Poster Presentation 27th Lorne Cancer Conference 2015

Radioprotection by the combination of DNA binding antioxidants and aminothiol radical scavengers (#266)

Jai Smith 1 2 , Andrea Smith 1 , Colin Skene 3 , Jonathan M White 3 , Pavel Lobachevsky 1 , Roger Martin 1 2
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia
  3. School of Chemistry, University of Melbourne and Bio21 Institute, Melbourne, VIC, Australia

The unavoidable irradiation of normal tissue during cancer radiotherapy can lead to serious dose limiting side effects. For example, radiation-induced oral mucositis during head and neck radiotherapy can lead to treatment interruptions. One strategy for ameliorating such problems is pharmacological radioprotection of “at risk” normal tissues.


The first clinically approved radioprotector was the aminothiol radical scavenger amifostine (a prodrug of WR1065). M2PB, an analogue of methylproamine, represents a new class of radioprotector that protects via a unique mechanism, involving electron transfer from the minor groove bound ligand to transient radiation induced oxidising species on the DNA. Additive radioprotection by M2PB in combination with amifostine (or WR1065) has been observed for both in vitro and in vivo endpoints, indicating complementary mechanisms of radioprotection.


In vitro clonogenic survival studies indicated near-additive radioprotection for the combination (DMF=4.4), compared to either WR1065 (DMF=2.5) or M2PB (DMF=2.8) alone. In vivo additive radioprotection in mice was also observed using the Withers micro colony survival assay when M2PB (DMF=1.21) and amifostine (DMF=1.13) were combined (DMF=1.49).


Additionally, in vivo radioprotection has been demonstrated using the mouse oral mucosa ulceration endpoint. The local irradiation of a 3mm by 3mm area of the dorsal surface of the mouse tongue leads to the formation of radiation induced ulcers 7-14 days post irradiation. Pre-treatment of the mice with M2PB in combination with amifostine resulted in a 50% reduction in ulcer formation, and an 80% reduction in the formation of severe ulcers when compared to the radiation-only control.


Further mechanistic studies involve the radiation induced mutagenesis endpoint. As well as confirming the protection by WR1065 of radiation induced mutations at the HPRT locus, preliminary data suggests M2PB also protects cells from radiation induced mutations. Experiments are planned to confirm these results, and to investigate the effect of the drug combination on this endpoint.