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, with direct comparison to
cisplatin and
oxaliplatin. The effects of
pyriplatin on gene expression and
platinum-
DNA adduct formation were also investigated.
Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC(50) = 171-443 μmol/L), with maximum cytotoxicity in HOP-62
non-small cell lung cancer cells after 72 hours (IC(50) = 24 μmol/L).
Pyriplatin caused a G(2)-M cell cycle block similar to that induced by
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 those of
cisplatin and
oxaliplatin. The
mRNA levels of genes implicated in
drug transport and DNA damage repair, including GSTP1 and MSH2, 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.