Paclitaxel and radiation in combination: mechanistic studies in a murine model

Concurrent use of chemotherapy and radiotherapy has become common in the treatment of locally advanced cancers. Ideally clinical combinations would be based on sound basic biological studies designed to determine the nature of any interaction between agents. Paclitaxel is a cytotoxic drug that acts on cellular microtubules. The combination of paclitaxel and radiation was studied in vivo with the aim of generating mechanistic data to guide translation of the combination into clinical practice. Mice (C3Hf/Kam) bearing syngeneic tumours were used. Antitumour efficacy was determined by tumour growth delay and TCD50 assays, for single agents and combinations. The potential mechanisms of interaction were investigated by micromorphological examination of treated tumours, by modelling response data to quantify changes in radiobiological hypoxia, by polarographic measurement oxygenation, and by flow cytometric study of cell cycle effects. Results were compared for individual tumour types to confirm predominant mechanisms. The potential for therapeutic gain was determined by examination of the acute radiation response of jejunum and skin. Using the MCa-4 mammary tumour it was established that paclitaxel enhanced the local tumour radiation response. The magnitude of this enhancement was dependant upon the interval between paclitaxel and radiation. Enhancement was evident 9 hours after paclitaxel and increased further up to 72 hours. The predominant mechanism responsible for this interaction was shown to be tumour reoxygenation. A favourable interaction between paclitaxel and radiation was demonstrated in both paclitaxel-sensitive and -resistant tumours. In the apoptosis prone MCa-29 mammary tumour reoxygenation was shown to be the predominant mechanism responsible, whereas cell cycle mediated interaction was likely to be the sole mechanism in paclitaxel resistant SCC-VII. No enhancement of acute normal tissue radiation response was observed. These studies confirmed that paclitaxel interacted favourably with radiation. The results support the continuation of clinical studies combining paclitaxel with radiation