The unavoidable irradiation of normal tissue during radiotherapy in cancer patients can lead to side effects such as oral or rectal mucositis. Pharmaceutical radioprotection of normal tissue could reduce these side effects and prevent radiotoxicity related treatment interruptions.
Aminothiol radioprotectors such as WR1065 and its prodrug amifostine, protect mainly by scavenging radiation induced hydroxyl radicals. A newer class of radioprotectors, the DNA-binding antioxidants such as methylproamine, are proposed to protect by electrons donation from DNA-bound ligand to transient radiation-induced reactive oxidising species on DNA. We hypothesised that by combining these two types of drugs, we could exploit their complementary mechanisms resulting in an increase in radioprotection. This was confirmed in vitro by combining WR1065 with methylproamine and subsequently its analogue 2PH.
We now report a similar in vitro result for WR1065 and M2PB, another analogue of methylproamine, using two endpoints to assess radioprotection; induction of γH2AX foci, reflecting radiation induced DNA double strand breaks, and clonogenic survival. For 30μM M2PB or 4mM WR-1065 alone, the Dose Modification factors (DMF), calculated from the γH2AX foci yield, were 1.9 and 2.1, respectively. Remarkably, the combination showed additive protection, with a DMF of 4.2. The results of counterpart experiments using the clonogenic survival endpoint yielded a similar outcome.
To determine if the in vitro additive radioprotection translates to an in vivo model, the effect of combination of M2PB with amifostine was investigated in the Withers mouse intestinal crypt survival assay. The DMF values achieved in vivo were somewhat lower than observed in vitro, however, the combination treatment provided a substantial increase in radioprotection compared to the individual compounds and an additive level of protection was achieved.
Although further studies are required, the combination of these two classes of radioprotector seems promising.