p53 function influences the effect of fractionated radiotherapy on glioblastoma tumors

被引:63
作者
Haas-Kogan, DA
Kogan, SS
Yount, G
Hsu, J
Haas, M
Deen, DF
Israel, MA [1 ]
机构
[1] Univ Calif San Francisco, Dept Neurol Surg, Brain Tumor Res Ctr, Preuss Lab Mol Neurooncol, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Sch Med, Dept Radiat Oncol, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Sch Med, GW Hooper Fdn, San Francisco, CA 94143 USA
[4] Univ Calif San Diego, Dept Biol, San Diego, CA 92103 USA
来源
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS | 1999年 / 43卷 / 02期
关键词
cell cycle; fractionation; glioblastoma; p53; radiotherapy;
D O I
10.1016/S0360-3016(98)00393-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Glioblastoma multiforme brain tumors (GM) are treated with a spectrum of fractionation regimens based on the clinical and anatomical characteristics of the tumor but rarely based on the molecular characteristics of the individual neoplasm. This study tests the hypothesis that the response of cell lines derived from GM to fractionated radiotherapy depends on the function of wild-type p53 (wt p53), a tumor suppressor gene frequently mutated in GM tumors. Methods & Materials: Isogenic derivatives of glioblastoma cells differing only in p53 function were prepared using a retroviral vector expressing a dominant negative mutant of p53 (mt p53). Radiation survival in vitro was quantitated using linear quadratic and repair-saturation mathematical models. Apoptosis was assayed by a terminal deoxynucleotide transferase-labeling technique and chromatin morphology. Results: We have previously reported the generation of isogenic GM cell lines differing only in p53 function. U87-175.4, lacking wt p53 function, had a significantly lower alpha/beta value than U87-LUX.8, expressing functional wt p53, leading us to hypothesize that fractionated irradiation would preferentially spare GM cells harboring mt p53 compared with those expressing functional, wt p53. Survival curves following either 2.0 Gy or 3.5 Gy/fraction demonstrated that lack of functional wt p53 was associated with resistance to fractionated irradiation. Radiation-induced apoptosis could not account for the observed differences in clonogenic survival. Rather, our data suggested that a deficit in the G1-checkpoint contributed to increased resistance to fractionated irradiation of cells expressing mutant p53. Conclusions: The effect of fractionated radiotherapy in GM may depend on the function of the tumor suppressor gene p53. A potential clinical consequence of these findings is that hyperfractionation regimens may provide a therapeutic advantage specifically for tumors expressing wt p53 whereas a radiotherapy course of fewer, larger fractions may be appropriate for the treatment of tumors carrying p53 mutations. Further studies are needed to confirm our proposal that the p53 status of GM tumors can be used to guide our choice of fractionation schemes. (C) 1999 Elsevier Science Inc.
引用
收藏
页码:399 / 403
页数:5
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