Novel targets for therapy in paediatric oncology.

Although the majority of children with cancer are now cured of their disease, a significant number either have disease resistant to current therapy, or are unable to tolerate the short and long term complications of their treatment. Therefore new therapeutic strategies which optimise existing agents by use of their clinical and molecular pharmacology are needed, along with the development of new agents. Accordingly, the agents chosen for the study need to be prioritized, and are thus selected on the basis of categories such as encouraging pre-clinical data from xenografts of paediatric tumours, novel mechanisms of action, drugs that modify or overcome cellular resistance and drugs that are active in adult studies. In this review, novel targets for chemotherapy such as topoisomerase I, angiogenesis and signal transduction will be discussed. In addition, the circumvention of methotrexate resistance by novel antifolate thymidylate synthase inhibition, and the modulation of alkylating agents by inhibition of 0(6)-alkylDNA-alkyltransferase will be discussed as strategies to overcome potentially important resistance mechanisms in paediatric oncology. Finally, recent advances in biological therapies, tumour vaccination and gene therapy will be highlighted. In the future, investigation of cancer biology, selection of new drugs, and securing of funds to support the conduct of integrated early clinical studies that maximise the pharmacological, cellular biological and molecular pathological information gained, will be the major challenges to be faced by paediatric oncologists.