Preclinical Development Spectrum of Cellular Responses to Pyriplatin, a Monofunctional Cationic Antineoplastic Platinum(II) Compound, in Human Cancer Cells

Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines,withdirect comparison tocisplatinandoxaliplatin.Theeffectsofpyriplatinongeneexpressionand platinum–DNAadduct formationwere also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC50 1⁄4 171–443 mmol/L), with maximum cytotoxicity in HOP-62 non–small cell lung cancer cells after 72hours (IC501⁄4 24mmol/L). Pyriplatin causedaG2-Mcell cycle blocksimilar to that inducedby cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin–DNA adducts are less cytotoxic than thoseof cisplatin andoxaliplatin.ThemRNAlevels of genes implicated indrug transport andDNAdamage repair, including GSTP1 andMSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use. Mol Cancer Ther; 10(9); 1709–19. 2011 AACR.