We have identified unique chemical and
biological properties of a cationic monofunctional
platinum(II) complex,
cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH(3))(2)(py)Cl](+) or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse
tumor model. This compound is an excellent substrate for organic
cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human
colorectal cancers, where they mediate uptake of
oxaliplatin, cis-[Pt(
DACH)(
oxalate)] (
DACH = trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line
therapy for
colorectal cancer. Unlike
oxaliplatin, however, cDPCP binds
DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH(3))(2)(py)}(2+) bound to the N7 atom of a single
guanosine residue in
a DNA dodecamer duplex. Although the quaternary structure resembles that of
B-form DNA, there is a base-pair step to the 5' side of the Pt adduct with abnormally large shift and slide values, features characteristic of
cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from
DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional
platinum(II) compounds like {
Pt(dien)}(2+). cDPCP-
DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional
platinum-
DNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other
cancers bearing appropriate
cation transporters.