Modifications of DNA by platinum complexes: Relation to resistance of tumors to platinum antitumor drugs
Introduction
Platinum antitumor compounds, such as cisplatin [cis-diamminedichloroplatinum(II)] and its analogues, are widely used in the treatment of testicular and ovarian cancers and a variety of other human solid tumors, but many are intrinsically resistant and, even among initially sensitive tumors, acquired resistance commonly develops during treatment. Acquired resistance is a particular problem, as tumors may become resistant not only to the drugs used to treat them, but also to other drugs with different mechanisms of action. Elucidation of the molecular mechanisms that mediate cisplatin resistance holds promise for the design of pharmacological strategies for preventing, overcoming, or reversing this form of drug resistance.
The target for platinum antitumor compounds is DNA, to which they bind efficiently forming a variety of adducts which 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). Along with factors that do not operate directly at the level of DNA adducts, this plays an important role in the biological activity of platinum complexes including their cytotoxicity and processes underlying resistance of tumor cells.
Platinum drug resistance can occur by several mechanisms, including increased drug efflux, drug inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis (Brabec and Kasparkova, 2002, Morin, 2003, Siddik, 2003). All these aspects of resistance span a broad area of molecular pharmacology and have been reviewed extensively. This review focuses on one of these aspects. We provide first some new insights into mechanisms of resistance and sensitivity of tumors to conventional cisplatin associated with DNA modifications, which have not been reviewed or have been reviewed only briefly. We also discuss molecular mechanisms underlying resistance and sensitivity of tumors to the new platinum compounds which differ in antitumor activity and were synthesized with the goal of overcoming tumor resistance to conventional platinum drugs in clinical use {cisplatin, cis-diaminecyclobutanedicarboxylatoplatinum(II) (carboplatin), [(1R,2R-diaminocyclohexane)oxalatoplatinum(II)] (oxaliplatin) and cis-diamine-glycolatoplatinum(II) (nedaplatin) (Fig. 1)}. These new platinum complexes also exhibit improved pharmacological properties and a narrower range of resistance in comparison to older platinum drugs. Importantly, a number of these new platinum compounds were designed to test the hypothesis that there is a correlation between clinical efficacy of platinum compounds (and/or extent of tumor resistance) and their ability to induce a certain sort of damage or conformational change in DNA (Vrana et al., 1986). Hence, information on DNA-binding modes, recognition and repair of DNA damage is also discussed, since such information may be exploited to develop new classes of platinum compounds with improved structure–activity relationships and pharmacological properties.
Section snippets
Cisplatin
Despite the clinical success of cisplatin, whose antitumor activity was discovered more than 30 years ago, details of the molecular mechanisms that underlie its antitumor effects and resistance of a broad range of human tumors remain elusive. Thus, there continues to be great interest in DNA modifications by this drug, repair of platinum-DNA adducts and recognition by proteins. These features of the mechanism of action of cisplatin have been reviewed extensively (Brabec, 2002, Brabec and
Cisplatin analogues
Since the introduction of cisplatin, thousands of its bifunctional analogues have been synthesized and evaluated as potential antitumor agents. Modifications include replacement of one or two non-leaving ammine groups with various organic carrier ligands and chloride groups with various leaving ligands. The replacement of the leaving chloride groups affects mainly tissue and intracellular distribution of the cisplatin analogues. On the other hand, the replacement of ammine groups can result in
Analogues of clinically ineffective transplatin
The original empirical structure–activity relationships considered the trans isomer of cisplatin and other transplatin analogues to be inactive (Reedijk, 1996). However, several groups have shown that some trans compounds are active in vitro and in vivo. A distinct difference between cisplatin and its trans isomer is that transplatin is chemically more reactive than cisplatin and more susceptible to deactivation. While cisplatin major adducts are intrastrand CLs between neighboring guanine
Trinuclear platinum complexes
Polynuclear platinum compounds comprise a unique class of anticancer platinum agents with distinct chemical and biological properties different from mononuclear platinum drugs (Farrell, 2004). The lead compound, [{trans-PtCl(NH3)2}2μ-trans-Pt(NH3)2{H2N(CH2)6NH2}2]4+ (BBR3464) (Fig. 6) is a trinuclear, bifunctional DNA-binding agent with an overall 4+ charge. Phase I trials of this agent demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin including
Conclusions and future directions
DNA adducts formed by cisplatin analogues which have achieved routine clinical use, such as carboplatin, oxaliplatin and nedaplatin, are similar to those produced by the parent drug, though different in their relative rates of formation. Hence, from a mechanistic DNA-binding point of view, it is not too surprising that the introduction of these new platinum antitumor drugs did not represent a fundamental breakthrough in the treatment of cancer with platinum agents. This conclusion is in
Acknowledgements
This work was supported by grants from the Grant Agency of the Czech Republic (305/05/2030) and the Grant Agency of the Ministry of Health of the Czech Republic (NR8562-4/2005). It is a pleasure to thank all our collaborators, especially Nicholas Farrell, Dan Gibson, Giovanni Natile, Carmen Navarro-Ranninger, and Peter J. Sadler for their expertise and providing us with the new platinum complexes discussed in this review. The authors also acknowledge that this work was also carried out within
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