Cellular pharmacology of cis and trans pairs of platinum complexes in cisplatin-sensitive and -resistant human ovarian carcinoma cells
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)
- et al.
Two consecutive phase II trials of oxaliplatin (l-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines
Ann. Oncol.
(1996) - et al.
Platinum(II) complexes containing iminoethers: a trans platinum antitumour agent
Chem.-Biol. Interact.
(1995) - et al.
DNA damage by anticancer agents: mapping in cells at the subgene level with quantitative PCR
Anal. Biochem.
(1994) - et al.
DNA repair in cisplatin-sensitive and resistant human cell lines measured in specific genes by quantitative polymerase chain reaction
Biochem. Pharmacol.
(1996) - et al.
Gene-specific formation and repair of cisplatin intrastrand adducts and interstrand cross-links in Chinese hamster ovary cells
J. Biol. Chem.
(1991) - et al.
Role of platinum–DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines
Biochem. Pharmacol.
(1994) - et al.
Cisplatin/carboplatin cross-resistance in ovarian cancer
Br. J. Cancer
(1989) Platinum complexes
- et al.
Preclinical antitumor evaluation of bis-acetato-amminedichloro cyclohexylamine platinum(IV): an orally active platinum drug
Cancer Res.
(1993) - et al.
Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer
J. Clin. Oncol.
(1997)
Cis-amminedichloro(2-methylpyridine) platinum(II) (AMD473), a novel sterically hindered platinum complex: In vivo activity, toxicology, and pharmacokinetics in mice
Clin. Cancer Res.
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.
Cytostatic trans-platinum(II) complexes
J. Med. Chem.
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.
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.
Structure-activity relationships of the antitumor platinum coordination complexes
Cancer Treat. Rep.
A trans-platinum complex showing higher antitumor activity than the cis congeners
J. Med. Chem.
DNA adducts of antitumor trans-[PtCl2(E-iminoether)2]
Nucl. Acids Res.
DNA modifications by antitumor trans-[PtCl2(E-Iminoether)2]
Mol. Pharmacol.
Cited by (23)
Synthesis and biological evaluation of mixed ammine/amine platinum(II) complexes with dicarboxylate containing organic nitrate as ligand
2014, Inorganica Chimica ActaCitation Excerpt :It exerted anticancer activity by losing its axial acetate groups to form a platinum(II) complex (JM118), an asymmetrical cisplatin analogue which binds to DNA via a similar mechanism to cisplatin [11–13]. JM118 is considerably more active than cisplatin in numerous cisplatin sensitive and resistant human tumor cells [14–17]. Hence, many mixed ammine/amine platinum(II) complexes analogous to JM118, have been synthesized and investigated for anticancer activity against various human solid tumor cell lines by other researchers.
Human steroidogenic factor-1 (hSF-1) regulates progesterone biosynthesis and growth of ovarian surface epithelial cancer cells
2010, Journal of Steroid Biochemistry and Molecular BiologyThe role of p53 in the cellular toxicity by active trans-platinum complexes containing isopropylamine and hydroxymethylpyridine
2010, European Journal of Medicinal ChemistryCitation Excerpt :Most of the reported inactivity of trans-platinum complexes is thought to be due to its kinetic instability, which would result in Pt deactivation prior to binding to DNA [10], and to the originated perturbations in the DNA structure, different from those of cisplatin [11]. However, several exceptions for the trans-platinum complexes have been reported [12–20] indicating that synthetic variations in the coordinating ligands to the central platinum atom could lead to new active platinum derivatives. Complexes with amines such as cyclic aliphatic amines [21], chiral aliphatic amines [22,23], planar aromatic amines with hydroxyl groups [24,25], polyamines, which can chelate the platinum atom [26], piperidinopiperidine ligands [27], acetonimines and cyclic ligands able to mimic imino ethers [28,29], and hindered phosphines with high lipophilic character [30,31], have shown enhanced activity in cisplatin-sensitive and resistant cell lines.
Cytotoxicity, mutagenicity, cellular uptake, DNA and glutathione interactions of lipophilic trans-platinum complexes tethered to 1-adamantylamine
2008, Journal of Inorganic BiochemistryNovel cisplatin-type platinum complexes and their cytotoxic activity
2006, Bioorganic and Medicinal Chemistry LettersPotential new antitumor agents from an innovative combination of camphorato, a ramification of traditional Chinese medicine, with a platinum moiety
2005, Bioorganic and Medicinal Chemistry Letters