161 Recent Results in Cancer Research ManagingEditors P.M. Schlag, Berlin (cid:2) H.-J. Senn, St. Gallen AssociateEditors P. Kleihues, Lyon (cid:2) F. Stiefel, Lausanne B. Groner, Frankfurt (cid:2) A. Wallgren, G(cid:2)teborg FoundingEditors P. Rentchnik, Geneva Springer-Verlag Berlin Heidelberg GmbH U. Reinhold W. Tilgen (Eds.) Chemosensitivity Testing in Oncology With 75 Figures, Some in Colour, and 45 Tables B D Prof.Dr.UweReinhold Prof.Dr.WolfgangTilgen Universit(cid:2)tsklinikendesSaarlandes HautklinikundPoliklinik 66421Homburg/Saar,Germany IndexedinCurrentContentsandIndexMedicus ISBN 978-3-642-62412-4 ISSN0080-0015 LibraryofCongressCataloging-in-PublicationData Chemosensitivitytestinginoncology/U.Reinhold,W.Tilgen(eds.). p. cm.– (Recentresultsincancerresearch;161)Includesbibliographicalreferencesandindex. ISBN 978-3-642-62412-4 ISBN 978-3-642-19022-3 (eBook) DOI 10.1007/978-3-642-19022-3 1.Cancer–Chemotherapy–Congresses.2. Drugresistanceincancercells–Congresses.3.Antineoplasticagents–Testing–Con- gresses.I.Reinhold,Uwe.II.Tilgen,W.(Wolfgang),1944– III.Series.[DNLM: 1. Drug Resistance, Neoplasm – Congresses. 2. Antineoplastic Agents – therapeutic use–Congresses.3.DrugTherapy–methods–Congresses.QZ267C51582002] RC271.C5C3972002 616.99'4061–dc21 2002066990 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartof thematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseofil- lustrations, recitation, broadcasting, reproduction on microfilm or in any other way, andstorageindatabanks.Duplicationofthispublicationorpartsthereofispermitted onlyundertheprovisionsoftheGermanCopyrightLawofSeptember9,1965,inits currentversion,andpermissionforusemustalwaysbeobtainedfromSpringer-Verlag. ViolationsareliableforprosecutionundertheGermanCopyrightLaw. http://www.springer.de (cid:3)Springer-VerlagBerlinHeidelberg2003 Originally published by Springer-Verlag Berlin Heidelberg New York in 2003 Softcover reprint of the hardcover 1st edition 2003 Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispubli- cationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesare exemptfromtherelevantprotectivelawsandregulationsandthereforefreeforgeneral use. Product liability: The publisher cannot guarantee the accuracy of any information aboutdosageandapplicationcontainedinthisbook.Ineveryindividualcasetheuser mustchecksuchinformationbyconsultingtherelevantliterature. Typesetting:St(cid:4)rtzAG,97080W(cid:4)rzburg,Germany Coverdesign:design&productionGmbH,69121Heidelberg,Germany Printedonacid-freepaper SPIN10833879 21/3130SM–5 4 3 2 1 0 Preface Over the past 50 years many in vitro and in vivo drug response assay systems have been developed to determine the potential ac- tivityofchemotherapyagents. The idea was to eliminate ineffective agents and unnecessary toxic treatment while selecting drugs active in vitro or in the mouse model that might increase the probability of response in the patient. None of these test models, however, achieved routine clinical application in the past. This might be at least in part re- lated to large discrepancies that were described between the suc- cessrateoftheassaysystemsandtheclinicalbenefitincancerpa- tients. The heterogeneity of chemosensitivity that exists between different tumors as well as between individual tumor lesions may beoneexplanationforthesefindings.Furthermore,differentassay endpointssuchasproliferation,metabolism,andvitalitywerede- veloped to evaluate the effects of cytostatic drugs on tumor cells, and these might be related to the differing results. However, knowledgeaboutproceduresforassay-assistedtreatmentselection hasincreasedrapidlywithinthepastfewyears,andseveralstudies suggest that test-directed chemotherapy selection now may im- proveresponseratesandsurvivalinvarioustypesoftumors. The International Society for Chemosensitivity Testing in On- cology (ISCO) was founded to promote, coordinate, and improve clinicalandlaboratory researchinthefieldofpredictivedrugtest- ing in human tumor cells. In this volume the Proceedings of the 1st ISCO Symposium, held September 14–15, 2001 in Homburg/ Saar,Germany,arepresented.Outstandingresearchersfromdiffer- ent oncological fields give an overview of the current state of the artinbasicresearchandclinicalresultsrelatedtothefieldofmul- tidrug resistance, experimental approaches to drug testing, and the clinical relevance of individualized chemosensitivity testing in oncology. The results show that pretherapeutic chemosensitivity testingisnowemergingasanimportantadjunctinthephysician's armamentarium. We wish to thank all the contributors as well as all those who helpedustoorganizethesymposiumandtoproducethisvolume. Homburg/Saar,Summer2002 UweReinhold,WolfgangTilgen Contents 1 In Vitro Drug Testing Methods: Recent Developments LuminescenceApplicationsforChemotherapeuticDrug Development .............................................. 3 P.E.Andreotti,G.Caceres,R.Zamkina,M.Dauphin(cid:2)e TheUseoftheMTTAssaytoStudyDrugResistance inFreshTumourSamples ..................................... 13 J.M.Sargent ChemosensitivityTestingofHumanTumorsUsingSi-sensorChips ...... 26 P.Mestres-Ventura MultiparametricSensorChipsforChemosensitivityTesting ofSensitiveandResistantTumorCells ........................... 39 A.M.Otto,M.Brischwein,H.Grothe,E.Motrescu,B.Wolf DevelopmentofNewInVitroChemosensitivityTest UsingCollagenGelDropletEmbeddedCultureandImageAnalysis forClinicalUsefulness ....................................... 48 H.Kobayashi InVitroChemosensitivityTestingofHematologicalCancerPatients: DetectionofOrnithineDecarboxylase ........................... 62 U.Bachrach,Y.Wang 2 Tumor Chemosensitivity Assays: Evaluation of In Vitro Results TheChemosensitivityProfileofRetinoblastoma .................... 73 F.DiNicolantonio,M.Neale,Z.Onadim,J.L.Hungerford, J.L.Kingston,I.A.Cree ChemosensitivityTestinginMalignantMelanoma .................. 81 S.Ugurel,W.Tilgen,U.Reinhold VIII Contents HumanMelanoma:DrugResistance ............................. 93 H.Helmbach,P.Sinha,D.Schadendorf Cisplatin,DoxorubicinandPaclitaxelInducemdr1GeneTranscription inOvarianCancerCellLines ................................... 111 T.Sch(cid:3)ndorf,R.Neumann,C.Benz,M.Becker, M.Riffelmann,U.-J.G(cid:3)hring,J.Sartorius, C.-H.W.vonK(cid:3)nig,M.Breidenbach,M.M.Valter, H.Hoopmann,F.DiNicolantonio,C.M.Kurbacher 3 Clinical Relevance of Tumor-Directed Therapy ChemosensitivityTestingasanAidtoAnti-CancerDrug andRegimenDevelopment ................................... 119 I.A.Cree Assay-AssistedTreatmentSelectionforWomen withBreastorOvarianCancer ................................. 126 J.P.Fruehauf,D.S.Alberts ChemosensitivityTestinginGynecologicOncology– DreamorReality? .......................................... 146 M.Untch,N.Ditsch,E.Langer,C.Kurbacher,C.Crohns, G.Konecny,S.Kahlert,I.Bauerfeind,H.Hepp TreosulfanintheTreatmentofMetastaticMelanoma: FromChemosensitivityTestingtoClinicalTrials .................... 159 K.Neuber ChemosensitivityTestingandTest-DirectedChemotherapy inHumanPancreaticCancer .................................. 180 M.Kornmann,H.G.Beger,K.H.Link ClinicalSignificanceofCellularDrugResistance inChildhoodLeukemia ...................................... 196 G.J.L.Kaspers,A.J.P.Veerman ATPChemosensitivityTestinginOvarianandBreastCancer: EarlyClinicalTrials .......................................... 221 C.M.Kurbacher,O.M.Grecu,U.Stier,T.J.Gilster, M.-M.Jan(cid:4)t,M.Untch,G.Konecny,H.W.Bruckner, I.A.Cree ChemosensitivityTesting–PresentandFutureinJapan ............. 231 T.Kubota,Y.Otani,T.Furukawa,H.Hasegawa, M.Watanabe,M.Kitajima SubjectIndex ............................................ 243 Principal Authors Andreotti,PeterE.,PhD,AtlanticScientificDevelopmentInc., PMB46,1511E.CommercialBlvd.,FortLauderdale,FL33334, USA Bachrach,Uriel,PhD,DepartmentofMolecularBiologyHebrew University-Hadassah,MedicalSchool,P.O.Box12272,Jerusalem, Israel Cree,IanA.,MD,TranslationalOncologyResearchCentre, DepartmentofHistopathology,QueenAlexandraHospital, Portsmouth,PO63LY,UK Fruehauf,JohnP.,MD,PhD,OncotechInc.,15501RedhillAvenue, Tustin,CA92780,USA Kaspers,G.J.L.,MD,DepartmentofPediatricHematology/ Oncology,VUUniversityMedicalCenter,DeBoelelaan1117, 1081Amsterdam,TheNetherlands Kobayashi,Hisayuki,MD,BiochemicalLaboratory, NittaGelatinInc.,2-22Futamata,Yao-City,Osaka5810024,Japan Kornmann,Marko,MD,DepartmentofGeneralSurgery, UniversityofUlm,Steinh(cid:2)velstraße9,89075Ulm,Germany Kurbacher,ChristianM.,MD,PhD,DivisionofClinicaland ExperimentalGynecologicOncology,DepartmentofGynecology andObstetrics,UniversityofCologneMedicalCenter, KerpenerStraße34,50931K(cid:2)ln,Germany Kubota,Tetsuro,MD,FACS,DepartmentofSurgery,Schoolof Medicine,KeioUniversity,35Shinanomachi,Shinjuku-ku, Tokyo160-8582,Japan X PrincipalAuthors Mestres-Ventura,Pedro,MD,InstituteofAnatomyandCell Biology,UniversityHospital,UniversityofSaarland, 66421Homburg/Saar,Germany Neuber,Karsten,MD,DepartmentofDermatology, UniversityHospitalHamburg,Martinistraße52,20246Hamburg, Germany Otto,AngelaM.,MD,Heinz-Nixdorf-ChairforMedicalElectronics, TechnicalUniversityofMunich,Arcisstraße21, 80290M(cid:3)nchen,Germany Sargent,JeanM.,MD,HaematologyResearch,PemburyHospital, TonbridgeRoad,Pembury,Kent,TN24QJ,UK Schadendorf,Dirk,MD,KlinischeKooperationseinheitf(cid:3)r Dermatoonkologie(DKFZ)anderUniversit(cid:4)ts-Hautklinik Mannheim,Universit(cid:4)tHeidelberg,68135Mannheim,Germany Sch(cid:2)ndorf,Thomas,PhD,DepartmentofGynecologyand Obstetrics,UniversityofCologne,KerpenerStraße34, 50931K(cid:2)ln,Germany Ugurel,Selma,MD,DepartmentofDermatology,TheSaarland UniversityHospital,66421Homburg/Saar,Germany Untch,Michael,MD,DepartmentofObstetricsandGynecology, UniversityofM(cid:3)nchen-Großhadern,Marchioninistraße15, 81377M(cid:3)nchen,Germany 1 In Vitro Drug Testing Methods: Recent Developments