Pifithrin-α as a potential cytoprotective agent in radiotherapy: protection of normal tissue without decreasing therapeutic efficacy in glioma cells.

Abstract

Activation of p53 has been causally linked to normal tissue damage after irradiation. Pifithrin-α (PFT-α), a specific inhibitor of p53, has been suggested as a combinatory agent in the treatment of p53-deficient tumors in which inhibition of p53 would not compromise therapeutic efficacy but would decrease p53-mediated side effects in normal tissue. We tested this concept for radiotherapy of p53-deficient and -proficient glioma. We observed significant interaction of PFT-α with radiation-induced G(1) checkpoint activation and plating efficiency only in glioma cells expressing at least one wild-type allele of p53. This interaction was correlated with PFT-α-mediated inhibition of radiation-induced expression of the p53 target gene p21(Waf1). Despite inhibition of p53 function we did not observe significant changes in radiosensitivity after treatment with PFT-α in either p53-deficient or p53-proficient tumor cells. We confirmed these results in p53-proficient lung cancer cells. In contrast, PFT-α significantly increased the fraction of normal astrocytes and fibroblasts surviving irradiation; this was accompanied by improved DNA damage repair, speaking against an accumulation of cells with genetic lesions after PFT-α treatment. In conclusion, PFT-α might prove useful in protecting normal tissue from the side effects of radiotherapy without reducing the efficacy of treatment for both p53-proficient and -deficient tumors.

• Authors: Brigitte Sinn, Joern Schulze, Gisela Schroeder, Robert Konschak, Dorette Freyer, Volker Budach, Ingeborg Tinhofer
• Journal: Radiation research (Radiat Res) Vol. 174 Issue 5 Pg. 601-10 (Nov 2010) ISSN: 1938-5404 [Electronic] United States
• PMID: 20718603 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzothiazoles
• Tumor Suppressor Protein p53
• Toluene
• pifithrin

Topics

• Animals
• Astrocytes (drug effects, metabolism, radiation effects)
• Benzothiazoles (pharmacology)
• Cell Line, Tumor
• Cytoprotection (drug effects)
• Fibroblasts (drug effects, metabolism, radiation effects)
• G1 Phase (drug effects, radiation effects)
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Glioma (genetics, metabolism, pathology, radiotherapy)
• Humans
• Radiation Injuries (pathology, prevention & control)
• Radiation Tolerance (drug effects)
• Rats
• Toluene (analogs & derivatives, pharmacology)
• Tumor Suppressor Protein p53 (deficiency, metabolism)