Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.
Authors
Hussein, DeemaHolt, 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
Show full item recordAbstract
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. CancerJournal
British Journal of CancerDOI
10.1038/sj.bjc.6605100PubMed ID
19491903Type
ArticleLanguage
enISSN
1532-1827ae974a485f413a2113503eed53cd6c53
10.1038/sj.bjc.6605100