Translation on this Article from γH2AX Expression in Tumors Exposed to Cisplatin and Fractionated Irradiation
ARTICLE ABSTRACT
Purpose: Is retention of γH2AX foci useful as a biomarker for predicting the response of xenograft tumors to cisplatin with X-ray? Is a similar approach feasible using biopsies from patients with cervical cancer?Experimental Design: Mice bearing SiHa, WiDr, or HCT116 xenograft tumors were exposed to cisplatin and/or three daily doses of 2 Gy. Tumors were excised 24 h after treatment and single cells were analyzed for clonogenic fraction and retention of γH2AX foci. Tumor biopsies were examined using 47 paraffin-embedded sections from untreated tumors and 24 sections from 8 patients undergoing radiochemotherapy for advanced cancer of the cervix.Results: Residual γH2AX measured 24 h after cisplatin injection accurately predicted surviving fraction in SiHa and WiDr xenografts. When a clinically equivalent protocol using cisplatin and fractionated irradiation was employed, the fraction of xenograft cells lacking γH2AX ranked survival accurately but underestimated tumor cell kill. Residual γH2AX foci were detected in clinical samples; on average, only 25% of tumor nuclei exhibited one or more γH2AX foci before treatment and 74% after the start of treatment.Conclusion: γH2AX can provide useful information on the response of human tumors to the combination of cisplatin and radiation, but prediction becomes less accurate as more time elapses between treatment and tumor biopsy. Use of residual γH2AX as a biomarker for response is feasible when cell survival exceeds ∼20%, but heterogeneity in endogenous and treatment-induced γH2AX must be considered.
