Value of functional in-vivo endpoints in preclinical radiation research.

BACKGROUND: Cancer research faces the problem of high rates of clinical failure of new treatment approaches after positive preclinical data. We hypothesize that a major confounding factor to this problem in radiooncology is the choice of the preclinical endpoint. METHODS: We present a comprehensive re-evaluation of large-scale preclinical in-vivo data on fractionated irradiation alone or simultaneously with Epidermal Growth Factor Receptor inhibition. Taking the permanent local tumour control assay as a gold standard, we evaluated different tumour volume dependent endpoints that are widely used for preclinical experiments. RESULTS: The analysis showed the highest correlations between volume related and local tumour control endpoints after irradiation alone. For combined treatments, wide inter-tumoural variations were observed with reduced correlation between the endpoints. Evaluation of growth delay per Gray (GD/Gy) based on two or more dose levels showed closest correlation with local tumour control dose 50% (TCD50). CONCLUSIONS: GD/Gy with at least two dose groups correlates with TCD50, but cannot replace the latter as the goldstandard.

Simultaneous PLK1 inhibition improves local tumour control after fractionated irradiation.

PURPOSE: Polo-like kinase 1 (PLK1) plays an important role in mitotic progression, is frequently overexpressed and associated with a poor prognosis of cancer patients, thus providing a promising target in anticancer treatment. Aim of the current project was to evaluate the effect of the novel PLK1 inhibitor BI 6727 in combination with irradiation. MATERIAL AND METHODS: In vitro proliferation and radiation cell survival assays as well as in vivo local tumour control assays after single treatment and combined radiation and drug application were carried out using the squamous cell carcinoma models A431 and FaDu. In addition, cell cycle phases were monitored in vitro and in vivo. RESULTS: BI 6727 showed a dose-dependent antiproliferative effect and an increase in the mitotic fraction. BI 6727 alone reduced clonogenic cell survival, while radiosensitivity in vitro (SF2) and in vivo (single-dose TCD(50) under clamped hypoxia) was not affected. In contrast, local tumour control was significantly improved after application of BI 6727 simultaneously to fractionated irradiation (A431: TCD(50) = 60.5 Gy [95% C.I. 57; 63] after IR alone and <30 Gy after combined treatment; FaDu: 49.5 Gy [43; 56 Gy] versus 32.9 Gy [26; 40]). CONCLUSIONS: Despite the lack of direct cellular radiosensitisation, PLK1 inhibition with BI 6727 during fractionated irradiation significantly improves local tumour control when compared to irradiation alone. This result is likely explained by a considerable effect on cell cycle and an independent cytotoxic potential of BI 6727.