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    Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.

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    Authors
    Hussein, Deema
    Holt, Sarah V
    Brookes, K E
    Klymenko, T
    Adamski, J K
    Hogg, Alison
    Estlin, E J
    Ward, Timothy H
    Dive, Caroline
    Makin, Guy W J
    Affiliation
    Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK.
    Issue Date
    2009-07-07
    
    Metadata
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    Abstract
    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.
    Citation
    Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours. 2009, 101 (1):55-63 Br. J. Cancer
    Journal
    British Journal of Cancer
    URI
    http://hdl.handle.net/10541/87534
    DOI
    10.1038/sj.bjc.6605100
    PubMed ID
    19491903
    Type
    Article
    Language
    en
    ISSN
    1532-1827
    ae974a485f413a2113503eed53cd6c53
    10.1038/sj.bjc.6605100
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research
    Clinical and Experimental Pharmacology Group

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