Modifications of DNA by platinum complexes: Relation to resistance of tumors to platinum antitumor drugs

doi:10.1016/j.drup.2005.04.006

Drug Resistance Updates

Volume 8, Issue 3, June 2005, Pages 131-146

https://doi.org/10.1016/j.drup.2005.04.006 Get rights and content

Abstract

The importance of platinum drugs in cancer chemotherapy is underscored by the clinical success of cisplatin [cis-diamminedichloroplatinum(II)] and its analogues and by clinical trials of other, less toxic platinum complexes that are active against resistant tumors. The antitumor effect of platinum complexes is believed to result from their ability to form various types of adducts with DNA. Nevertheless, drug resistance can occur by several ways: increased drug efflux, drug inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis. This review focuses on mechanisms of resistance and sensitivity of tumors to conventional cisplatin associated with DNA modifications. We also discuss molecular mechanisms underlying resistance and sensitivity of tumors to the new platinum compounds synthesized with the goal to overcome resistance of tumors to established platinum drugs. Importantly, a number of new platinum compounds were designed to test the hypothesis that there is a correlation between the extent of resistance of tumors to these agents and their ability to induce a certain kind of damage or conformational change in DNA. Hence, information on DNA-binding modes, as well as recognition and repair of DNA damage is discussed, since this information may be exploited for improved structure–activity relationships.

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

References (140)

K.R. Barnes et al.
Synthesis, characterization, and cytotoxicity of a series of estrogen-tethered platinum(IV) complexes
Chem. Biol.
(2004)
V. Brabec
DNA modifications by antitumor platinum and ruthenium compounds: their recognition and repair
Prog. Nucleic Acid Res. Mol. Biol.
(2002)
V. Brabec et al.
Molecular aspects of resistance to antitumor platinum drugs
Drug Resist. Update
(2002)
M. Brendel et al.
Role of PSO genes in repair of DNA damage of Saccharomyces cerevisiae
Mutat. Res.
(2003)
R.A. Britten et al.
Collateral resistance to photon and neutron irradiation is associated with acquired cis-platinum resistance in human ovarian tumour cells
Radiother. Oncol.
(1992)
G.J. Bubley et al.
Differences in in vivo and in vitro sequence-specific sites of cisplatin-DNA adduct formation and detection of a dose–response relationship
Biochem. Pharmacol.
(1994)
A.M. Burger et al.
Inhibition of telomerase activity by cisplatin in human testicular cancer cells
Eur. J. Cancer
(1997)
Z. Chen et al.
Telomerase inhibitors: a new option for chemotherapy
P. Cheung et al.
Signaling to chromatin through histone modifications
Cell
(2000)
S.M. Cohen et al.
Cisplatin: from DNA damage to cancer chemotherapy
Prog. Nucleic Acid Res. Mol. Biol.
(2001)

B. Desoize et al.

Particular aspects of platinum compounds used at present in cancer treatment

Crit. Rev. Oncol. Hematol.

(2002)

P.W. Doetsch et al.

Yeast base excision repair: interconnections and networks

Prog. Nucleic Acid Res. Mol. Biol.

(2001)

J.T. Drummond et al.

Cisplatin and adriamycin resistance are associated with MutL alpha and mismatch repair deficiency in an ovarian tumor cell line

J. Biol. Chem.

(1996)

N. Farrell et al.

Cytotoxicity, DNA strand breakage and DNA–protein crosslinking by a novel transplatinum compound in human A2780 ovarian and MCF-7 breast carcinoma cells

Biochem. Pharmacol.

(2004)

M. Foka et al.

Interaction of cis-diamminedichloroplatinum(II) to chromatin. Specificity of the drug distribution

Biochem. Pharmacol.

(1986)

L. Fourrier et al.

Binding discrimination of MutS to a set of lesions and compound lesions (base damage and mismatch) reveals its potential role as a cisplatin-damaged DNA sensing protein

J. Biol. Chem.

(2003)

A.M. Galea et al.

The interaction of cisplatin and analogues with DNA in reconstituted chromatin

Biochim. Biophys. Acta

(2002)

S. Ghosh et al.

Missing pieces in the NF-kappa B puzzle

Cell

(2002)

T.D. Gilmore

NF-kappa-B, Kbf1, dorsal, and related matters

Cell

(1990)

J. Hayes et al.

cis-Diamminedichloroplatinum(II) modified chromatin and nucleosomal core particle

Biochim. Biophys. Acta

(1991)

R. Holmes et al.

cis-Dichloroplatinum(II) complexes tethered to 9-aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro

J. Inorg. Biochem.

(2001)

S.W. Johnson et al.

Recent insights into platinum drug resistance in cancer

Drug Resist. Update

(1998)

M. Kartalou et al.

Recognition of cisplatin adducts by cellular proteins

Mutat. Res.

(2001)

M. Kartalou et al.

Mechanisms of resistance to cisplatin

Mutat. Res.

(2001)

J. Kasparkova et al.

Different recognition of DNA modified by antitumor cisplatin and its clinically ineffective trans isomer by tumor suppressor protein p53

J. Biol. Chem.

(2001)

J. Kasparkova et al.

Effect of the geometry of the central coordination sphere in antitumor trinuclear platinum complexes on DNA binding

J. Inorg. Biochem.

(2004)

J. Kasparkova et al.

DNA interstrand cross-links of the novel antitumor trinuclear platinum complex BBR3464. Conformation, recognition by high mobility group domain proteins, and nucleotide excision repair

J. Biol. Chem.

(2002)

J. Kwon et al.

Mol. Cell

(2000)

L. Lan et al.

Functional and physical interactions between ERCC1 and MSH2 complexes for resistance to cis-diamminedichloroplatinum(II) in mammalian cells

DNA Repair

(2004)

S. Mabuchi et al.

Inhibition of NF-kappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models

J. Biol. Chem.

(2004)

K. Masutomi et al.

Telomerase and tumorigenesis

Cancer Lett.

(2003)

J.T. Millard

DNA modifying agents as tools for studying chromatin structure

Biochimie

(1996)

P.J. Morin

Drug resistance and the microenvironment: nature and nurture

Drug Resist. Update

(2003)

A. O’Brate et al.

The importance of p53 location: nuclear or cytoplasmic zip code?

Drug Resist. Update

(2003)

R.Z. Orlowski et al.

NF-kappa B as a therapeutic target in cancer

Trends Mol. Med.

(2002)

P. Perego et al.

The cellular basis of the efficacy of the trinuclear platinum complex BBR 3464 against cisplatin-resistant cells

J. Inorg. Biochem.

(1999)

J.W. Pierce et al.

Novel inhibitors of cytokine-induced I-kappaB alpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo

J. Biol. Chem.

(1997)

S. Aebi et al.

Loss of DNA mismatch repair in acquired resistance to cisplatin

Cancer Res.

(1996)

R. Altaha et al.

Excision repair cross complementing-group 1: gene expression and platinum resistance

Int. J. Mol. Med.

(2004)

T. André et al.

Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer

N. Engl. J. Med.

(2004)

P.A. Andrews et al.

cis-Diamminedichloro-platinum(II) accumulation in sensitive and resistant ovarian carcinoma cells

Cancer Res.

(1988)

C.G. Barry et al.

Duplex-promoted platination of adenine-N3 in the minor groove of DNA: challenging a longstanding bioinorganic paradigm

J. Am. Chem. Soc.

(2005)

V. Beljanski et al.

DNA damage-processing pathways involved in the eukaryotic cellular response to anticancer DNA cross-linking drugs

Mol. Pharmacol.

(2004)

V. Bergoglio et al.

Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents

Oncogene

(2001)

F.A. Blommaert et al.

Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells

Biochemistry

(1995)

V. Brabec et al.

DNA modifications by a novel bifunctional trinuclear platinum Phase I anticancer agent

Biochemistry

(1999)

V. Brabec et al.

Steric control of DNA interstrand cross-link sites of trans platinum complexes: specificity can be dictated by planar nonleaving groups

J. Biol. Inorg. Chem.

(2000)

V. Brabec et al.

DNA adducts of antitumor trans-[PtCl₂(E-imino ether)₂]

Nucleic Acids Res.

(1996)

J.N. Burstyn et al.

Formation of cis-diamminedichloroplatinum(II) 1,2-intrastrand cross-links on DNA is flanking-sequence independent

Nucleic Acids Res.

(2000)

P.A. Clarke et al.

Characterisation of molecular events following cisplatin treatment of two curable ovarian cancer models: contrasting role for p53 induction and apoptosis in vivo

Br. J. Cancer

(2004)

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Modifications of DNA by platinum complexes: Relation to resistance of tumors to platinum antitumor drugs

Abstract

Introduction

Section snippets

Cisplatin

Cisplatin analogues

Analogues of clinically ineffective transplatin

Trinuclear platinum complexes

Conclusions and future directions

Acknowledgements

Chem. Biol.

Prog. Nucleic Acid Res. Mol. Biol.

Drug Resist. Update

Mutat. Res.

Radiother. Oncol.

Biochem. Pharmacol.

Eur. J. Cancer

Cell

Prog. Nucleic Acid Res. Mol. Biol.

Crit. Rev. Oncol. Hematol.

Prog. Nucleic Acid Res. Mol. Biol.

J. Biol. Chem.

Biochem. Pharmacol.

Biochem. Pharmacol.

J. Biol. Chem.

Biochim. Biophys. Acta

Cell

Cell

Biochim. Biophys. Acta

J. Inorg. Biochem.

Drug Resist. Update

Mutat. Res.

Mutat. Res.

J. Biol. Chem.

J. Inorg. Biochem.

J. Biol. Chem.

Mol. Cell

DNA Repair

J. Biol. Chem.

Cancer Lett.

Biochimie

Drug Resist. Update

Drug Resist. Update

Trends Mol. Med.

J. Inorg. Biochem.

J. Biol. Chem.

Loss of DNA mismatch repair in acquired resistance to cisplatin

Cancer Res.

Excision repair cross complementing-group 1: gene expression and platinum resistance

Int. J. Mol. Med.

Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer

N. Engl. J. Med.

cis-Diamminedichloro-platinum(II) accumulation in sensitive and resistant ovarian carcinoma cells

Cancer Res.

Duplex-promoted platination of adenine-N3 in the minor groove of DNA: challenging a longstanding bioinorganic paradigm

J. Am. Chem. Soc.

DNA damage-processing pathways involved in the eukaryotic cellular response to anticancer DNA cross-linking drugs

Mol. Pharmacol.

Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents

Oncogene

Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells

Biochemistry

DNA modifications by a novel bifunctional trinuclear platinum Phase I anticancer agent

Biochemistry

Steric control of DNA interstrand cross-link sites of trans platinum complexes: specificity can be dictated by planar nonleaving groups

J. Biol. Inorg. Chem.

DNA adducts of antitumor trans-[PtCl2(E-imino ether)2]

Nucleic Acids Res.

Formation of cis-diamminedichloroplatinum(II) 1,2-intrastrand cross-links on DNA is flanking-sequence independent

Nucleic Acids Res.

Characterisation of molecular events following cisplatin treatment of two curable ovarian cancer models: contrasting role for p53 induction and apoptosis in vivo

Br. J. Cancer

DNA adducts of antitumor trans-[PtCl₂(E-imino ether)₂]