LABORATORY–CLINIC INTERFACEDNA-based drug interactions of cisplatin
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.
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