gammaH2AX expression in tumors exposed to cisplatin and fractionated irradiation.
OBJECTIVE
Is retention of gammaH2AX 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?


METHODS
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 gammaH2AX 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 gammaH2AX 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 gammaH2AX ranked survival accurately but underestimated tumor cell kill. Residual gammaH2AX foci were detected in clinical samples; on average, only 25% of tumor nuclei exhibited one or more gammaH2AX foci before treatment and 74% after the start of treatment.


CONCLUSIONS
gammaH2AX 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 gammaH2AX as a biomarker for response is feasible when cell survival exceeds approximately 20%, but heterogeneity in endogenous and treatment-induced gammaH2AX must be considered.
Bañuelos
C Adriana
CA
Medical Biophysics Department, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Banáth
Judit P
JP
Kim
Joo-Young
JY
Aquino-Parsons
Christina
C
Olive
Peggy L
PL
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D045325:HCT116 Cells; D006657:Histones / Q000096:biosynthesis*; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D018365:Neoplasm, Residual / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C468783:H2AX protein, human; D006657:Histones; D002945:Cisplatin