WR-1065 [2-((aminopropyl)amino)ethanethiol] is metabolically active form of amifostine (also known as Ethyol, an agent used to mitigate side effects of chemo-radiotherapy in head and neck cancer). In vitro, WR-1065 was also found to decrease DNA damage caused by cisplatin. In some human studies, amifostine was found to be effective against chemotherapy-induced peripheral neuropathy (CIPN). While this effect was not dramatic in all such studies, it was notable in patients who received cisplatin alone. Because CIPN is the most common and longest lasting side effect of chemotherapy we decided to explore possible biological and chemical basis of amifostine mediated protection against platinum (II). Two human cell lines were used in this study: SK-N-SH neuroblastoma cells and NT2/D1 embryonal carcinoma cells. Importantly, their response to cisplatin treatment corresponded to their differentiation. In both cases, differentiated cells survived exposure to cisplatin better than their non-differentiated counterparts; cisplatin IC50 doses in differentiated cells were regularly two times higher. Addition of WR-1065 to cisplatin treated differentiated cells increased their viability regardless of whether that treatment was done, before, during or after cisplatin treatment. Similar approach was used to prepare samples for chemical studies using X-ray absorption near edge structure (XANES) spectroscopy. XANES can be used to investigate oxidation-reduction changes of Pt in biological samples. This was used by others to follow gradual reduction of Pt(IV) into Pt(II) inside cells. In this work, XANES was used to estimate Pt (II) to Pt (IV) ratio in samples of cisplatin treated cells and cisplatin mixed with cellular components such as DNA. Comparisons were done between such samples and their counterparts additionally exposed to WR-1065. In all cases, presence of WR-1065 changed the ratio of two forms of Pt, suggesting that chemistry of this interaction may be a possible mechanism of WR-1065 protection against cisplatin. At the moment, amifostine is not used in clinical practice in combination with platinum based chemotherapy drugs. Reasons for that may lay in the fact that there remains a concern that Amifostine could possibly protect cancer cells from therapy and not only normal tissues. This work shows that the mechanisms underlying ability of amifostine to decrease detrimental effects of platinum (II) are compatible with delayed CIPN treatment. This means that amifostine could be used to reduce CIPN symptoms significantly after cancer treatment, in patients who are cured from cancer but suffer treatment complications.
Citation Format: Tatjana Paunesku, Jelena Popovic, Andrijana Klajn, Natasa Kovacevic-Grujicic, Qing Ma, Milena Stevanovic, Gayle E. Woloschak. WR1065, the active metabolite of amifostine modulates chemistry and biology of cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 456.