cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects.
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.
Lovejoy
Katherine S
KS
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Todd
Ryan C
RC
Zhang
Shuzhong
S
McCormick
Michael S
MS
D'Aquino
J Alejandro
JA
Reardon
Joyce T
JT
Sancar
Aziz
A
Giacomini
Kathleen M
KM
Lippard
Stephen J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry; D004260:DNA Repair / Q000187:drug effects; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D000077150:Oxaliplatin; D012319:RNA Polymerase II / Q000737:chemistry / Q000378:metabolism; D012996:Solutions; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D018736:DNA Adducts; D027702:Organic Cation Transporter 1; D009944:Organoplatinum Compounds; D012996:Solutions; C530333:cis-diammine(pyridine)chloroplatinum(II); D000077150:Oxaliplatin; D004247:DNA; D012319:RNA Polymerase II; D002945:Cisplatin