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  • Registered Charity No. 207890

    1477-9226(2010)39:35;1-1

    ISSN 1477-9226

    DaltonTransactionsAn international journal of inorganic chemistry

    Volume 39 | N

    umber 35 | 2010

    Dalton Transactions

    Pages 80978340

    www.rsc.org/dalton Volume 39 | Number 35 | 21 September 2010 | Pages 80978340

    PERSPECTIVEWheate et al.The status of platinum anticancer drugs in the clinic and in clinical trials

    COMMUNICATIONKloo et al.Dichloromethane as solvent for the synthesis of polycationic clusters at room temperature a link to standard organometallic chemistry

    dt039035_cover_PRINT_LITHO.indd 1-3dt039035_cover_PRINT_LITHO.indd 1-3 8/16/10 4:35:56 PM8/16/10 4:35:56 PM

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    View Article Online / Journal Homepage / Table of Contents for this issue

    http://dx.doi.org/10.1039/c0dt00292ehttp://pubs.rsc.org/en/journals/journal/DThttp://pubs.rsc.org/en/journals/journal/DT?issueid=DT039035

  • PERSPECTIVE www.rsc.org/dalton | Dalton Transactions

    The status of platinum anticancer drugs in the clinic and in clinical trials

    Nial J. Wheate,* Shonagh Walker, Gemma E. Craig and Rabbab Oun

    Received 12th April 2010, Accepted 8th May 2010First published as an Advance Article on the web 30th June 2010DOI: 10.1039/c0dt00292e

    Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes forthe treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas andmelanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects andintrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have enteredclinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketingapproval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individualnations. During this time there have been more failures than successes with the development of 14 drugsbeing halted during clinical trials. Currently there are four drugs in the various phases of clinical trial(satraplatin, picoplatin, LipoplatinTM and ProLindacTM). No new small molecule platinum drug hasentered clinical trials since 1999 which is representative of a shift in focus away from drug design andtowards drug delivery in the last decade. In this perspective article we update the status of platinumanticancer drugs currently approved for use, those undergoing clinical trials and those discontinuedduring clinical trials, and discuss the results in the context of where we believe the field will develop overthe next decade.

    Introduction

    Since the discovery of the therapeutic potential of cis-diamminedichloridoplatinum(II), or cisplatin, by Barnett Rosen-berg (19262009)1 it has become one of the major drugs incancer chemotherapy. Today it is used in 32 of 78 treatmentregimes listed in Martindale2 in combination with a wide rangeof other drugs including: topoisomerase II inhibitors (doxoru-bicin, etoposide, mytomycin, bleomycin and epirubicin), mustards(cyclophosphamide, melphalan and ifosfamide), antimetabolites

    Strathclyde Institute of Pharmacy, and Biomedical Sciences, University ofStrathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow, UK G40NR. E-mail: nial.wheate@strath.ac.uk; Fax: +44 141 548 4962

    Nial J. Wheate

    Nial completed a BSc (Hons I)and PhD (2002) at the Uni-versity of New South Walesunder the direction of Assoc.Prof. J. Grant Collins. He isalso a graduate of the AustralianDefence Force Academy (1997)and served as an Officer in theRoyal Australian Navy (19952005). After leaving the Navy in2005, Nial was a Senior Fellow atthe University of Western Sydneywhere he worked in the groupof Assoc. Prof. Janice Aldrich-

    Wright. Currently he holds a lectureship in medicinal chemistry atthe University of Strathclyde, where his group undertakes researchinto novel platinum drugs and drug delivery systems.

    Shonagh Walker

    Shonagh recently completed aMSci in Chemistry with DrugDiscovery (Hons I) at the Uni-versity of Strathclyde. During herdegree she completed a place-ment year in industry with PfizerVeterniary Medicine where sheworked on a number of projectsdealing with quality control,pharmaceutical formulation andmaterials science. Shonagh iscurrently completing a PhD inplatinum anticancer drug deliv-ery, where her time is split be-

    tween drug delivery research and pharmaceutical formulation re-search. She enjoys taiko drumming, walking and is a warrantedleader in Girlguiding UK.

    (gemcitabine, 5-fluorouracil (5-FU) and methotrexate), vincaalkaloids (vinblastine and vinorelbine) and taxols (paclitaxel).2

    Cisplatin is currently used to treat testicular cancer (for which ithas a 90% cure rate), ovarian, bladder, melanoma, non-small celllung cancer (NSCLC), small cell lung cancer (SCLC), lymphomasand myelomas.2,3

    In the blood stream where the chloride concentration isrelatively high (100 mM) the chloride ligands stay attached tothe drug although binding to serum proteins, such as humanserum albumin, does occur (Fig. 1).4 When it reaches the tumour,cisplatin is thought to be taken up into the cells by three possiblemechanisms: passive diffusion, copper transporter proteins (e.g.CTR1) and/or organic cation transporters.5 Once inside thecell, the lower chloride concentration (420 mM) results in drug

    This journal is The Royal Society of Chemistry 2010 Dalton Trans., 2010, 39, 81138127 | 8113

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    View Article Online

    http://dx.doi.org/10.1039/c0dt00292e

  • Fig. 1 Simplified biological processing of cisplatin inside cells showing(blue) drug aquation, (red) DNA binding through the N7 of guanineand (green) deactivation and degradation by the tripeptide L-glutathione.Charges have been omitted for charity.

    aquation with the loss of one or both of the chloride ligands.4

    When aquated, cisplatin can go on to bind to its target, DNA.

    Cisplatin will bind at the N7 position of guanine, and to a lesserextent adenine, through the formation of a covalent coordinatebond with the lone pair of the nitrogen atom.4 Ring closurethrough the formation of a second DNA bond forms a rangeof adducts, particularly 1,2-GpG intrastrand adducts that bendthe DNA (between 30 and 60 towards the major groove) andunwinds the helix (up to 23 ).6 This DNA distortion preventsreplication and transcription, which ultimately leads to cellularapoptosis.4 Cisplatin is also known to bind to RNA and interferewith cellular RNA processing, which may assist in the action ofthe drug.7

    Unfortunately, the use of cisplatin is restricted because of severedose-limiting side effects which arise from the indiscriminateuptake of the drug into all rapidly dividing cells (tumours,but also for example bone marrow) and the bodys attemptto excrete the drug through the kidneys. These side effectsinclude: nephrotoxicity (reduced kidney function and damage),neurotoxicity (nervous system damage), ototoxicity (hearing loss),and myelosuppression (reduction in bone marrow activity). Tosome degree the nephrotoxicity of cisplatin can be reduced throughthe use of saline hyperhydration before and after treatment.8 As asingle agent, cisplatin does not cause alopecia (hair loss).

    The severe side effects of cisplatin mean that the dose deliveredto patients can be sub-lethal to tumours, particularly ovariancancers, which means they are then able to develop resistanceto further drug treatment. There are three main mechanisms ofdrug resistance:9

    Reduced drug uptake and/or increased drug efflux. Degradation and deactivation by intracellular thiols. In

    particular this may be due to raised glutathione levels which canbe as high as 10 mM inside resistant cells.

    Improved repair or tolerance of DNAcisplatin adducts.

    The toxicity of, and cellular resistance to, cisplatin have driventhe development of improved platinum-based anticancer drugsthat display fewer or more tolerable side effects and/or areable to overcome one or more resistance mechanisms. In the30 years since cisplatins first approval for human use, 23 otherplatinum-based drugs have entered clinical trials with only two

    Gemma E. Craig

    Gemma completed her BSc(Hons I) Chemistry with Foren-sics at the University of Strath-clyde. During her degree she alsocompleted a placement year in in-dustry with Procter and Gamblein London where she worked onClairol Perfect 10 hair colorant.Gemma is currently undertakinga PhD in platinum anticancerdrug delivery and has an interestin rugby, cooking, reading andsocialising.

    Rabbab Oun

    Ruby completed a BSc (Hons) inMedical Biochemistry at the Uni-versity of Glasgow then attendedNapier University, Edinburghand graduated with an MSc inDrug Design and Biomedical Sci-ence (with distinction). RubysPhD project is split between theUniversity of Strathclyde and theBeatson Institute for Cancer Re-search, University of Glasgowthrough a studentship from theScottish Universities Life Sci-ence Alliance. She has an in-

    terest in photography, enjoys travelling, cooking, reading andswimming.

    8114 | Dalton Trans., 2010, 39, 81138127 This journal is The Royal Society of Chemistry 2010

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