Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.
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.
Hussein
D
D
Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK.
Holt
S V
SV
Brookes
K E
KE
Klymenko
T
T
Adamski
J K
JK
Hogg
A
A
Estlin
E J
EJ
Ward
T
T
Dive
C
C
Makin
G W J
GW
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
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