Elsevier

Cancer Treatment Reviews

Volume 28, Issue 6, December 2002, Pages 291-303
Cancer Treatment Reviews

LABORATORY–CLINIC INTERFACE
DNA-based drug interactions of cisplatin

https://doi.org/10.1016/S0305-7372(02)00093-2Get rights and content

Abstract

The interactions of cisplatin with other anti-cancer agents on the DNA level have been studied extensively in pre-clinical experiments. In general, combination of cisplatin with an antimetabolite, taxane, or topoisomerase inhibitor, can result in a modulation of platinum pharmacology on the DNA, for example, enhanced retention of the platinum-DNA adducts. These interactions are mostly sequence and cell type dependent. In cell line models, antimetabolites can enhance the number of platinum-DNA adducts, probably by inhibition of DNA repair pathways. However, in clinical trials, the opposite effect has been observed, with a reduction of these adducts upon combined treatment. For the taxanes it has been shown that they can inhibit the formation of platinum-DNA adducts, whereas topoisomerase I inhibitors increase the number of adducts, resulting in strong synergistic cytotoxicity. For this last interaction a mechanistic model has recently been proposed, in which the topoisomerase I enzyme directly binds to the platinum-DNA adduct. Thereafter, the topoisomerase I inhibitor binds to this complex, which yields large stabilised lesions to the DNA that are probably difficult to repair. Ongoing studies will proceed to elucidate the exact mechanism underlying the interactions between cisplatin and other anti-neoplastic agents on the DNA level. Such increased understanding might help in designing new and more effective treatment regimens for cancer. In this paper, we review the pre-clinical and clinical studies investigating the observed interactions between cisplatin, the antimetabolites, taxanes, and topoisomerase inhibitors on the DNA level.

Introduction

Cisplatin (cis-diammine-dichloroplatinum(II)) is one of the most potent chemotherapeutic anticancer drugs. It is in clinical use against a wide variety of tumours, including testicular, ovarian, esophageal, head and neck, and lung cancer (reviewed in (1)). Cisplatin acts by binding to DNA, after its chloride ions have been displaced by hydroxyl groups [2], [3]. Several types of adducts can be formed (Figure 1), the most abundant of which are the intrastrand crosslinks between two adjacent bases (1,2-d(GpG) Figure 1d, and 1,2-d(ApG) Figure 1f). These adducts represent approximately 65 and 25%, respectively, of the total number of adducts formed. Minor adducts are monofunctionally bound cisplatin to a guanine base (Figure 1a,c), interstrand crosslinks (ICLs) between two guanines (Figure 1b) and intrastrand crosslinks between two guanines separated by one or more other bases (Figure 1e). The ICLs represent about 3% of the total adducts (4). Which type of adduct is most responsible for the cytotoxic effect of cisplatin has never been fully elucidated. By forming adducts to the DNA, cisplatin inhibits DNA replication and chain elongation (5), which is believed to be the main cause of its antineoplastic activity.

In clinical practice, cisplatin is mainly used in combination regimens. Synergy of other chemotherapeutics with cisplatin can occur by multiple pathways, including different pharmacokinetic interactions, e.g., a decrease of one of the agents in clearance, increased intracellular drug accumulation either by enhanced uptake, reduced efflux or reduced inactivation, enhanced binding to DNA, decreased repair of bound DNA, or a difference in cellular response to DNA damage. The converse mechanisms all appear to be involved in either intrinsic or acquired resistance to cisplatin [6], [7], [8], [9], [10], [11], which constitutes a major clinical hindrance in its application. Hence, combination chemotherapy with an agent that can affect any of the above-mentioned phenomena could increase the response of tumour cells to cisplatin, and also enhance cisplatin’s efficacy in relatively insensitive cells.

As yet, three classes of chemotherapeutics have been identified that modulate cisplatin sensitivity by an interaction on the DNA level, which is the focus of this paper. These classes are the antimetabolites, taxanes, and topoisomerase inhibitors. The antimetabolites are older types of cytostatics. They can be divided into three categories: the folic acid-, the purine- and the pyrimidine analogues. Only for the latter two DNA-based interactions with cisplatin have been described. The taxanes have been discovered more recently. As yet, there are two registered representatives of this class: paclitaxel and docetaxel. The topoisomerase inhibitors finally can be divided in topoisomerase I and II inhibitors. The first class mainly comprises the camptothecins, whereas the most important representatives of the second class are the epipodophyllotoxins etoposide and teniposide.

Drugs of these three types can interfere with the binding of cisplatin to the DNA or with the removal of the platinum-DNA adducts, thereby increasing the cytotoxicity of cisplatin. Conversely, cisplatin can induce a secondary lesion on the primary lesion caused by the combination drug. Cellular DNA repair is most likely implicated in these interactions. In this paper, we will first outline the DNA repair mechanisms available to the cell to repair damage caused by cytotoxic agents that have been identified thus far. Thereafter, we will review the results of combinational studies as well as investigations into the underlying mechanisms for the observed interactions between cisplatin and other anticancer agents. Increased understanding of the pharmacology of combinations of cisplatin with other cytostatics could be of great value in designing optimal treatment regimens in the clinic.

Section snippets

DNA-repair

When DNA is damaged, cells have several mechanisms available to repair the lesions. In the case of cisplatin-induced damage, nucleotide excision repair (NER) as well as recombinational repair are involved. Intrastrand platinum-DNA adducts are primarily repaired by the NER pathway. In brief, NER specific damage recoginition proteins bind to the DNA on the damaged spot. Next, the damaged strand is incised at both sides of the lesion and removed. The remaining gap is filled by DNA synthesis and

Antimetabolites

Antimetabolites have structural resemblance to nucleotides and act by interfering with DNA or RNA synthesis. They require intracellular phosphorylation to become activated [17], [18]. It is possible that cisplatin has an effect on this activation, however, this interaction does not take place on the level of the DNA, and therefore falls beyond the scope of this paper. For several of the antimetabolites, synergy with cisplatin has been described in both cell line and mouse models. In general,

Taxanes

Paclitaxel and docetaxel are relatively new and highly active chemotherapeutics. Good anticancer activity has been described in a number of solid tumours, including ovarian, lung and breast carcinomas. The taxanes exert their antineoplastic activity by stabilising the microtubuli and disrupting the balance between microtubuli assembly and disassembly (46). Their combination with cisplatin showed synergy in various pre-clinical models, prompting a number of clinical investigations.

Topoisomerase I inhibitors

The camptothecin analogues topotecan and irinotecan reversibly inhibit DNA topoisomerase I (topI). This enzyme plays a pivotal role in DNA replication. The camptothecins act by binding to the so-called cleavable complex (consisting of the enzyme topoisomerase I covalently bound to DNA), thereby interfering with the religation step. If the replication fork encounters a cleavable complex stabilised by a topoisomerase I inhibitor, DNA double-strand breaks are formed which may lead to cell death

Topoisomerase II inhibitors

The enzymes topoisomerase I and II are closely related in terms of sequence homology and function. They both alter the topology of the DNA, necessary for DNA synthesis and transcription. Topoisomerase I creates single-strand breaks whereas topoisomerase II alters the DNA topology through induction of double-strand breaks. Because of the similarity of TopI and II, it is possible that the interaction of TopI with platinum DNA adducts also occurs with TopII, and that synergy with cisplatin of

Discussion

DNA-based drug interactions with cisplatin occur with at least three types of chemotherapeutics: the antimetabolites, the taxanes, and the topoisomerase inhibitors. Even though numerous investigations have pointed out that these drugs can modulate the formation and/or repair of platinum-DNA adducts, exact mechanisms for the interaction have not been elucidated. It is striking that for each of the three classes, DNA repair inhibition has been demonstrated, but not in all cell lines tested.

References (96)

  • C.J.A. van Moorsel et al.

    Schedule-dependent pharmacodynamic effects of gemcitabine and cisplatin in mice bearing Lewis lung murine non-small cell lung tumours

    Eur. J. Cancer

    (2000)
  • E.K. Rowinsky et al.

    The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics

    Pharmacol. Ther.

    (1991)
  • J.Y. Douillard et al.

    Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial

    Lancet

    (2000)
  • Z.Z. Zdraveski et al.

    MutS preferentially recognizes cisplatin- over oxaliplatin-modified DNA

    J. Biol. Chem.

    (2002)
  • W.E. Ross

    DNA topoisomerases as targets for cancer therapy

    Biochem. Pharmacol.

    (1985)
  • E.J. Katz et al.

    Effect of topoisomerase modulators on cisplatin cytotoxicity in human ovarian carcinoma cells

    Eur. J. Cancer

    (1990)
  • S. Loehrer et al.

    Diagnosis and treatment: drugs five years later: Cisplatin

    Ann. Int. Med.

    (1984)
  • J.M. Roberts et al.

    DNA as the target for the cytotoxic and anti-tumour action of platinum coordination complexes: comparative in vitro and in vivo studies of cisplatin and carboplatin

  • A. Eastman

    Activation of programmed cell death by anticancer agents: cisplatin as a model system

    Cancer Cells

    (1990)
  • D.P. Gately et al.

    Cellular accumulation of the anticancer agent cisplatin: a review

    Br. J. Cancer

    (1993)
  • Y. Kondo et al.

    Metallothionein localization and cisplatin resistance in human hormone-independent prostatic tumor cell lines

    Cancer Res.

    (1995)
  • P. Mistry et al.

    The relationships between glutathione, glutathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines

    Br. J. Cancer

    (1991)
  • P. Perego et al.

    Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems

    Cancer Res.

    (1996)
  • A. Sancar

    DNA excision repair

    Ann. Rev. Biochem.

    (1996)
  • E.C. Friedberg

    Relationships between DNA repair and transcription

    Ann. Rev. Biochem.

    (1996)
  • F. Paques et al.

    Multiple pathways of recombination induced by double-strand breaks in saccharomyces cerevisiae

    Microbiol. Mol. Biol. Rev.

    (1999)
  • H.M. Pinedo et al.

    Fluorouracil: biochemistry and pharmacology

    J. Clin. Oncol.

    (1998)
  • W. Plunkett et al.

    Metabolism and action of fludarabine phosphate

    Sem. Oncol.

    (1990)
  • K.J. Scanlon et al.

    Biochemical basis for cisplatin and fluorouracil synergism in human ovarian carcinoma cells

    Proc. Natl. Acad. Sci. USA

    (1986)
  • M.C. Etienne et al.

    Dose reduction without loss of efficacy for 5-fluorouracil and cisplatin combined with folinic acid. In vitro study on human head and neck carcinoma cell lines

    Br. J. Cancer

    (1991)
  • G. Pratesi et al.

    Sequence dependence of the antitumor and toxic effects of 5-fluorouracil and cis-diamminedichloroplatinum combination on primary colon tumors in mice

    Cancer Chemother. Pharmacol.

    (1988)
  • T. Esaki et al.

    Inhibition by 5-fluorouracil of cis-diamminedichloroplatinum(II)-induced DNA interstrand cross-link removal in a HST-1 human squamous carcinoma cell line

    Cancer Res.

    (1992)
  • T. Tanaka et al.

    Pretreatment with 5-fluorouracil enhances cytotoxicity and retention of DNA-bound platinum in a cisplatin resistant human ovarian cancer cell line

    Anticancer Res.

    (2001)
  • H. Fujishima et al.

    Inhibition by 5-fluorouracil of ERCC1 and γ-glutamylcysteine synthetase messenger RNA expression in a cisplatin-resistant HST-1 human squamous carcinoma cell line

    Oncol. Res.

    (1997)
  • L.Y. Yang et al.

    Arabinosyl-2-fluoroadenine augments cisplatin cytotoxicity and inhibits cisplatin–DNA cross-link repair

    Mol. Pharmacol.

    (1995)
  • L. Li et al.

    Fludarabine-mediated repair inhibition of cisplatin-induced DNA lesions in human chronic myelogenous leukemia-blast crisis K562 cells: induction of synergistic cytotoxicity independent of reversal of apoptosis resistance

    Mol. Pharmacol.

    (1997)
  • L. Li et al.

    Fludarabine triphosphate inhibits nucleotide excision repair of cisplatin-induced DNA adducts in vitro

    Cancer Res.

    (1997)
  • J.P. Bergerat et al.

    Synergistic lethal effect of cis-dichlorodiammineplatinum and 1-β-d-arabinofuranosylcytosine

    Cancer Res.

    (1981)
  • J.S. Berek et al.

    Synergistic effect of combined intraperitoneal cisplatin and cytosinearabinoside in a murine ovarian cancer model

    Obstet. Gynecol.

    (1989)
  • R.J. Fram et al.

    Interactions of cis-diamminedichloroplatinum (II) with 1-β-d-arabinofuranosylcytosine in LoVo colon carcinoma cells

    Cancer Res.

    (1987)
  • L.J. Swinnen et al.

    1-β-d-arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy with cis-diamminedichloroplatinum (II) and modification of platinum-induced DNA interstrand cross-linking

    Cancer Res.

    (1989)
  • J.A. Ellerhorst et al.

    2-Deoxy-5-azacytidine increases binding of cisplatin to DNA by a mechanism independent of DNA hypomethylation

    Br. J. Cancer

    (1993)
  • A.M. Bergman et al.

    Synergistic interaction between cisplatin and gemcitabine in vitro

    Clin. Cancer Res.

    (1996)
  • C.J.A. van Moorsel et al.

    Mechanism of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer cell lines

    Br. J. Cancer

    (1999)
  • C. Theodossiou et al.

    Interaction of gemcitabine with paclitaxel and cisplatin in human tumor cell lines

    Int. J. Oncol.

    (1998)
  • W. Voigt et al.

    Schedule-dependent antagonism of gemcitabine and cisplatin in human anaplastic thyroid cancer cells

    Clin. Cancer Res.

    (2000)
  • C.J.A. v Moorsel et al.

    Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors

    Ann. Oncol.

    (1999)
  • Crul M, Schoemaker NE, Pluim D, et al. Phase I/II clinical and pharmacokinetic study of dose-intensive cisplatin and...
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