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dc.contributor.authorHussein, Deema
dc.contributor.authorHolt, Sarah V
dc.contributor.authorBrookes, K E
dc.contributor.authorKlymenko, T
dc.contributor.authorAdamski, J K
dc.contributor.authorHogg, Alison
dc.contributor.authorEstlin, E J
dc.contributor.authorWard, Timothy H
dc.contributor.authorDive, Caroline
dc.contributor.authorMakin, Guy W J
dc.date.accessioned2009-12-08T11:50:55Z
dc.date.available2009-12-08T11:50:55Z
dc.date.issued2009-07-07
dc.identifier.citationPreclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours. 2009, 101 (1):55-63 Br. J. Canceren
dc.identifier.issn1532-1827
dc.identifier.pmid19491903
dc.identifier.doi10.1038/sj.bjc.6605100
dc.identifier.urihttp://hdl.handle.net/10541/87534
dc.description.abstractBACKGROUND: 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.isoenen
dc.subjectChildhood Canceren
dc.subjectBone Canceren
dc.subjectCell Line Tumouren
dc.subject.meshAnimals
dc.subject.meshAntineoplastic Agents, Alkylating
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols
dc.subject.meshApoptosis
dc.subject.meshAziridines
dc.subject.meshBenzoquinones
dc.subject.meshBone Neoplasms
dc.subject.meshCell Growth Processes
dc.subject.meshCell Line, Tumor
dc.subject.meshChild
dc.subject.meshCisplatin
dc.subject.meshDiphtheria Toxin
dc.subject.meshDoxorubicin
dc.subject.meshDrug Screening Assays, Antitumor
dc.subject.meshDrug Synergism
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshMice, Inbred BALB C
dc.subject.meshMice, Nude
dc.subject.meshNAD(P)H Dehydrogenase (Quinone)
dc.subject.meshNeuroblastoma
dc.subject.meshOsteosarcoma
dc.subject.meshSarcoma, Ewing's
dc.subject.meshXenograft Model Antitumor Assays
dc.titlePreclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.en
dc.typeArticleen
dc.contributor.departmentClinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK.en
dc.identifier.journalBritish Journal of Canceren
html.description.abstractBACKGROUND: 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.


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