BACKGROUND: Radiotherapy is central in the treatment of cervical cancer. The formation of DNA double-strand breaks is considered to be critical for the radiotherapeutic effect. The non-homologous end joining (NHEJ) proteins DNA -PKcs, Ku70 and Ku86 have a major role in repairing DNA lesions. The objective of this study was to analyse if the expression of DNA -PKcs, Ku70 and Ku86 and their downstream signalling molecules p53, p21 and Mdm-2 are altered in residual cervical tumours after radiotherapy. METHODS: Retrospective analysis of 127 patients with cervical cancer stage IB-IIA treated with preoperative radiotherapy and radical surgery, revealed residual tumour in the cervical specimen in 30 patients. In 22 cases tumour material from residual and corresponding primary tumour were retrieved and the expression of DNA -PKcs, Ku86, Ku70, p53, p21 and Mdm-2 were assessed by immunohistochemistry. RESULTS: Residual tumours showed increased frequency of DNA -PKcs (P ¼ 0.037), Ku70 (P ¼ 0.018), Ku86 (P ¼ 0.008) positive cells. A correlation in DNA -PKcs expression between primary and residual tumours was found. The frequency of p21-positive cells was decreased (P ¼ 0.007) in residual tumours whereas no change in p53 or Mdm-2-positive cells were observed. CONCLUSION: Our results show that cervical carcinoma surviving radiotherapy have an increased DNA -PK expression. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of DNA -PK function may be part of a radioresistance mechanism within this tumour type.

Negative health effects of airborne particles have clearly been shown in epidemiological studies. People get exposed to particles from various sources such as the combustion of, for example, diesel and wood and also from particles arising from tire-road wear. Another source of importance for certain populations is exposure to particles in subway systems. We recently reported that these particles were more genotoxic when compared to that of several other particle types. The aim of this study was to further investigate and compare the toxicity of subway particles and particles from other sources as well as investigate some mechanisms behind the genotoxicity of subway particles. This was done by comparing the ability of subway particles and particles from a street, pure tire-road wear particles, and particles from wood and diesel combustion to cause mitochondrial depolarization and to form intracellular reactive oxygen species (ROS). Furthermore, the genotoxicity and ability to cause oxidative stress was compared to magnetite particles since this is a main component in subway particles. It was concluded that the subway particles and also street particles and particles from wood and diesel combustion caused mitochondrial depolarization. The ability to damage the mitochondria is thus not the only explanation for the high genotoxicity of subway particles. Subway particles also formed intracellular ROS. This effect may be part of the explanation as to why subway particles show such high genotoxicity when compared to that of other particles. Genotoxicity can, however, not be explained by the main component, magnetite, by water-soluble metals, or by intracellular mobilized iron. The genotoxicity is most likely caused by highly reactive surfaces giving rise to oxidative stress.

Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non -small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycininduced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJmediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells. [Mol Cancer Ther 2007;6(8):2303 -9]

The primary aim of this study was to investigate if the expression of the DNA damage identifying protein DNA-PKcs known to be involved in DNA repair after treatment with ionising radiation can be used as a predictive marker for radiotherapy (RT) response in cervical cancer. Formalin-fixed primary tumour biopsies from 109 patients with cervical cancer, FIGO-stage IB -IIA, treated with preoperative brachytherapy followed by radical surgery were analysed by immunohistochemistry. In addition, correlation studies between early pathological tumour response to radiation and expression of Ku86, Ku70, Mdm-2, p53 and p21 in primary tumours were also performed. We found that tumour-transformed tissue shows positive immunostaining of DNA-PKcs, Ku86 and Ku70, while non-neoplastic squamous epithelium and tumour-free cervix glands show negative immunoreactivity. Expression of DNA-PKcs positively correlated with both Ku86 and Ku70, and a statistically significant correlation between the Ku subunits was also found. After RT, 85 patients demonstrated pathologic complete remission (pCR), whereas 24 patients had residual tumour in the surgical specimen (non-pCR). The main finding of our study is that there was no correlation between the outcome of RT and the expression of DNA-PK subunits. Positive p53 tumours were significantly more common among non-pCR cases than in patients with pCR (P ¼ 0.031). Expression of p21 and Mdm-2 did not correlate with the outcome of RT.

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M059J and M059K cells both display radiation-induced apoptosis, which occur independently of caspase-3 activation. The apoptotic course differs between the two cell lines and is dependent on the quality of radiation.

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