Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug

Abstract

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 sulfurcontaining 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).Platinum antitumor compounds, such as cisplatin [cis-diamminedichloroplatinum(II)] (Fig. 1A) and its analogs, are widely used in the treatment of testicular and ovarian cancers and a variety of other human solid tumors. Much progress had been made to understand the mechanisms involved in antitumor effects of platinum compounds and drug resistance, which are multifactorial processes (Brabec, 2002;Fuertes et al., 2003). The target for platinum antitumor compounds is DNA, to which they bind efficiently, forming a variety of adducts that block replication and transcription and induce cell death (Johnson et al., 1989). The nature of DNA adducts affects a number of transduction pathways and triggers apoptosis or necrosis in tumor cells (Fuertes et al., 2003). In addition to alterations in the target and processing of platinum-induced damage to DNA, including gene-specific DNA repair pathways, cellular accumulation and inactivation from thiol-containing reductants [e.g., glutathione (GSH) and metallothionein (MT)] belong among further pharmacological factors affecting antitumor effects of platinum compounds that do not operate directly at the level of DNA adducts.Since the introduction of cisplatin, thousands of its bifunctional analogs have been synthesized and evaluated as po- Article, publi...

Different cell cycle modulation following treatment of human ovarian carcinoma cells with a new platinum(IV) complex vs cisplatin

“…On the other hand, LA-12 treatment of A2780 cells still led to a permanent S phase arrest, which lasted at least until 72 h of treatment (unpublished results). Our previous results concerning cell cycle modulation of several ovarian (A2780, A2780cis, SK-OV-3) and colon cancer (HT-29) cell lines suggest that LA-12 typically induces a permanent S phase arrest [10,11], which may be the consequence of DNA damage [12].…”

“…LA-12 has been found to be significantly more efficient than cisplatin in A2780 (parent, cisplatin sensitive), A2780cis (with acquired cisplatin resistance) or SK-OV-3 (with intrinsic cisplatin resistance) ovarian cancer cell lines, suggesting that it is able to overcome both acquired and intrinsic cisplatin resistance [10,11]. LA-12 demonstrated a higher hydrophobicity than cisplatin estimated by HPLC [9], and a higher cellular uptake in comparison with cisplatin in A2780 and A2780cis ovarian cancer cell lines [12].…”

Unique Properties of DNA Interstrand Cross‐Links of Antitumor Oxaliplatin and the Effect of Chirality of the Carrier Ligand

“…HMGB1b also recognized and bound to the duplex containing the interstrand CL of this metallodrug (indicated by the presence of a shifted, more slowly migrating band) in the same way as shown previously, for instance, in our recent papers. [32,41] The results of the titration of the duplexes containing the interstrand CL of…”

“…[32,41] In these experiments, the 22-bp duplex with blunt ends (see Figure 7C for its sequence) was modified so that it contained a single, site-specific interstrand CL formed by […”

Current Researches and Applications of Azole-BasedSupermolecules as Medicinal Agents

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