Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.
Autor: | Hussein D; Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK., Holt SV, Brookes KE, Klymenko T, Adamski JK, Hogg A, Estlin EJ, Ward T, Dive C, Makin GW |
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Jazyk: | angličtina |
Zdroj: | British journal of cancer [Br J Cancer] 2009 Jul 07; Vol. 101 (1), pp. 55-63. Date of Electronic Publication: 2009 Jun 02. |
DOI: | 10.1038/sj.bjc.6605100 |
Abstrakt: | 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. |
Databáze: | MEDLINE |
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