How to make an anti-cancer drug; the quest for non-toxic anthracyclines
Many cancer patients are treated with doxo- or daunorubicine, two effective drugs from the anthracycline class. These drugs are very toxic and induce therapy-related second tumors and cardiotoxicity. For this reason, treatment is restricted to only six courses and older cancer patients are excluded from this treatment. The anthracyclines work by inhibiting the enzyme topo-isomerase II thus generating DNA breaks. We have identified a second mechanism of action, histone eviction that would classify these drugs as epigenetic modifiers. We have combined chemistry with cell biology and other experiments to generate non-toxic variant drugs that still have anti-cancer activity. One of these drugs is currently being made for a Phase III trial on relapsed AML patients. The quest to make an off-patent drug that has to be made by fermentation is presented.
About Jacques Neefjes
Jacques Neefjes is head of the department of Cell and Chemical Biology at the LUMC in Leiden. He has studied the cell biology of MHC class I and MHC class II molecules, a system that is central in immunotherapy of cancer. He also pioneered radioimmunotherapy, the combination of radiotherapy and immunotherapy. Neefjes was one of the first to use GFP to trace proteins in living cells. Neefjes applied cell biological technologies to identify new activities of old anti-cancer drugs. He modified doxorubicin to remove its toxicities and extended these observations in producing one such a variant for clinical studies. Neefjes is a member of the Dutch and of the Norwegian Academy of Sciences and Arts and of the European Academy of Sciences and EMBO.
An interview with Jacques Neefjes appeared in C2W magazine which you can read here (Dutch).