Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-κB. Therefore, compounds that inhibit NF-κB stimulation might overcome chemotherapy resistance. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. Twenty patients were enrolled, and a total of 35 cycles were administered. The most frequent haematological side-effect was mild grade 1-2 anaemia. Non-haematological toxicities included fatigue, nausea, vomiting, diarrhoea and constipation, all grade 1-2. Two lethal events were observed in which an increase in caspase-3 activity and overt apoptosis in monocytes and neutrophils could be seen. Pharmacokinetic studies showed high inter-individual variability and rendered F60008 a far from optimal derivate of triptolide.

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Keywords Pharmacodynamic, Pharmacokinetic, Targeted therapy, Triptolide
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Journal European Journal of Cancer
Kitzen, J.J.E.M, de Jonge, M.J.A, Lamers, C.H.J, Eskens, F.A.L.M, van der Biessen, D, van Doorn, L, … Verweij, J. (2009). Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. European Journal of Cancer, 45(10), 1764–1772. doi:10.1016/j.ejca.2009.01.026