Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours
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Published on: September 18, 2013
D Hussein1, S V Holt, K E Brookes
1Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK.
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.
Insights
The novel cytotoxic agent RH1 shows promise in treating pediatric cancers like neuroblastoma and osteosarcoma by inducing apoptosis and delaying tumor growth. Its effectiveness is linked to DT-diaphorase levels, suggesting potential clinical utility in childhood cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Drug resistance is a significant challenge in treating pediatric cancers, necessitating novel therapeutic agents.
- Early pre-clinical evaluation of pediatric tumor models alongside adult drug development can expedite access to new treatments.
Purpose of the Study:
- To evaluate the efficacy of the novel cytotoxic agent RH1 in pre-clinical pediatric cancer models.
- To assess the correlation between DT-diaphorase (DTD) levels and RH1 potency.
- To investigate the synergistic effects of RH1 with existing chemotherapies.
Main Methods:
- RH1 cytotoxicity was assessed using acute viability and clonogenic assays in neuroblastoma, osteosarcoma, and Ewing's sarcoma cell lines.
- DT-diaphorase (DTD) expression levels were measured in relation to RH1 potency.
- Tumor growth delay was evaluated in xenograft models of Ewing's sarcoma and osteosarcoma following RH1 administration.
Main Results:
- RH1 demonstrated potent activity against pediatric cancer cell lines with IC50 values in the nanomolar range, correlating with DTD levels in viability assays.
- Synergistic effects between RH1 and cisplatin or doxorubicin were observed in cell lines with low DTD expression.
- RH1 induced apoptosis and significantly delayed tumor growth in mouse xenograft models.
Conclusions:
- RH1 exhibits significant pre-clinical efficacy against key pediatric tumor types, including neuroblastoma, osteosarcoma, and Ewing's sarcoma.
- The findings support the potential clinical utility of RH1 as a novel therapeutic agent for childhood cancers.
- Concurrent evaluation in pediatric models during adult drug development can identify promising agents for pediatric oncology.