Abstract B71: DNA damage responses to cisplatin and dicycloplatin, a new platinum analog

• Published in: Molecular cancer therapeutics Vol. 12; no. 11_Supplement; p. B71
• Main Authors: Yu, Jing Jie, Yang, Xuqing, Song, Qinhua, Mueller, Michael D., Remick, Scot C.
• Format: Journal Article
• Language: English
• Published: 01.11.2013
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-13-B71

Abstract Background: Dicycloplatin (DCP), a new platinum compound approved by the Chinese FDA in March of 2012, shows better water solubility, greater stability, and lower toxicity, compared to cisplatin and carboplatin. Preclinical in vitro and in vivo studies and a Phase I clinical trial demonstrated that DCP possesses strong antitumor activity and lower adverse events than carboplatin. Phase II clinical trials using dicycloplatin plus paclitaxel in chemotherapy-naïve patients with advanced NSCLC found that efficacy and safety of DCP plus paclitaxel regimen were comparable to those of carboplatin plus paclitaxel regimen, with slightly better tolerance. Materials and Methods: Pharmacokinetic study of DCP characteristics was conducted using AP-4000TM LC-MS/MS System in patient blood samples. Molecular mechanism studies of dicycloplatin-induced gene-signature profiling were determined by Immunoblotting and compared to cisplatin profiling in human ovarian cancer cells. Results: Pharmacokinetic mass spectrometry shows different spectrums of dicycloplatin and of carboplatin in plasma. Two hours after administration, plasma concentration of dicycloplatin prototype is still high (17.1 μg/ml), following a peak concentration of 26.9 µg/ml at 0.5-h. Molecular mechanism investigation showed DCP-induced activation of several kinases including phosphorylations of Chk2 at threonine 68, p53 at serine 15 and BRCA1 at serine 1497. The increases in p-Chk2 and p-BRCA1 showed that the amount of DCP-induced phosphorylation doubled at 48-h and tripled for p-p53 at 24-h, compared to controls. Conclusion: Dicycloplatin appears to activate DNA damage-repair pathways through mechanisms similar to cisplatin. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B71. Citation Format: Jing Jie Yu, Xuqing Yang, Qinhua Song, Michael D. Mueller, Scot C. Remick. DNA damage responses to cisplatin and dicycloplatin, a new platinum analog. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B71.