Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.
dc.contributor.author | Hussein, Deema | |
dc.contributor.author | Holt, Sarah V | |
dc.contributor.author | Brookes, K E | |
dc.contributor.author | Klymenko, T | |
dc.contributor.author | Adamski, J K | |
dc.contributor.author | Hogg, Alison | |
dc.contributor.author | Estlin, E J | |
dc.contributor.author | Ward, Timothy H | |
dc.contributor.author | Dive, Caroline | |
dc.contributor.author | Makin, Guy W J | |
dc.date.accessioned | 2009-12-08T11:50:55Z | |
dc.date.available | 2009-12-08T11:50:55Z | |
dc.date.issued | 2009-07-07 | |
dc.identifier.citation | Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours. 2009, 101 (1):55-63 Br. J. Cancer | en |
dc.identifier.issn | 1532-1827 | |
dc.identifier.pmid | 19491903 | |
dc.identifier.doi | 10.1038/sj.bjc.6605100 | |
dc.identifier.uri | http://hdl.handle.net/10541/87534 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.subject | Childhood Cancer | en |
dc.subject | Bone Cancer | en |
dc.subject | Cell Line Tumour | en |
dc.subject.mesh | Animals | |
dc.subject.mesh | Antineoplastic Agents, Alkylating | |
dc.subject.mesh | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject.mesh | Apoptosis | |
dc.subject.mesh | Aziridines | |
dc.subject.mesh | Benzoquinones | |
dc.subject.mesh | Bone Neoplasms | |
dc.subject.mesh | Cell Growth Processes | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Child | |
dc.subject.mesh | Cisplatin | |
dc.subject.mesh | Diphtheria Toxin | |
dc.subject.mesh | Doxorubicin | |
dc.subject.mesh | Drug Screening Assays, Antitumor | |
dc.subject.mesh | Drug Synergism | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Mice, Inbred BALB C | |
dc.subject.mesh | Mice, Nude | |
dc.subject.mesh | NAD(P)H Dehydrogenase (Quinone) | |
dc.subject.mesh | Neuroblastoma | |
dc.subject.mesh | Osteosarcoma | |
dc.subject.mesh | Sarcoma, Ewing's | |
dc.subject.mesh | Xenograft Model Antitumor Assays | |
dc.title | Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours. | en |
dc.type | Article | en |
dc.contributor.department | Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK. | en |
dc.identifier.journal | British Journal of Cancer | en |
html.description.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. |