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1 2007

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Kompleksy platyny (IV) jako potencjalne związki przeciwnowotworowe

Ciołkowski M., Budzisz E.

Wiadomości Chemiczne

2007

[Z] 61, 1-2

43-60

Cisplatin is an important anticancer drug. Unfortunately it does not bring satisfactory effects in all types of tumor. Other problems are its toxicity and intrinsic or acquired resistance of tumor cells. That is why new drugs based on this molecule are being searched. One of the promising group of chemical compounds are neutral platinum(IV) complexes. They are more inert than platinum(II) complexes. In consequence their reactivity in bloodstream is weaker and more molecules can reach their target. Many studies were done to establish the relation among the structure, lipophilicity, reduction potential and cytotoxicity of those complexes. It is believed that platinum(IV) complexes must be reduced to platinum(II) complexes to obtain cytotoxicity. The speed of reduction depends on the nature of axial ligands. The complexes with chloride ligands are reduced the most quickly and complexes with hydroxide ligands are reduced the most slowly. In vitro cytotoxic activity of those complexes was shown to depend on their reduction potential. However suggestions exist that this result can be misleading for their in vivo activity, as platinum(IV) complexes are pro-drugs and might be inactive before reaching cancer cells. In a study of group of platinum(IV) complexes, derivatives of cisplatin and dichloroethylenediamineplatinum(II), a tendency for an increase of cytotoxic activity when lipophilicity increased was observed. However in a study of tetrakis(carboxylato)(1,2-diaminocyclohexane)platinum(IV) complexes, different cytotoxic activity of complexes possessing similar lipophilicity was observed. Hence lipophilicity of complex is important but it is not the only factor that determines complex activity. In other studies complexes of general structure cis, trans, cis-[PtNH3(RNH2)Cl2(OCOR')2] were examined. The research showed an increased activity of compounds with longer carbon chains of carboxylate axial ligands. It was also revealed that complexes with alicyclic amine ligands were more cytotoxic than those with aliphatic or aromatic amine ligands. Hall et al. revealed that platinum(IV) complexes, derivatives of cisplatin and dichloroethylenediamineplatinum(II), are active against DLD-1 colon cancer cell line in hypoxic environment. An examination of trans-dichlorodihydroxo(dimethylamine)(isopropylamine)platinum(IV) revealed its greater cytotoxic activity against A2780, CH1 and 41M human ovarian cancer cell lines, in vitro. Moreover this complex was shown to be active against A2780cisR, CH1cisR and 41McisR human ovarian cell lines which are resistant to cisplatin. Two platinum(IV) complexes: iproplatin (cis, trans, cis-dichlorodihydroxobis(isopropylamine)platinum(IV)) and tetraplatin (tetrachloro(cyclohexane-1,2-diamine)platinum(IV)) have had entered clinical trials. However iproplatin occurred to be less active than cisplatin and tetraplatin turned out to be neurotoxic. Presently two other complexes seem to be very promising: satraplatin (bis(acetato)amminedichlorocyclohexylamineplatinum(IV)) and adamplatin (bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)). Both have entered clinical trials. There are some "nonstandard" approaches to investigating platinum complexes. For example platinum(IV) complexes with radioactive iodine isotope or with enzyme inhibitor were examined. Studies mentioned above present different approaches to searching for anticancer drugs among platinum(IV) complexes. Despite all encountered difficulties during researching platinum(IV) complexes, this group of compounds still seems to be potential source of new anticancer drugs.