Cisplatin is a major chemotherapeutic which continues to have significant impact in the treatment of more than 50% of all cancers. Since its FDA approval in 1978 for the treatment of advanced ovarian and bladder cancer, this chemotherapeutic has made significant strides and its application has been extended to a large variety of other cancers. However, the vast majority of patients who receive cisplatin therapy often suffer from nephrotoxicity, neurotoxicity, nausea, and ototoxicity. Numerous methods currently exist for overcoming nephrotoxicity and nausea related side effects but there is no clear prevention to fight ototoxicity and neurotoxicity. In this work, we examined Platin-A, a prodrug of cisplatin and aspirin, using pre-clinical mouse and guinea pig based models and demonstrated its efficacy with reduced ototoxicity. Further, in vitro studies documented that when Platin-A is used in combination with clinically relevant dose of radiation, its efficacy can further be improved by attacking cellular bio-energetic profiles, producing multiple modes of DNA damage, delaying repair of damaged DNA. These studies demonstrated novel properties of the prodrug, Platin-A, highlighting its superior efficacy with reduced toxicity.
Biochemistry. 2018 Oct 03 [Epub ahead of print]
Bapurao Surnar, Nagesh Kolishetti, Uttara Basu, Anis Ahmad, Erik Goka, Brian Marples, David Kolb, Marc Lippman, Shanta Dhar