Kaspárková Jana, Nováková Olga, Vrána Oldrich, Intini Francesco, Natile Giovanni, Brabec Viktor
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Mol Pharmacol. 2006 Nov;70(5):1708-19. doi: 10.1124/mol.106.027730. Epub 2006 Aug 8.
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).
新型铂（IV）配合物顺式、反式、顺式-[PtCl₂(CH₃COO)₂-(NH₃)(1-金刚烷胺)] [氨铂（IV）]在相应肿瘤治疗的潜在应用方面似乎很有前景。因此，了解其生物学效应背后机制的细节非常重要。药物的细胞摄取、铂类药物诱导的靶DNA改变以及铂诱导的DNA损伤处理和含硫化合物对药物的失活作用，都属于影响铂类化合物抗肿瘤作用的主要药理学因素。在本研究中，我们考察了这些因素在氨铂（IV）抗肿瘤作用机制中的重要性，并将结果与用“传统”顺铂进行的平行研究结果进行了比较。结果表明，与这些反应在顺铂作用中的作用相比，含硫化合物（如谷胱甘肽或金属硫蛋白）对氨铂（IV）的失活作用在肿瘤细胞对氨铂（IV）的耐药机制中可能起的作用较小。此外，用氨铂（IV）处理肿瘤细胞不会导致与顺铂产生的DNA修饰有明显差异的DNA修饰。相反，其他因素的影响，如药物在细胞中的积累增加、这些加合物对DNA聚合的强烈抑制、DNA修复降低以及DNA-蛋白质交联，与这些因素在顺铂活性机制中的影响不同。因此，本研究在分子水平上观察到的氨铂（IV）和顺铂作用的差异可能有助于理解氨铂（IV）的独特活性。
