title: Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours.
abstract: Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-kappaB. Therefore, compounds that inhibit NF-kappaB 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.
authors.affiliation: Dept of Medical Oncology, Erasmus University Medical Center, EA Rotterdam, The Netherlands. jjemkitzen@yahoo.com
authors.forename: J J E M
authors.initials: JJ
authors.lastname: Kitzen
authors.forename: M J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: C H J
authors.initials: CH
authors.lastname: Lamers
authors.forename: F A L M
authors.initials: FA
authors.lastname: Eskens
authors.forename: D
authors.initials: D
authors.lastname: van der Biessen
authors.forename: L
authors.initials: L
authors.lastname: van Doorn
authors.forename: J
authors.initials: J
authors.lastname: Ter Steeg
authors.forename: M
authors.initials: M
authors.lastname: Brandely
authors.forename: Ch
authors.initials: Ch
authors.lastname: Puozzo
authors.forename: J
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D017209:Apoptosis / Q000187:drug effects*; D004224:Diterpenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; C542679:F60008; D010616:Phenanthrenes