Mattias Hedman

Effects of redox modulation by inhibition of thioredoxin reductase on radiosensitivity and gene expression.

The thioredoxin system is a promising target when aiming to overcome the problem of clinical radiation resistance. Altered cellular redox status and redox sensitive thiols contributing to induction of resistance strongly connect the ubiquitous redox enzyme thioredoxin reductase (TrxR) to the cellular response to ionizing radiation. To further investigate possible strategies in combating clinical radiation resistance, human radio‐resistant lung cancer cells were subjected to a combination of single fractions of γ‐radiation at clinically relevant doses and non‐toxic levels of a well‐characterized thioredoxin reductase inhibitor, the phosphine gold(I) compound [Au(SCN)(PEt3)]. The combination of the TrxR‐inhibitor and ionizing radiation reduced the surviving fractions and impaired the ability of the U1810 cells to repopulate by approximately 50%. In addition, inhibition of thioredoxin reductase caused changes in the cell cycle distribution, suggesting a disturbance of the mitotic process. Global gene expression analysis also revealed clustered genetic expression changes connected to several major cellular pathways such as cell cycle, cellular response to stress and DNA damage. Specific TrxR‐inhibition as a factor behind the achieved results was confirmed by correlation of gene expression patterns between gold and siRNA treatment. These results clearly demonstrate TrxR as an important factor conferring resistance to irradiation and the use of [Au(SCN)(PEt3)] as a promising radiosensitizing agent.

Comparison of predicted and clinical response to radiotherapy: A radiobiology modelling study

Introduction. A model to predict clinical outcome after radiation therapy would be a valuable aid in the effort of developing more tailored treatment regimes for different patients. In this work we evaluate the clinical utility of a model that incorporates the following individually measured radiobiology parameters: intrinsic radiosensitivity, proliferation and number of clonogenic cells. The hypothesis underlying the study was that the incorporation of individually measured tumour parameters in a model would increase its reliability in predicting treatment outcome compared with the use of average population derived data. Material and methods. Forty-six patients with head and neck tumours were analyzed, the majority of whom received both external beam radiotherapy and brachytherapy. Eighteen patients received external beam treatment alone and statistical analyses were carried out on this subgroup. Results. Four of the 18 patients had a >95% calculated probability of cure and none developed a local recurrence resulting in a negative predictive value of 100% (compared with 67% for population-derived data). The sensitivity of the model in predicting local recurrence was 75% (compared with 38% for population-derived data). Using a model that incorporated individually measured radiobiology data, there was a statistically significant difference in local control levels for patients with >95% and <5% predicted probability of local control (χ2, p = 0.04). Discussion. This study suggests, therefore, that incorporation of measured biological data within a radiobiological model improves its ability to predict radiation therapy outcome compared with the use of population-derived data.

Predictive value of modelled tumour control probability based on individual measurements of in vitro radiosensitivity and potential doubling time.

OBJECTIVE The aim of this study was to compare patient-specific radiobiological parameters with population averages in predicting the clinical outcome after radiotherapy (RT) using a tumour control probability (TCP) model based on the biological effective dose (BED). METHODS A previously published study of 46 head and neck carcinomas with individually identified radiobiological parameters, radiosensitivity and potential doubling time (Tpot), and known tumour size was investigated. These patients had all been treated with external beam RT, and the majority had also received brachytherapy. The TCP for each individual based on the BED using patient-specific radiobiological parameters was compared with the TCP based on the BED using average radiobiological parameters (α=0.3 Gy(-1), Tpot=3 days). RESULTS 43 patients remained in the final analysis. There was only a weak trend for increasing local tumour control with increasing BED in both groups. However, when the TCP was calculated, the use of patient-specific parameters was better for identifying local control correctly. The sensitivity and specificity for tumour-specific parameters were 63% and 80%, respectively. The corresponding values for population-based averages were 0% and 91%, respectively. The positive predictive value was 92% when tumour-specific parameters were used compared with 0% for population-based averages. A receiver operating characteristic curve confirmed the superiority of patient-specific parameters over population averages in predicting local control. CONCLUSION Individual radiobiological parameters are better than population-derived averages when used in a mathematical model to predict TCP after curative RT in head and neck carcinomas. ADVANCES IN KNOWLEDGE TCP based on individual radiobiological parameters is better than TCP based on population-based averages for identifying local control correctly.

The value of individual measurements for tumor control probability predictions in head and neck patients

In the age of personalized cancer medicine, individual measurements of in vitro radiosensitivity and proliferation parameters have great potential for predicting treatment outcome. However, cellular radiosensitivity is quite heterogeneous and therefore concerns exist towards its impact on treatment predictions. It was therefore the purpose of this study to investigate this aspect. Individually-determined radiosensitivities and potential doubling times, as well as tumor volumes from 46 head-and-neck carcinomas treated with radiotherapy, were used to predict tumor control probabilities (TCP) under various biologically-relevant assumptions for heterogeneity in radiosensitivity. TCP predictions were then compared to clinical local control using a ROC curve analysis. The analysis showed that TCP calculated under the assumption of heterogeneous radiosensitivity have the same power of distinguishing between patients with or without local control as from single values for the radiobiological parameters (a sensitivity of 66% and a specificity of 80% for an area under the curve of 0.69). The only difference was in the discrimination criterion (TCP>93% for single parameters and TCP>65% for heterogeneous parameters), illustrating the difference in appearance of the TCP curve under the assumption of heterogeneity. Nevertheless, the results showed that individually determined radiobiological parameters could be quite effective towards predicting treatment outcome for individual patients.

P-502 Tissue polypeptide antigen (TPA), hyaluronan and CA 125 as serum markers in malignant mesothelioma

Mesothelioma is a rare disease with poor prognosis. Monitoring the effect of treatment is a problem and a serum marker might be of use for this purpose. We have studied three serum markers TPA, Hyaluronan and CA 125 in a limited material (11 patients) with the purpose of finding out if they might reflect treatment effect and/or indicate prognosis. The results in our material show that correspondence between initial TPA levels and survival seems to be better than corresponding data regarding Hyaluronan and CAI 25. Five patients show increasing serum levels of all three serum markers from first to last sample as the mesothelioma progressed according to consecutive CT scans. In three of these patients stable disease was followed by a decrease in the serum marker levels. Our results indicate that these three serum markers and mainly TPA might be useful as markers of disease progression and TPA for prediction of survival.