Yoko Nagata

p53- dependent hyperthermic enhancement of tumour growth inhibition by X-ray or carbon-ion beam irradiation

To elucidate p53 -dependency on combined treatment with radiation and hyperthermia, growth inhibition and apoptosis were analysed using transplantable human tumour. Human head and neck squamous cell carcinoma (HNSCC) cells carrying different p53 genes were transplanted into the thigh of nude mice. When the mean diameter of tumour reached 5-6 mm, the tumours were exposed to X-rays (2 Gy) or Carbon-ion (C-) beams (1 Gy) followed by heating at 42°C for 20 min. Tumour growth inhibition was evaluated by measuring the diameters of tumour. The induction of apoptosis and accumulation of apoptosis-related proteins were also analysed by immunohistochemical staining. Synergistic enhancement of tumour growth inhibition by hyperthermia was observed in wild-type p53 tumours treated with X-rays or C-beams but not in mutant p53 tumours. The incidence of apoptotic cells and activated-caspase-3-positive cells after combined treatment with them were significantly high in wild-type p53 tumours compared with that in mutant p53 tumours. The hyperthermic enhancement of tumour growth inhibition by X-ray- or C-beam-irradiation was p53 -dependent, suggesting that it might be highly correlated with p53 -dependent apoptosis.

Effects of a simple intraoperative intrathoracic hyperthermotherapy for lung cancer with malignant pleural effusion or dissemination

We examined the effect of a simple intraoperative intrathoracic hyperthermotherapy (IIH) and a simple intraoperative intrathoracic hyperthermo-chemotherapy (IIHC) on malignant pleural effusion and/or dissemination with primary non-small lung cancer. This study included 19 patients who had malignant pleural effusion and/or dissemination recognized for the first time at the time of surgery. We performed surgical procedures on the primary lesions and then the additional therapies followed. Seven patients received IIH (group A), five patients underwent IIHC (group B), and seven patients did not have any additional therapy (group C). There was no death during the follow-up period (9-35 months) in the group A. The median survival time was 41 months in the group B and 25 months in the group C. The group A was completely free of pleural effusion and one patient in the group B suffered from pleural effusion 26 months after surgery, although the median term of freedom from pleural effusion was three months in the group C. In patients with malignant pleural effusion and/or dissemination with primary non-small lung cancer, not only IIHC but also IIH might be beneficial in the prevention of pleural effusion instead of the improvement in prognosis.

Abstract 5549: p53-independent radiosensitization of lung cancer cells by inhibition of mTOR pathway

A high extent of activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and mutations in the p53 gene are involved in lung cancer therapeutic resistance. The mammalian target of rapamycin (mTOR) acts as a downstream effector for Akt and activation of the Akt/mTOR signal is a contributing factor to decreased radiation sensitivity. The aim of this study was to examine whether the effect of rapamycin on radiation sensitivity is affected by cellular p53 gene status in two human non-small cell lung cancer (NSCLC) cell lines with the same genetic background except for their p53 gene status (H1299/wtp53 and H1299/mp53). Cellular radiation sensitivity was evaluated with colony formation assays and apoptosis assays, using Hoechst33342 staining. Rapamycin synergistically enhanced the cytotoxicity of radiation regardless of p53 gene status, and promoted the induction of apoptosis. Moreover, the combined treatment augmented the cytostatic effects of radiation independently of cellular p53 gene status. In agreement with this result, cell cycle analysis by flow cytometry showed increased G 1 arrest and suppression of progression to S phase in both cell lines. Western blotting revealed a prominent p53-independent down-regulation of the mTOR signal and pro-survival molecule, cyclin D1 after the combined treatment, suggesting that rapamycin can enhance the effect of radiation through the repression of pro-survival signals and the reduction in the apoptotic threshold. This study indicates that inhibition of the mTOR signal may be a promising strategy for radiosensitization with no relevance to p53 gene status from two aspects of cell lethality and cell growth depression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5549.