title: Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK.
authors.forename: D
authors.initials: D
authors.lastname: Hussein
authors.forename: S V
authors.initials: SV
authors.lastname: Holt
authors.forename: K E
authors.initials: KE
authors.lastname: Brookes
authors.forename: T
authors.initials: T
authors.lastname: Klymenko
authors.forename: J K
authors.initials: JK
authors.lastname: Adamski
authors.forename: A
authors.initials: A
authors.lastname: Hogg
authors.forename: E J
authors.initials: EJ
authors.lastname: Estlin
authors.forename: T
authors.initials: T
authors.lastname: Ward
authors.forename: C
authors.initials: C
authors.lastname: Dive
authors.forename: G W J
authors.initials: GW
authors.lastname: Makin
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001388:Aziridines / Q000008:administration & dosage / Q000494:pharmacology*; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004167:Diphtheria Toxin / Q000096:biosynthesis; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D009447:Neuroblastoma / Q000188:drug therapy*; D012516:Osteosarcoma / Q000188:drug therapy*; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: C117776:2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone; D018906:Antineoplastic Agents, Alkylating; D001388:Aziridines; D016227:Benzoquinones; D004167:Diphtheria Toxin; D004317:Doxorubicin; D016660:NAD(P)H Dehydrogenase (Quinone); D002945:Cisplatin