DNA interactions of pH-sensitive, antitumor bis(aminoalcohol)dichloroplatinum(II) complexes.
(SP-4-2)-Bis(2-aminoethanol)dichloroplatinum(II) (KP1356) and (SP-4-2)-bis[(R)-(-)-2-aminobutanol)]dichloroplatinum(II) (KP1433) are promising cytotoxic agents capable of changing their chemical structure depending on the pH value. On the basis of this, they are supposed to be active only in or preferentially in hypoxic tumors with low pH. In this study, we investigated the kinetics of changes of the DNA secondary structure, of the DNA modification degree, and of the formation of interstrand cross-links caused by these complexes in comparison to the parental compound cis-diamminedichloroplatinum(II) (cisplatin). All examinations were performed at physiological pH 7.4 and at pH 6.0 mimicking the acidified environment of many tumor tissues. In general, cisplatin displayed a higher reactivity accompanied by more pronounced DNA compaction, untwisting, and formation of interstrand cross-links at both pH values. Additionally, it was shown for the first time that cisplatin generates interstrand cross-links faster at pH 6.0 than at 7.4. However, the difference between pH 7.4 and 6.0 was much larger for KP1356 and KP1433 than for cisplatin, since they were essentially nonreactive and induced almost no secondary structures at pH 7.4, as contrasted to cisplatin. Our data suggest that formed adducts, i.e., intra- and/or interstrand cross-links, may be the sole cause of the cytotoxicity of KP1356 and KP1433 at pH 6.0. The results of this study may stimulate and contribute to further improvement of these novel, specific cytotoxic drugs that are anticipated to exert their full power in the tumor while being reasonably inactive in normal tissue.
Zorbas-Seifried
Stefanie
S
Max-Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany. seifried@biochem.mpg.de
Hartinger
Christian G
CG
Meelich
Kristof
K
Galanski
Mathea Sophia
MS
Keppler
Bernhard K
BK
Zorbas
Haralabos
H
D000970:Antineoplastic Agents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D053938:DNA Fragmentation; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000737:chemistry*; D010957:Plasmids / Q000737:chemistry; D017671:Platinum Compounds / Q000737:chemistry*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; C516534:bis(2-aminobutanol)dichloroplatinum(II); D004247:DNA