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Understanding and Improving Platinum Anticancer Drugs – Phenanthriplatin

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Understanding and Improving Platinum Anticancer Drugs – Phenanthriplatin ANTICANCER RESEARCH 34: 471-476 (2014) Review Understanding and Improving Platinum Anticancer Drugs – Phenanthriplatin TIMOTHY C. JOHNSTONE1, GA YOUNG PARK1 and STEPHEN J. LIPPARD1,2* 1Department of Chemistry and 2Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, U.S.A. Abstract. Approximately half of all patients who receive cells can acquire resistance over time through a process of anticancer chemotherapy are treated with a platinum drug. somatic evolution (4). Moreover, a number of side-effects, Despite the widespread use of these drugs, the only cure ranging from minor to dose-limiting in toxicity, accompany that can be claimed is that of testicular cancer following treatment with platinum agents (5). In an attempt to cisplatin treatment. This article reviews some of our recent circumvent these problems, a large number of platinum work on phenanthriplatin, a cisplatin derivative in which a complexes have been prepared and tested for anticancer chloride ion is replaced by phenanthridine, and on one of activity. One strategy that has been used by chemists has its analogues, the previously reported pyriplatin. These been to devise target compounds that differ significantly cationic complexes form monofunctional adducts on DNA from those prescribed by the traditional structure–activity that do not significantly distort the duplex, yet efficiently relationships (SARs) established in the 1970s (6). Such ‘non- block transcription. Cell-based assays reveal altered classical’ platinum complexes include Pt(IV) pro-drugs, cellular uptake properties and a cancer cell-killing profile complexes with trans stereochemistry, polyplatinum different from those of established platinum drugs. compounds, platinum-tethered intercalators, and Mechanistic work, including a crystal structure analysis of monofunctional complexes. Compounds in the latter category platinum-modified DNA in the active site of RNA polymerase are distinguished from the classical platinum drugs in that II, is discussed herein. they form monofunctional adducts as opposed to bifunctional cross-links. Recently we described the potent anticancer Platinum-based drugs have become a mainstay of cancer activity of the monofunctional complex cis- + therapy; approximately half of all patients undergoing [Pt(NH3)2Cl(phenanthridine)] , or phenanthriplatin (7). This chemotherapeutic treatment receive a platinum drug (1). The review summarizes some of our recent results derived from widespread use of platinum agents in the treatment of cancer investigations of the biological properties of began with the discovery of the anti-neoplastic activity of phenanthriplatin. We begin with a brief overview of the cisplatin by Barnett Rosenberg in the 1960s (2). Despite the discovery of the anticancer activity of cisplatin and how pervasiveness of platinum drugs in cancer treatment subsequent work led to the formulation of SARs. The regimens, a number of attendant disadvantages exist (3). For success of these SARs in guiding researchers to the instance, no single-agent is equally effective against all discovery of carboplatin and oxaliplatin is described, cancer types and some types appear to be inherently resistant together with recent efforts to move away from these to treatment with any of the currently approved platinum traditional SARs. Our work leading to the discovery of agents. In addition to such resistance, populations of cancer phenanthriplatin is then discussed, along with recent results that may help shed light on the potency of this monofunctional compound. Structures of key platinum complexes discussed in this review are depicted in Figure 1. Correspondence to: Stephen J. Lippard, Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Av., Cisplatin and the Structure–Activity Relationships Cambridge, MA, 02139, U.S.A. Tel: +1 6172531848, e-mail: [email protected] The preparation of a coordination complex with the simple Key Words: Cytotoxicity, transcription, RNA polymerase II, X-ray formula cis-[Pt(NH3)2Cl2] was first described by Peyrone in structure, monofunctional platinum, pyriplatin, review. the mid-19th century and, as was often the custom at the 0250-7005/2014 $2.00+.40 471 ANTICANCER RESEARCH 34: 471-476 (2014) Figure 1. Platinum anticancer agents discussed in this review. time, the compound came to bear his name as Peyrone’s platinum complex to have activity (12). These SARs specified chloride (8). The discovery of the anti-neoplastic properties that the platinum complex have square-planar geometry, be of this complex by Barnett Rosenberg is a great example of charge neutral, contain two cis am(m)ine ligands, and have the role that serendipity can play in science (9). During the two cis anionic ligands. The anionic ligands could not bind the course of investigating the effect of electric fields on platinum too tightly, or activity would be reduced. If these bacterial cell division, platinum electrodes that had been ligands were too labile, however, the compounds exhibited chosen for their inertness began to leach platinum ions into prohibitively high levels of toxicity. Moreover, the two the ammonia-containing growth medium. The bacteria am(m)ine ligands or two anionic ligands could be replaced by incubated in this growth medium continued to grow but did a chelating diamine or chelating dicarboxylate, respectively. not divide. Rigorous control experiments revealed that the Extensive drug discovery programs were initiated that relied most potent agent to recapitulate this effect in bacteria was on systematic variation of ligands according to these rules. As Peyrone’s chloride. In a deductive leap, Rosenberg proposed a result of these programs, two other platinum agents, cis- that if this platinum complex could inhibit bacterial cell diamminecyclobutanedicarboxylatoplatinum(II) and R,R- division then it might be able to stop the uncontrolled cell cyclohexane-1,2-diamineoxalatoplatinum(II) were approved growth that characterizes cancer. In 1969, Rosenberg by the FDA for clinical use in the United States (13). The published the results of a study showing that cis- former is commonly referred to as carboplatin and the latter [Pt(NH3)2Cl2] was effective in treating sarcoma 180 and as oxaliplatin (Figure 1). These two compounds obey the leukemia L1210 in mice (2). In 1978, only nine years after classical SARs and were thought to operate by a mechanism the initial publication describing its anticancer activity, this of action similar to that of cisplatin. compound, which came to be known as cisplatin (Figure 1), was approved by the US Food and Drug Administration Mechanism of Action of Classical Platinum Agents (FDA) for clinical treatment of genitourinary tumors (10). In years following the initial clinical implementation of The rapid approval resulted from a combination of a dire cisplatin, much research by laboratories worldwide was need for new chemotherapeutic drugs at the time and the conducted to determine the mechanism by which this drug diligent persistence of Rosenberg (11). carries out its anticancer action. As a result, a relatively clear Following the initial reports of the anticancer activity of picture has emerged of the steps involved in this process cisplatin, inorganic chemists began preparing a variety of (14). Although some details continue to be refined, the four platinum complexes with different ligands and testing their main steps in the mechanism of action are (i) cellular uptake, anti-neoplastic effects. The collective result of these many (ii) aquation/activation, (iii) DNA platination, and (iv) separate studies was the emergence of a set of rules governing cellular processing of Pt–DNA lesions, leading to cell molecular structure that appeared to be required in order for a survival or apoptosis. 472 Johnstone et al: Understanding and Improving Platinum Anticancer Drugs – Phenanthriplatin (Review) Passive diffusion was initially thought to play a significant myelosupression (24, 25). In many treatment regimens, one or role in the uptake of cisplatin (15). The importance of more of these side-effects will often be dose-limiting. Another passive diffusion was embedded in the SARs through the serious limitation of current platinum-based therapies is that requirement of charge neutrality. In recent years, however, some types of cancer are inherently resistant to treatment and active transport via the copper transporters CTR1 and CTR2 many others develop resistance with time (26). In an effort to has been implicated as a major route of platinum access into circumvent the mechanisms that give rise to such inherent or the cell (16). The matter has not been unambiguously acquired resistance, and to mitigate other side-effects, resolved, however, and new iconoclastic data continue to platinum compounds deviating in structure from the prescripts surface (17). Studies of overexpression of the organic cation of the traditional SARs have been investigated. The hypothesis transporters (OCTs) 1 and 2 revealed that these proteins help is that a difference in structure will result in an altered facilitate the entry of oxaliplatin into cells, and the mechanism of action and, consequently, a different spectrum propensity of colorectal cancer cells to overexpress these of anticancer activity. transporters may explain the efficacy of this drug in the Several structural motifs have been explored (6). Some of treatment of this particular malignancy (18). As discussed the most commonly investigated
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