Bp44mT: an orally active iron chelator of the thiosemicarbazone class with potent anti‐tumour efficacy

BACKGROUND AND PURPOSE Our previous studies demonstrated that a thiosemicarbazone iron chelator (di‐2‐pyridylketone‐4,4‐dimethyl‐3‐thiosemicarbazone; Dp44mT) possesses potent and selective anti‐cancer activity but led to cardiotoxicity at non‐optimal doses. In this study, we examined the in vivo anti‐tumour efficacy and tolerability of a new‐generation 2‐benzoylpyridine thiosemicarbazone iron chelator (2‐benzoylpyridine‐4,4‐dimethyl‐3‐thiosemicarbazone; Bp44mT) administered via the oral or i.v. routes. EXPERIMENTAL APPROACH BpT chelators were tested in vitro against human lung cancer cells (DMS‐53) and in vivo in DMS‐53 tumour xenografts in mice. The toxicity of Bp44mT in vivo and its effects on the expression of iron‐regulated molecules involved in growth and cell cycle control were investigated. KEY RESULTS Administration of Bp44mT by either route resulted in marked dose‐dependent inhibition of tumour growth. When administered at 50 mg·kg−1 via oral gavage three times per week for 23 days, the net xenograft growth was inhibited by 75%, compared with vehicle‐treated mice. Toxicological examination showed reversible alterations including slight reduction of RBC count, with a decrease of liver and splenic iron levels, which confirmed iron chelation in vivo. Importantly, in contrast to Dp44mT, the chelator‐treated mice did not show cardiac histological abnormalities. There was also no significant weight loss in mice, suggesting oral administration of Bp44mT was well tolerated. CONCLUSIONS AND IMPLICATIONS This is the first study to show that Bp44mT can be given orally with potent anti‐tumour efficacy. Oral administration of a novel and effective chemotherapeutic agent provides the benefits of convenience for chronic dosing regimens.