Table Of ContentRazoxane and Dexrazoxane –
Two Multifunctional Agents
·
Kurt Hellmann Walter Rhomberg
Editors
Razoxane and Dexrazoxane –
Two Multifunctional Agents
Experimental and Clinical Results
123
Editors
Prof.Dr.KurtHellmann Prof.Dr.WalterRhomberg
WindleshawHouse Unterfeldstrasse32
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Theauthorshavenoconflictofinterestofanykind
ISBN978-90-481-9167-3 e-ISBN978-90-481-9168-0
DOI10.1007/978-90-481-9168-0
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Preface
Therearenow(in2009)some900publishedpapersonthedevelopmentofrazox-
ane (Rz) and dexrazoxane (DXRz). This book inevitably, therefore, represents
an account of only a selected few of what the authors feel are the most impor-
tant discoveries. Moreover, the history of the two drugs justifies, if justification
were needed, that random screening is still a valid method for the discovery
of novel and useful drugs. A compound is just a compound which is a long
way from being a drug which in turn may be a long way from being a useful
medicament.
Experience helpsustopredictwhichsubstancesmaybetoxic,buttheoriescan
not help us to decide which compounds are not toxic so that we can move on and
decide post Hippocrates (and the US-FDA and EMA) to give the compound to
patients.Wecannotinadvancetellhowmuchofanewdrugmayenteracell(normal
or abnormal); how long it may stay there and how much will be rapidly excreted;
where it will locate in the cell and how much of it and with what immediate or
delayed consequences, and, critically, how answers to these questions will affect
eachorgan.Itwasnotsurprising,therefore,thatonlyexperimentationcouldanswer
thesequestions and crucially,how willthenew drugs affectdifferentdiseases and
howwilltheyinteractwithotherdrugs.
What could not be anticipated at all, were some of the extraordinary properties
displayedbyRzandDXRz.EventodaywehavenoideawhytheenantiomerDXRz
isatleast5timesassolubleinwaterasrazoxane.Webelieve,weknow,butcannot
besurewhyDXRzcanpreventthecardiotoxicityofdoxorubicinintheisolatedor
intact dog heart and 5 other species including humans. Also unknown is why and
howtherazoxanesaregeneralcytoprotectants.
The influence of these drugs on the differentiation of a pathologic neovascula-
tureoftumorsagainwasnotanticipated.Suchdifferentiationornormalizationofa
pathologicalvasculaturehasprobablyavarietyofimplicationsinmalignantornon-
malignantdiseases,butwasnotuntilrecentlyagoalfordrugdevelopment.Perhaps,
themostastonishingdiscoveryalongthedevelopmentroutewasthediscoverythat
it is possible by a drug to ‘take out’ one malignant characteristic, the metastasis
formation,ofthethreeusuallyneededtocharacteriseatissueasmalignant(uncon-
trolledproliferation,tumourdissemination,andmetastasisformation)andleavethe
othertwocharacteristicsunimpaired.
v
vi Preface
Ofconsiderablesignificancewasthediscoverythatrazoxanepreventedcelldivi-
sionataspecificpointinthecellgenerationcyclenamelyatG2/M.Moredetailed
aspectsofthechemistryandbiologywillbediscussedin3.2.
Surprising was also the readiness and effectiveness of the combination of
radiotherapyandrazoxanewithorwithoutotheranticancerdrugs.Thecombination
of radiotherapy and razoxane and its clinical effectiveness will be discussed in
Section2.3.2.
Dexrazoxanewasshowninthe1980stoaffordprotectionfromcardiotoxicityin
womenwithbreastcancer.Thedefinitivepapersonthecardiacprotectioninbreast
cancerpatientsreceivinganthracyclineswerethosebySandraSwain(1997).They
will be commented on and discussed as to their relevance in 2009 in Section 3.6.
Further trials were subsequently conducted in patients with different pediatric
cancers.Thesetrialsshowedcardioprotectionwhendexrazoxanewasadministered
withtheinitialchemotherapywithnodecreaseinanticancerefficacyandallowing
cumulativedoxorubicindosesupto600mg/m2.
Furtherdevelopmentsarethecytoprotectiveactivityofdexrazoxaneinmitigating
accidental anthracycline extravasation. This was first shown in animal studies by
SeppoLangerin1999.Meanwhile,thisuseofdexrazoxanebecameanFDA/EMA
approved established treatment for the accidental extravasation of anthracyclines.
Finally,newdataemergingfromNigelGreigsLaboratoryofNeuro-sciences(NIH,
USA)providesarationaleforthepotentialclinicaluseofrazoxane/dexrazoxanein
specificneurodegenerativeconditionssuchasAlzheimer’sorParkinson’sdisease.
Altogether,awiderangeofinterestingactivitieshavebeendiscoveredforrazox-
aneanddexrazoxanedespitehavingreceivedonlylimitedattentionfromclinicians.
Thismonographmaycontributetotheknowledgeofthesedrugs,hopefullyleading
toimprovedtreatments.
Withyham,UK KurtHellmann
Acknowledgments
The editors acknowledge with grateful thanks the following persons: S. Carter,
Suzanne Eccles, H. Eiter, E.O. Field, C. Franks, J. Gilbert, A. Goldin,
SirA.Haddow,JeanHartley,E.Herman,G.Mathe,GillianMurkin,K.A.Newton,
K.H. Renner, A. Salsbury, J. Speyer, R. Steiner, and Sandra Swain. Our special
thankstoDr.RudolfSteiner,Zurich,forhisreviewandeditorialsuggestions.
vii
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
K.Hellmann
1.1 OverviewandHistoricalDevelopmentofRazoxaneandDexrazoxane 1
1.1.1 History. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.2 InfluenceontheCellCycle . . . . . . . . . . . . . . . . . 2
1.1.3 AntimetastaticActivity . . . . . . . . . . . . . . . . . . . 3
1.1.4 Cardioprotection(TissueProtection) . . . . . . . . . . . . 4
1.1.4.1 PediatricTrials . . . . . . . . . . . . . . . . . . 5
1.1.5 FurtherAspects . . . . . . . . . . . . . . . . . . . . . . . 6
2 Razoxane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.1 PreclinicalData–InVitroandInVivo . . . . . . . . . . . . . . . 9
K.Hellmann
2.2 ModesofAction:ABriefSummary . . . . . . . . . . . . . . . . 11
W.Rhomberg
2.2.1 EffectsontheCellCycle . . . . . . . . . . . . . . . . . . 11
2.2.2 NormalizationofTumourBloodVessels . . . . . . . . . . 12
2.2.3 AntiinvasiveActivity . . . . . . . . . . . . . . . . . . . . 12
2.2.4 InhibitionofTopoisomeraseII . . . . . . . . . . . . . . . 12
2.2.5 ChelationofMetals . . . . . . . . . . . . . . . . . . . . . 13
2.2.6 CytorallentaricModeofAction . . . . . . . . . . . . . . . 14
2.3 ClinicalStudiesinMalignantTumors . . . . . . . . . . . . . . . 16
W.Rhomberg
2.3.1 Razoxane(ICRF-159)asAntitumorAgent . . . . . . . . . 16
2.3.1.1 LeukaemiasandMalignantLymphomas . . . . . 16
2.3.1.2 SolidTumors,SingleAgentTherapy. . . . . . . 18
2.3.1.3 SolidTumors,MultiagentTherapy . . . . . . . . 22
2.3.1.4 AdjuvantUseofRazoxane . . . . . . . . . . . . 23
2.3.2 RazoxaneasRadiosensitizer . . . . . . . . . . . . . . . . 28
2.3.2.1 SoftTissue-,Osteosarcomas,Chordomas . . . . 29
2.3.2.2 Gastro-IntestinalMalignancies . . . . . . . . . . 74
2.3.2.3 LungCancer . . . . . . . . . . . . . . . . . . . 91
2.3.2.4 OtherSolidTumors. . . . . . . . . . . . . . . . 92
ix
x Contents
2.3.3 AntimetastaticEfficacyofRazoxane . . . . . . . . . . . . 97
2.3.3.1 PreclinicalEvidence . . . . . . . . . . . . . . . 97
W.Rhomberg
2.3.3.2 MetastasisandtheEntryofCancerCells
intotheVasculature–PreventionbyRazoxane . 99
K.Hellmann
2.3.3.3 ClinicalEvidence . . . . . . . . . . . . . . . . . 110
W.Rhomberg
2.3.4 Razoxane–ACytorallentaricDrug. . . . . . . . . . . . . 123
K.Hellmann
2.3.5 ToxicityofRazoxane . . . . . . . . . . . . . . . . . . . . 138
W.Rhomberg
2.4 StudiesinNon-malignantDiseases . . . . . . . . . . . . . . . . . 146
W.Rhomberg
2.4.1 PsoriasisandPsoriaticArthropathy . . . . . . . . . . . . . 146
2.4.2 Crohn’sDiseaseandUlcerativeColitis . . . . . . . . . . . 151
3 Dexrazoxane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
3.1 Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
3.2 The Pharmacology of Dexrazoxane: Iron Chelating
ProdrugandTopoisomeraseIIInhibitor . . . . . . . . . . . . . . 158
B.B.Hasinoff
3.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 158
3.2.2 ChemistryofDexrazoxane . . . . . . . . . . . . . . . . . 160
3.2.2.1 BiochemistryandPharmacologyofDexrazoxane 160
3.2.2.2 PharmacokineticsandMetabolismofDexrazoxane 161
3.2.2.3 Tests of Other Iron Chelators as
AnthracyclineProtectiveAgents . . . . . . . . . 161
3.2.2.4 Dexrazoxane Inhibition of
TopoisomeraseII . . . . . . . . . . . . . . . . . 162
3.2.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . 164
3.3 ToxicologyandPharmacokinetics . . . . . . . . . . . . . . . . . 167
K.Hellmann
3.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 167
3.3.2 SingleDoseToxicity . . . . . . . . . . . . . . . . . . . . 168
3.3.3 RepeatedDoseToxicity . . . . . . . . . . . . . . . . . . . 170
3.3.4 TeratogenicityStudies. . . . . . . . . . . . . . . . . . . . 172
3.3.5 Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . 173
3.3.6 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . 174
3.3.7 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . 175
3.3.8 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . 176
3.3.9 LocalTolerance . . . . . . . . . . . . . . . . . . . . . . . 177
3.4 IdentificationofDexrazoxaneasaCardioprotector . . . . . . . . 178
E.H.Herman
Contents xi
3.5 DexrazoxaneasAntitumourAgent . . . . . . . . . . . . . . . . . 181
W.Rhomberg
3.6 ProtectionAgainstAnthracycline-InducedCardiotoxicity.
ClinicalAspects . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
3.6.1 Two Pivotal Studies of Dexrazoxane
as Cardioprotector: A Report Including
PharmacologyandSafetyIssues . . . . . . . . . . . . . . 185
R.Rubens
3.6.2 CommentsontheDefinitiveTrialsofDexrazoxane
ProtectionagainstAnthracyclineCardiotoxicity:
TheSwainTrails . . . . . . . . . . . . . . . . . . . . . . 203
K.Hellmann
3.6.3 StudiesofDexrazoxaneAgainsttheCardiotoxicity
ofAnthracyclinesinAdultandPaediatricPatients–
AnUpdate . . . . . . . . . . . . . . . . . . . . . . . . . . 207
R.L.Jones
3.7 Non-cardioprotectiveEfficacy . . . . . . . . . . . . . . . . . . . 214
S.W.Langer
3.7.1 AnthracyclineExtravasation . . . . . . . . . . . . . . . . 214
3.7.2 OtherPossibleIndications . . . . . . . . . . . . . . . . . 219
3.8 Neurodegenerative Diseases, a Future Avenue
forRazoxaneandDexrazoxaneTherapeuticUse? . . . . . . . . . 222
N.H.Greig,R.E.Becker,K.Hellmann
3.8.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . 222
3.8.2 Alzheimer’sDisease. . . . . . . . . . . . . . . . . . . . . 223
3.8.3 Parkinson’sDisease . . . . . . . . . . . . . . . . . . . . . 224
3.8.4 MetalsinADandPDBrain . . . . . . . . . . . . . . . . . 225
3.8.5 ChelatingAgentsinADandPD . . . . . . . . . . . . . . 228
4 SummaryandOutlook . . . . . . . . . . . . . . . . . . . . . . . . . 237
K.HellmannandW.Rhomberg
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
