Increased anti-tumour efficacy of doxorubicin when combined with sulindac in a xenograft model of an MRP-1-positive human lung cancer

Background: A number of cellular proteins, including P-glycoprotein (P-gp) and Multiple drug Resistance Protein (MRP-1), act as drug efflux pumps and are important in the resistance of many cancers to chemotherapy. We previously reported that a small number of NSAIDs could inhibit the activity of MRP-1. Materials and Methods: We chose sulindac as a candidate agent for further investigation as it has the most favourable efficacy and toxicity profile of the agents available for a potential specific MRP-1 inhibitor. NCI H460 cells expressed MRP-1 protein (by Western blot) and also the toxicity, of doxorubicin (a substrate of MRP-1) could be potentiated in this line using non-toxic concentrations of the MRP-1 substrate/inhibitor sulindac. These cells were implanted in nude mice and the animals divided into various groups which were administered doxorubicin and/or sulindac. Results: Sulindac was shown to significantly potentiate the tumour growth inhibitor activity of doxorubicin in this MRP-1-overexpressing human tumour xenograft model. Conclusion: Sulindac may be clinically useful as an inhibitor of the MRP-1 cancer resistance mechanism.

Linear quadratic and tumour control probability modelling in external beam radiotherapy

The standard linear-quadratic (LQ) survival model for external beam radiotherapy is reviewed with particular emphasis on studying how different schedules of radiation treatment planning may be affected by different tumour repopulation kinetics. The LQ model is further examined in the context of tumour control probability (TCP) models. The application of the Zaider and Minerbo non-Poissonian TCP model incorporating the effect of cellular repopulation is reviewed. In particular the recent development of a cell cycle model within the original Zaider and Minerbo TCP formalism is highlighted. Application of this TCP cell-cycle model in clinical treatment plans is explored and analysed.

Gamma ray-induced bystander effect in tumour glioblastoma cells: a specific study on cell survival, cytokine release and cytokine receptors.

Recent experimental evidence has challenged the paradigm according to which radiation traversal through the nucleus of a cell is a prerequisite for producing genetic changes or biological responses. Thus, unexposed cells in the vicinity of directly irradiated cells or recipient cells of medium from irradiated cultures can also be affected. The aim of the present study was to evaluate, by means of the medium transfer technique, whether interleukin-8 and its receptor (CXCR1) may play a role in the bystander effect after gamma irradiation of T98G cells in vitro. In fact the cell specificity in inducing the bystander effect and in receiving the secreted signals that has been described suggests that not only the ability to release the cytokines but also the receptor profiles are likely to modulate the cell responses and the final outcome. The dose and time dependence of the cytokine release into the medium, quantified using an enzyme linked immunosorbent assay, showed that radiation causes alteration in the release of interleukin-8 from exposed cells in a dose-independent but time-dependent manner. The relative receptor expression was also affected in exposed and bystander cells.

Isolated conjugate gaze palsy after frontal lobe tumour surgery

Isolated conjugate gaze palsy following unilateral frontal lobe surgery is uncommon. When it does occur, usually it recovers within hours. We report a case of isolated conjugate gaze palsy which persisted for four weeks post-operatively before recovery commenced.