Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours

Background:Despite substantial improvements in childhood cancer survival, drug resistance remains problematic for several paediatric tumour types. The urgent need to access novel agents to treat drug-resistant disease should be expedited by pre-clinical evaluation of paediatric tumour models during the early stages of drug development in adult cancer patients.Methods/results:The novel cytotoxic RH1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone) is activated by the obligate two-electron reductase DT-diaphorase (DTD, widely expressed in adult tumour cells) to a potent DNA interstrand cross-linker. In acute viability assays against neuroblastoma, osteosarcoma, and Ewing′s sarcoma cell lines RH1 IC 50 values ranged from 1-200 nM and drug potency correlated both with DTD levels and drug-induced apoptosis. However, synergy between RH1 and cisplatin or doxorubicin was only seen in low DTD expressing cell lines. In clonogenic assays RH1 IC 50 values ranged from 1.5-7.5 nM and drug potency did not correlate with DTD level. In A673 Ewing's sarcoma and 791T osteosarcoma tumour xenografts in mice RH1 induced apoptosis 24 h after a single bolus injection (0.4 mg/kg) and daily dosing for 5 days delayed tumour growth relative to control.Conclusion:The demonstration of RH1 efficacy against paediatric tumour cell lines, which was performed concurrently with the adult Phase 1 Trial, suggests that this agent may have clinical usefulness in childhood cancer. © 2009 Cancer Research

Specific and enantioselective sulfoxidation of an aryl-trifluoromethylsulfide by rat liver cytochromes P-450

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Specific and enantioselective sulfoxidation of an aryl-trifluoromethylsulfide by rat liver cytochromes P-450

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Bis-macrocyclic diketal diamines, analogue of the anti-viral and anti-tumoral bicyclam AMD 3100

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Semisynthesis of (+)- and (?)-goniomitine from (?)- and (+)-vincadifformine

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Specific and enantioselective sulfoxidation of an aryl-trifluoromethylsulfide by rat liver cytochromes P-450

International audienc

First-in-class combination therapy of a copper(II) metallo-phosphorus dendrimer with cytotoxic agents

International audienceThe metallo-phosphorus dendrimer 1G3-Cu (generation 3 dendrimer bearing 48 conjugated copper(II) on its surface) has antiproliferative activity related to its capacity to activate Bax translocation. In the present study, we evaluate the activity of an association of 1G3-Cu with 5 cytotoxic agents used in chemotherapy having different modes of action. Data show no additive effect with camptothecin and cisplatin, additivity with paclitaxel and MG132, and synergy with doxorubicin. Results suggest that the multivalent Cu-conjugated dendrimer 1G3-Cu (activator of Bax translocation) plays an important role in boosting the clinical impact of Bax accumulation stimulated by the proteasome inhibitor MG132, antimitotic taxanes, and the topo II inhibitor doxorubicin