New Insights About the Interaction of Cisplatinum with Intracellular Components
The now classic antitumor compound cis-PtCl2(NH3)2 (abbreviated as cisPt) is known to react with cellular components, such as DNA and proteins. Initially most attention was focussed on the binding of cisPt with DNA, as the antitumor properties are likely to be based upon selective interaction with DNA. After injection in the blood, the drug is transported through the body, probably entering both normal and tumor cells. Inside the cell relatively slow hydrolysis occurs, followed by binding to DNA and possible other targets.
To understand the details of the DNA binding, studies of the binding of platinum compounds with relatively small single-stranded and double-stranded oligonucleotides under a variety of in-vitro conditions have been studied and the results will be summarized. Other possible binding sites for platinum compounds in cells are those at proteins; these are generally believed to be the most likely origin of the several toxic side effects of cisPt and the several derivatives. In fact significant amounts of administrated cisPt are lost as a result of binding to proteins; some of these bonds can be “rescued” by certain agents, like thiourea.
To explore this type of protein-binding reactions a variety of Pt amine compounds (including the inactive trans isomer of cisPt and also the reference compound [PtCl(dien)]Cl) have been reacted with synthetic peptides and with proteins. To study the competition between proteins and nucleic acids, in-vitro reactions have been carried out between Pt compounds and nucleopeptides. It has been found that the degree of hydrolysis of cisPt determines the rate of binding to DNA (at guanine-N7) and to S-donor atoms (most rapidly at thioethers) in proteins and peptides.
Using advanced NMR techniques, in combination with spectroscopy and X-ray diffraction studies, the structures and conformations of the obtained Pt-DNA adducts and Pt-peptide adducts have been determined. The results are of importance for a better understanding of the mechanism of action for cisPt and related compounds, and will also be used to make predictions for possible third-generation Pt compounds.
During the last decades cis-diamminedichloroplatinum(II) has emerged as a classical compound in antitumor drug therapy. It has been generally accepted that binding of the compound to DNA is a major requirement for its biological activity, and as a result many scientists have focussed their attention especially on platinum-DNA interactions. However, also Pt-protein interactions and especially with S-containing biomolecules are of great importance, as will be shown below.
The compound [cis-PtCl2(NH3)2], often abbreviated as cisplatin, cisplatinum, cis-DDP, DDP, c-DDP, or cis-Pt, has been known since the last century. Renewed interest in cisplatin and in its trans isomer has resulted from experiments by Rosenberg1–6, who investigated the role of electric fields on cell division of cultured bacterial cells. The field generated between platinum electrodes seemed to stop cell division without hampering cell growth, which later turned out to be the result of small amounts of dissolved compounds like [cis-PtCl4(NH3)2], formed during electrolysis by interaction of the electrolyte (NH4Cl) and the “inert” Pt electrodes2.
Later many other Pt(II) and Pt(IV) compounds were found to show similar effects on bacterial growth3. Surprisingly, only the cis- and not the trans-isomer appeared to be effective. The antitumor activity of these and other platinum compounds have been studied. In particular on tumors induced in animals, such as Sarcoma 180 and Leukemia L1210 in mice4,5, [cis-PtCl2(NH3)2] turned out to be a very active compound against a variety of animal tumors6.
For testicular and ovarian cancer the progress in the curing of these tumor types, effected by the use of cis-Pt is spectacular7 and especially for early recognized testicular cancer, the curing rate is approaching 100%.
They contain carrier molecules as ligands for achieving higher drug concentrations, or slower release in tumor tissues11.
They contain also other chemotherapeutic agents, like intercalators12,13 or, contain radiosensitizers as ligands14 for use in radiation therapy and phosphono carboxylates15 as co-ligands in the hope of obtaining some sort of synergistic effect.
They contain more than one platinum atom16.
KeywordsTesticular Cancer Antitumor Drug Platinum Complex Platinum Compound Toxic Side Effect
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