Cellular pharmacology of cis and trans pairs of platinum complexes in cisplatin-sensitive and -resistant human ovarian carcinoma cells

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Abstract

The cellular pharmacology of two pairs of cis and trans platinum complexes has been studied in three human ovarian carcinoma cell lines, a parental relatively cisplatin-sensitive line (CH1), a subline possessing acquired cisplatin resistance (3-fold; CH1cisR) and an intrinsically cisplatin resistant line (13-fold; SKOV-3). Growth inhibition studies showed that both JM335 [trans ammine (cyclohexylaminedichloro dihydroxo) platinum(IV)] and its platinum(II) dichloro homolog JM334 were relatively less cross-resistant against both acquired and intrinsic cisplatin resistant cells. In contrast, resistance circumvention was not apparent in these cell lines with their cis isomeric counterparts (JM149 for JM335 and JM118 for JM334). The trans compound JM335 was more potent than its cis isomer against all three cell lines. There was no clear correlation between intracellular accumulation following 2 h exposure to each compound and resulting DNA platination or growth inhibition. The selective activity of the trans platinum complexes against the SKOV-3 cell line correlated with a deficiency in the repair of adducts within a fragment of the N-ras gene induced by trans compounds whereas adducts induced by the cis counterparts, and cisplatin, were repaired. The CH1 parental line appeared repair deficient at the gene-specific level to adducts induced by both cis (including cisplatin) and trans compounds. Resistance in CH1cisR was associated with a lack of gene-specific repair of lesions formed by JM118 and JM149. All four compounds induced apoptosis in all three cell lines, as measured by fluorescent microscopy and field inverted gel electrophoresis, although the kinetics of apoptosis was markedly faster for the trans versus cis compounds. In summary, the trans platinum complexes JM335 and JM334 possess unique cellular properties compared to their cis counterparts particularly with respect to gene specific repair of DNA adducts and the rate of induction of apoptosis.

Introduction

The platinum coordination complexes cisplatin, and its less toxic analog, carboplatin represent two of the major drugs currently used in the treatment of cancer. However, for some time it has been recognised that these two drugs are active against broadly the same types of tumour [1]. Thus one major theme of analog development has involved attempting to widen the spectrum of antitumour activity to tumours that are initially, or have become, unresponsive to cisplatin/carboplatin. Despite considerable effort illustrated by the description of hundreds of analogs, and the phase I clinical evaluation of around 25 compounds, only one, carboplatin, is widely registered for use [2 for a review]. While carboplatin, and the orally active platinum drug, JM216 [3], [4] have addressed issues of patient quality of life, in terms of circumvention of tumour resistance to cisplatin, there has been less progress. Current platinum drugs undergoing clinical trial such as oxaliplatin (which has exhibited some activity in colorectal cancer, especially in combination with 5-fluorouracil [5], and the sterically hindered drug, AMD473 (ZD0473), which demonstrated in vivo circumvention of acquired cisplatin resistance in human tumour xenografts [6] may provide some widening of the spectrum of antitumor activity obtained with the parent drugs.

One rational approach to the discovery of more broad-spectrum third generation platinum drugs is to design novel platinum agents which bind to DNA in a manner distinct from that of cisplatin and carboplatin, which both ultimately form a similar spectrum of DNA adducts [7]. This strategy is probably best exemplified by the discovery of active trans platinum complexes, initially by Farrell and co-workers [8], [9], [10]. This surprising finding broke one of the original structure-activity rules for platinum complexes, namely that only the cis isomers were endowed with antitumor activity [11]. Active trans platinum complexes have also been described based on platinum(II) iminoether complexes [12], [13], [14] and as part of our collaboration with the Johnson Matthey Technology Centre, namely JM335 [trans ammine (cyclohexylaminedichlorodihydroxo) platinum(IV)] [15].

Some of the preclinical antitumor properties of JM335 have been previously described [15], [16], [17], [18]. The aim of this study was to undertake a detailed comparative analysis of the cellular pharmacological properties of JM335, its cis isomer, JM149 and their respective platinum(II) counterparts, trans ammine(cyclohexylamine) dichloro platinum(II) JM334, and its cis isomer JM118 (which, notably, has also been shown to be the major in vivo metabolite of the oral platinum drug JM216 [19], [21]). The study has used three human ovarian carcinoma cell lines, the parent relatively cisplatin-sensitive, CH1, an acquired cisplatin-resistant subline, CH1cisR, and the relatively intrinsically resistant, SKOV-3. Growth inhibition, cellular transport, DNA platination, gene-specific repair of platinum drug induced DNA adducts and induction of p53 and apoptosis has been determined.

Section snippets

Cell lines

Two parent human ovarian carcinoma cell lines, the relatively cisplatin sensitive CH1 and the relatively resistant SKOV-3, have been used [22]. In addition, a subline of CH1 possessing acquired resistance to cisplatin, CH1cisR, has been included. This was derived through in vitro exposure as described previously [23]. These three lines have been used by us previously in studies of cisplatin-induced DNA platination [24] and apoptosis [25].

Lines were grown as monolayers in Dulbecco’s Modified

Growth inhibition

The growth inhibitory properties of the two pairs of cis and trans isomers following 2 h exposure to the three ovarian carcinoma cell lines, are shown in Fig. 2. Mean IC50 values in μM against CH1 cells were 1.3 for JM118, 3.4 for JM334, 35.3 for JM149 and 18.6 for JM335. A degree of resistance was observed in CH1cisR cells to all four agents; resistance factors (Rf; IC50 resistant/IC50 CH1 cells) were 2.5 for JM118 (IC50 3.3), 1.5 for JM334 (IC50 5.1), 2.3 for JM149 (IC50 83) and 1.6 for JM335

Discussion

In recent years within the platinum drug development field there has been a burgeoning interest in trans platinum complexes exemplified by the discovery of active trans platinum complexes by at least three independent Groups. Within our collaboration with the Johnson Matthey technology Company, we previously described some of the antitumor and pharmacological properties of the JM mixed amine class of trans platinum compounds exemplified by JM335 [16], [17], [18], [19], [20]. These studies

References (38)

  • F.I. Raynaud et al.

    Cis-amminedichloro(2-methylpyridine) platinum(II) (AMD473), a novel sterically hindered platinum complex: In vivo activity, toxicology, and pharmacokinetics in mice

    Clin. Cancer Res.

    (1997)
  • R.J. Knox et al.

    Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloro platinum(II) and cis-diammine(1,1-cyclobutanedicarboxylato) platinum(II) differ only in the kinetics of their interaction with DNA

    Cancer Res.

    (1986)
  • N. Farrell et al.

    Cytostatic trans-platinum(II) complexes

    J. Med. Chem.

    (1989)
  • M. Van Beusichem et al.

    Activation of the trans geometry in platinum antitumor complexes. Synthesis, characterization, and biological activity of complexes with the planar ligands pyridine, N-methylimidazole, thiazole and quinoline. Crystal and molecular structure of trans-dichlorobis (thiazole) platinum(II)

    Inorg. Chem.

    (1992)
  • N. Farrell et al.

    Activation of the trans geometry in platinum antitumor complexes: a survey of the cytotoxicity of trans complexes containing planar ligands in murine L1210 and human tumor panels and studies on their mechanism of action

    Cancer Res.

    (1992)
  • T.A. Connors et al.

    Structure-activity relationships of the antitumor platinum coordination complexes

    Cancer Treat. Rep.

    (1979)
  • M. Coluccia et al.

    A trans-platinum complex showing higher antitumor activity than the cis congeners

    J. Med. Chem.

    (1993)
  • V. Brabec et al.

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

    Nucl. Acids Res.

    (1996)
  • R. Zaludova et al.

    DNA modifications by antitumor trans-[PtCl2(E-Iminoether)2]

    Mol. Pharmacol.

    (1997)
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