Resistance and non-specific cytotoxicity greatly hamper the effectiveness of existing cancer chemotherapy. Cell-culture-based screens have yet to provide a comprehensive explanation for multidrug resistance. This reflects the multiple modes of action of chemotherapy drugs and their diverse chemical natures, that chemoresistance is itself multifactorial, the genetic heterogeneity of tumour cells, and technical constraints of somatic cell genetics.

Further, such studies cannot address the full spectrum of targets available for chemosensitization; nor is it simple to model the interaction between host and tumour or chemotherapy-induced myeloablation in cell culture systems. As an entirely novel approach to investigating these issues, my group is using forward and reverse genetics in zebrafish embryos to analyze determinants of sensitivity and resistance to cancer chemotherapy. The high rates of proliferation and relative immaturity of embryo cells mirror properties of tumours. An unbiased genome wide scan is free of the technical constraints inherent to somatic cell genetics and allows identification of genes conferring increased sensitivity to chemotherapy and potentially factors that impact on myeloablation. Genetics is combined with experimental carcinogenesis in adult fish to address the influence of such determinants on tumour and host responses to chemotherapy. The genetic conservation between zebrafish and man and comparable disease aetiology, combined with forward genetic power that surpasses other vertebrate models (e.g. mouse) makes zebrafish an invaluable research tool for such investigation.