Long-term in vivo effects of cisplatin on gamma-H2AX foci signaling in peripheral lymphocytes of tumor patients after irradiation

Clin Cancer Res. 2009 Apr 15;15(8):2927-34. doi: 10.1158/1078-0432.CCR-08-0650. Epub 2009 Mar 31.

Abstract

Purpose: This study determined the effects of cis-diamminedichloroplatinum(II) on radiation-induced foci formation of gamma-H2AX and Rad51 in lymphocytes.

Experimental design: Twenty-eight cancer patients were irradiated for intrathoracic, pelvic, or head and neck tumors and received simultaneous cisplatin containing chemotherapy. The effect of cisplatin on radiation-induced gamma-H2AX and Rad51 foci as a response to ionizing radiation-induced DNA double-strand breaks was measured in lymphocytes after in vivo and in vitro radiochemotherapy. The role of DNA-dependent protein kinase and ataxia-telangiectasia mutated kinase in gamma-H2AX signaling, the consequences of altered gamma-H2AX foci formation on double-strand break end joining, was studied.

Results: Cisplatin decreased the number of induced gamma-H2AX foci in lymphocytes after in vivo or in vitro irradiation by 34% +/- 6% at days 0 to 3 after cisplatin (P < 0.0001) and remained significant until day 6. The variation in this cisplatin effect from patient to patient was larger than the retest error within the same patient (P = 0.01). The cisplatin effect was not accompanied by an inhibition of end joining of double-strand break as analyzed using gel electrophoresis of DNA under neutral conditions. Cisplatin also decreased radiation induced Rad51 foci formation in lymphocytes after stimulation of proliferation with phytohemagglutinin by 47% +/- 6% (P < 0.0001).

Conclusion: Cisplatin has long-term effects on the early double-strand break response of gamma-H2AX and Rad51 foci formation after ionizing radiation. Inhibition of sensing and processing of double-strand break by gamma-H2AX and Rad51 foci formation are important mechanisms by which cisplatin can alter the radiation response.

MeSH terms

  • Cisplatin / administration & dosage*
  • Combined Modality Therapy
  • DNA Breaks, Double-Stranded
  • Enzyme Inhibitors / pharmacology
  • Gamma Rays
  • Histones / metabolism*
  • Humans
  • Lymphocytes / drug effects*
  • Lymphocytes / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / radiotherapy
  • Neoplasms / therapy*
  • Phytohemagglutinins / pharmacology
  • Rad51 Recombinase / metabolism*
  • Radiation-Sensitizing Agents / administration & dosage*
  • Time

Substances

  • Enzyme Inhibitors
  • H2AX protein, human
  • Histones
  • Phytohemagglutinins
  • Radiation-Sensitizing Agents
  • RAD51 protein, human
  • Rad51 Recombinase
  • Cisplatin