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
Scopus Count
Related articles
- Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice.
- Authors: Loadman PM, Phillips RM, Lim LE, Bibby MC
- Issue date: 2000 Apr 1
- Development of a new isogenic cell-xenograft system for evaluation of NAD(P)H:quinone oxidoreductase-directed antitumor quinones: evaluation of the activity of RH1.
- Authors: Dehn DL, Winski SL, Ross D
- Issue date: 2004 May 1
- Preclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone.
- Authors: Ward TH, Danson S, McGown AT, Ranson M, Coe NA, Jayson GC, Cummings J, Hargreaves RH, Butler J
- Issue date: 2005 Apr 1
- Cytotoxicity of the bioreductive agent RH1 and its lack of interaction with radiation.
- Authors: Kim JY, West CM, Valentine H, Ward TH, Patterson AV, Stratford IJ, Roberts SA, Hendry JH
- Issue date: 2004 Mar
- The anti-tumour compound, RH1, causes mitochondria-mediated apoptosis by activating c-Jun N-terminal kinase.
- Authors: Park MT, Song MJ, Oh ET, Lee H, Choi BH, Jeong SY, Choi EK, Park HJ
- Issue date: 2011 Jun