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

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.

Hyperfractionated accelerated radiotherapy versus conventional fractionation both combined with chemotherapy in patients with locally advanced head and neck carcinomas: a retrospective analysis of a monoinstitutional series.

OBJECTIVE: Hyperfractionated accelerated radiotherapy (HART) has been combined with chemotherapy (CC) for locally advanced head and neck cancer, but no data from randomized trials are available for a comparison with conventionally fractionated radiotherapy (CFRT) and CC. METHODS: This monoinstitutional retrospective study compares the results of both treatment schedules: 315 patients with locally advanced carcinoma (UICC stage III and IV) of the oral cavity and the orohypopharynx were treated from January 1990 to March 2006 with a radiochemotherapy combination based on mitomycin C and fluorouracil (HART-CC: 203 patients, CFRT-CC: 112 patients, total dose: 70-72 Gy) with curative intent. RESULTS: Two- and 4-year survival was 60 and 42 (HART-CC) and 59 and 42% (CFRT-CC; p = 0.82, log-rank test), respectively. Using multivariate Cox regression, pretreatment hemoglobin level, N stage, tumor site but not the year of treatment, gender and T stage were significant prognosticators for survival. For locoregional control, only N stage was significant. The prognostic value of these pretreatment factors did not variate with the fractionation schedule used. CONCLUSIONS: In combination with CC, there was no trend towards an improved efficacy of HART in comparison with CFRT.