Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.

2.50
Hdl Handle:
http://hdl.handle.net/10541/87534
Title:
Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.
Authors:
Hussein, Deema; Holt, Sarah V; Brookes, K E; Klymenko, T; Adamski, J K; Hogg, Alison; Estlin, E J; Ward, Timothy H; Dive, Caroline ( 0000-0002-1726-8850 ) ; Makin, Guy W J
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.
Affiliation:
Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK.
Citation:
Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours. 2009, 101 (1):55-63 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
7-Jul-2009
URI:
http://hdl.handle.net/10541/87534
DOI:
10.1038/sj.bjc.6605100
PubMed ID:
19491903
Type:
Article
Language:
en
ISSN:
1532-1827
Appears in Collections:
All Paterson Institute for Cancer Research; Clinical and Experimental Pharmacology Group

Full metadata record

DC FieldValue Language
dc.contributor.authorHussein, Deemaen
dc.contributor.authorHolt, Sarah Ven
dc.contributor.authorBrookes, K Een
dc.contributor.authorKlymenko, Ten
dc.contributor.authorAdamski, J Ken
dc.contributor.authorHogg, Alisonen
dc.contributor.authorEstlin, E Jen
dc.contributor.authorWard, Timothy Hen
dc.contributor.authorDive, Carolineen
dc.contributor.authorMakin, Guy W Jen
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.en
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

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