Pifithrin-α as a potential cytoprotective agent in radiotherapy: protection of normal tissue without decreasing therapeutic efficacy in glioma cells.
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.
Sinn
Brigitte
B
Translational Radiobiology & Radiooncology Research Laboratory, Department of Radiotherapy, Charité Universitätsmedizin-Berlin, Germany.
Schulze
Joern
J
Schroeder
Gisela
G
Konschak
Robert
R
Freyer
Dorette
D
Budach
Volker
V
Tinhofer
Ingeborg
I
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D052160:Benzothiazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016193:G1 Phase / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D006801:Humans; D011832:Radiation Injuries / Q000473:pathology / Q000517:prevention & control; D011836:Radiation Tolerance / Q000187:drug effects; D051381:Rats; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism
D052160:Benzothiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin