A fish is probably the last animal most people think of as a good model for human disease, yet the humble zebrafish has swum its way to the forefront in the race to provide successful leukaemia treatments.
Leukaemia is the most common malignancy diagnosed in children, representing around 30% of all cancers in patients under 15 years of age. In acute lymphoblastic leukaemia (ALL), too many immature lymphocytes are produced by the bone marrow leading to an inability to fight infections, a build up of cells in joints, organs and also anaemia and other complications caused by a lack of red blood cells and platelets. The causes of leukaemia in children are still unknown, so providing an effective therapy against the malignancy is paramount.
Commonly, screening for new anti-cancer molecules use cell lines, particular cells modified to continuously reproduce. However potential candidates gained from these assays often fail the next stage of clinical trials in whole body systems due to additional interactions and organ-toxicity which are unforeseen in a cell only model. Zebrafish provide a valuable method of screening as researchers can see the effect of potential drugs on an entire vertebrate organism, rather than a modified cell line. They are further suited for human drug development as, perhaps surprisingly to some, their immune systems are very similar to ours - they can even get cancer. This makes zebrafish an ideal model for leukaemia studies.
Nikolaus Trede of the Huntsman Cancer Institute and colleagues, used immature zebrafish to screen 26,400 molecules and 5 potential compounds were found. Toxicity studies narrowed this down to one particular candidate, Lenaldekar (LDK), which successfully reduced the number of immature lymphocytes in larvae and caused remission of a particularly hard to treat type of ALL in 85% of adult zebrafish. Further tests revealed that LDK also reduced human leukaemia cells that are resistant to other therapies and is effective in mice. LDK promotes leukemic cell death via an indirect inhibition of a vital messaging pathway within the cell and induces a delay in the normal cycling of the cell. Importantly, it does not show toxicity to other cell types.
This is the first major success in the use of zebrafish for drug compound screening against human cancer. Questions remain as to how LDK specifically targets leukaemia cells and exactly how it affects the pathways within the cell itself. However LDK certainly shows promise and it is a splash in the right direction for zebrafish and new potential anti-leukemic drugs.
Incidence of childhood leukaemia, WHO Factsheet 4.1 (2009). Link
Renshaw, S. A. and Trede, N. S. (2012). A model 450 million years in the making: zebrafish and vertebrate immunity. Disease models and mechanisms. 5(1): 38-47
Ridges S. et al. (2012). Zebrafish screen identifies novel compound with selective toxicity against leukemia. Blood. 119(24): 5621-5631