As a direct inhibitor of poly(ADP-ribose) (PAR) polymer dexrazoxane has access to the epigenome and this offers a new insight into protection by dexrazoxane against doxorubicin-induced late-onset damage. Notably, McCormack Pharma’s CEME has enabled the first report of the capacity of a small molecule to catalyse the hybrid self-assembly of a nucleic acid biopolymer via canonical and non-canonical, non-covalent interactions analogous to Watson Crick and Hoogsteen base-pairing, respectively.
These new findings data are provocative and indicate that in some part, the cardiotoxic effects of anthracyclines and the cardioprotective effects of dexrazoxane, converge upon the epigenome. By comparison with acute damage, delayed-onset toxicity is consistent with a phenotypic switch that results from anthracycline-induced alteration(s) at the epigenome. Sequestration of PAR through both canonical Watson–Crick base pairing, and non-canonical Hoogsteen base-pairing provides a mechanism for the cardioprotective effects of dexrazoxane against the toxic effects of doxorubicin in the acute term, and abrogation of delayed-onset cardiomyopathy.
If this discovery leads to an increase in the use of dexrazoxane throughout different patient populations, then the clinicians should be alert to novel/atypical/unexpected clinical benefits and outcomes if dexrazoxane is acting in some part by sequestering PAR by base-pairing.
Given the focal role of PAR in an overwhelming number of diseases, it is indeed thought provoking that dexrazoxane provides for the first time, a unique opportunity to investigate the impact of sequestration of PAR, by comparison with an inhibition of poly(ADP-ribose) polymerase (PARP), within a remarkably broad context. By way of example, the interaction between dexrazoxane and PAR offers the prospect that dexrazoxane can function as a cytoprotectant within several physiological systems. Neuroprotection offered by dexrazoxane in a preclinical model of neurological dysfunction outperformed that of established neuroprotectants that included a blocker of the N-methyl-D-aspartate receptor channel, dizolcipline (MK-801), a calcium channel blocker, nimodipine, and an iron chelator, deferoxamine (desferal), resulting in significantly greater survival rates and attenuated neurological deficits. In that study, Rodriguez et al (Drug Dev Res 2003 60 294) conclude that dexrazoxane has ‘very important neuroprotective properties’.
Additionally, Keith McCormack has argued that dexrazoxane may have a role in abrogating resistance to the use of PARP inhibitors in some patient groups (unpublished data).