Molecular aspects of antitumor effects of a new platinum(IV) drug.
The new platinum(IV) complex cis,trans,cis-[PtCl(2)(CH(3)COO)(2)-(NH(3))(1-adamantylamine)] [adamplatin(IV)] seems promising for the perspective application in therapy of corresponding tumors. It is therefore of great interest to understand details of mechanisms underlying its biological efficacy. Cellular uptake of the drug, alterations in the target DNA induced by platinum drugs along with processing of platinum-induced damage to DNA and drug inactivation by sulfur-containing compounds belong to major pharmacological factors affecting antitumor effects of platinum compounds. We examined in the present work the significance of these factors in the mechanism of antitumor effects of adamplatin(IV) and compared the results with those of the parallel studies performed with "conventional" cisplatin. The results show that deactivation of adamplatin(IV) by sulfur-containing compounds (such as glutathione or metallothioneins) is likely to play a less significant role in the mechanism of resistance of tumor cells to adamplatin(IV) in contrast to the role of these reactions in the effects of cisplatin. Moreover, the treatment of tumor cells with adamplatin(IV) does not result in DNA modifications that would be markedly different from those produced by cisplatin. In contrast, the effects of other factors, such as enhanced accumulation of the drug in cells, strong inhibition of DNA polymerization by these adducts, lowered DNA repair, and DNA-protein cross-linking are different from the effects of these factors in the mechanism underlying activity of cisplatin. Hence, the differences between effects of adamplatin(IV) and cisplatin observed in the present work on molecular level may help understand the unique activity of adamplatin(IV).
Kaspárková
Jana
J
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Nováková
Olga
O
Vrána
Oldrich
O
Intini
Francesco
F
Natile
Giovanni
G
Brabec
Viktor
V
D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D002474:Cell-Free System; D003432:Cross-Linking Reagents; D004247:DNA / Q000096:biosynthesis; D018736:DNA Adducts / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D010957:Plasmids / Q000235:genetics; D010984:Platinum / Q000378:metabolism; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D051381:Rats; D013457:Sulfur Compounds / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D006609:High Mobility Group Proteins; D009944:Organoplatinum Compounds; D013457:Sulfur Compounds; D014764:Viral Proteins; D010984:Platinum; D004247:DNA; C062210:bacteriophage T7 RNA polymerase; D012194:RNA-Directed DNA Polymerase; D012321:DNA-Directed RNA Polymerases; C586743:(PtCl(2)(CH(3)COO)(2)-(NH(3))(1-adamantylamine)); D000218:Adamantane; D001205:Ascorbic Acid