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{sub 3}){sub 2}(py)Cl]{sup +} 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-{l_brace}Pt(NH{sub 3}){sub 2}(py){r_brace}{sup 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{prime} 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 {l_brace}Pt(dien){r_brace}{sup 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.
- Research Organization:
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC02-76SF00515
- OSTI ID:
- 953094
- Report Number(s):
- SLAC-REPRINT-2009-190; PNASA6; TRN: US200914%%307
- Journal Information:
- Proc. Nat. Acad. Sci. 105:8902,2008, Vol. 105, Issue 26; ISSN 0027-8424
- Country of Publication:
- United States
- Language:
- English
Similar Records
Synthesis and /sup 1/H NMR spectroscopic characterization of trans-(Pt(NH/sub 3/)/sub 2//d(ApGpGpCpCpT)-N7-A(1),N7-G(3)/)
Conformational changes in a single- and double-stranded nonanucleotide upon complexation of a monofunctional platinum compound as studied by sup 1 H NMR, sup 31 P NMR, and CD methods