Abstract
Mechanistic studies are presented of a novel class of aminophosphine platinum(II) complexes as potential anticancer agents. These new agents, which have demonstrated activity against murine and human tumor cells including those resistant to cisplatin arecis-[PtCl2(Me2N(CH2)3PPh2-P)2] (Com1) and cis-[PtCl(C6H11NH(CH2)2PPh2-N,P)(C6H11NH(CH2)2PPh2-P)] (Com2). We studied modifications of natural and synthetic DNAs in cell-free media by Com1 and Com2 by various biomedical and biophysical methods and compared the results with those obtained when DNA was modified by cisplatin. The results indicated that Com1 and Com2 coordinated to DNA faster than cisplatin. Bifunctional Com1 formed DNA adducts coordinating to single adenine or guanine residues or by forming cross-links between these residues. In comparison with cisplatin, Com1 formed the adducts more frequently at adenine residues and also formed fewer bidentate lesions. The monofunctional Com2 only formed DNA monodentate adducts at guanine residues. In addition, Com1 terminated DNA synthesis in vitro more efficiently than cisplatin whereas Com2 blocked DNA synthesis only slightly. DNA unwinding studies, measurements of circular dichroism spectra, immunochemical analysis, and studies of the B-Z transition in DNA revealed conformational alterations induced by the adducts of Com1, which were distinctly different from those induced by cisplatin. Com2 had little influence on DNA conformation. It is suggested that the activity profile of aminophosphine platinum(II) complexes, which is different from that of cisplatin and related analogs, might be associated with the specific DNA binding properties of this new class of platinum(II) compounds.
Footnotes
- Received November 23, 1998.
- Accepted April 5, 1999.
-
Send reprint requests to: Dr. Viktor Brabec, Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, CZ-61265 Brno, Czech Republic. E-mail:brabec{at}ibp.cz
-
This work was supported by Grants 305/99/0695, 301/98/P231, 307/97/P029, and 204/97/P028 from the Grant Agency of the Czech Republic, Grants A5004702 and A7004805 from the Grant Agency of the Academy of Sciences of the Czech Republic, the Biotechnology and Biological Sciences Research Council, and the Engineering and Physical Sciences Research Council. V.B. is the recipient of an International Research Scholar’s award from the Howard Hughes Medical Institute. This research is part of the European Cooperation in the Field of Scientific and Technical Research program (Projects D8/0009/97 and D8/0012/97).
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|