EXPERIMENTAL DESIGN: As an indicator of HDAC inhibition in vivo, the histone acetylation status in tumor lysates was determined after two, four, and six injections of MS-275 delivered at 12-hour intervals, as well as 24 and 48 hours after the last injection. Tumor growth delay studies were then performed using this DU-145 xenograft model with radiation administered to leg tumors after the fourth dose of MS-275, which corresponded to the time of maximum histone hyperacetylation. RESULTS: An increase in histone hyperacetylation was detected in each tumor after two injections of MS-275 with a maximum hyperacetylation occurring after four to six injections. In tumor growth delay studies, the combination of MS-275 and radiation resulted in a greater than additive inhibition of tumor growth as compared with the individual modalities. As alternative sources for an indicator of drug radiosensitizing activity, histone hyperacetylation was determined in a series of normal tissues, including lymphocytes. Each of the normal tissues also had a maximal histone hyperacetylation after four to six injections of MS-275. CONCLUSIONS: These studies show that MS-275 enhances the radiosensitivity of DU145 xenografts and suggest that histone hyperacetylation status can serve as a useful marker for drug radiosensitizing activity.
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Authors | Kevin Camphausen, Tamalee Scott, Mary Sproull, Philip J Tofilon |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 10
Issue 18 Pt 1
Pg. 6066-71
(Sep 15 2004)
ISSN: 1078-0432 [Print] United States |
PMID | 15447991
(Publication Type: Journal Article)
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Chemical References |
- Benzamides
- Biomarkers, Tumor
- Histone Deacetylase Inhibitors
- Histones
- Pyridines
- Radiation-Sensitizing Agents
- entinostat
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Topics |
- Acetylation
- Animals
- Benzamides
(pharmacology)
- Biomarkers, Tumor
- Biopsy
- Cell Line, Tumor
- Cell Proliferation
- Histone Deacetylase Inhibitors
- Histones
(metabolism)
- Humans
- Lymphocytes
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, SCID
- Neoplasm Transplantation
- Prostatic Neoplasms
(metabolism)
- Pyridines
(pharmacology)
- Radiation Tolerance
- Radiation-Sensitizing Agents
(pharmacology)
- Time Factors
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