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Synergism Between Cisplatin and Topoisomerase I Inhibitors, NB-506 and SN-38, in Human Small Cell Lung Cancer Cells'

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Synergism Between Cisplatin and Topoisomerase I Inhibitors, NB-506 and SN-38, in Human Small Cell Lung Cancer Cells' CANCERRESEARCH56,789-793,FebruaryII, 19961 Synergism between Cisplatin and Topoisomerase I Inhibitors, NB-506 and SN-38, in Human Small Cell Lung Cancer Cells' Minoru Fukuda, Kazuto Nishio, Fumihiko Kanzawa, Hayato Ogasawara, Tomoyuki Ishida, Hitoshi Arioka, Krzysztof Bojanowski, Mikio Oka, and Nagahiro Sai.jo2 Medical Oncology, National (‘ancerCenter Hospital (M. F.. N. £1and Pharmacology Division, National C'ancer Center Research Institute (K. N., F. K., H. 0., T. 1., H. A., K. B., N. S.!, Tsukiji 5J.J Chuo-ku, Tokyo 104, and The Second Department ofinternal Medicine. Nagasaki University School ofMedicine, Nagasaki, (M. F., M. 0.], Japan ABSTRACT among potent topoisomerase inhibitors and its cytotoxic mechanisms are not the same as those of CPT derivatives (6). Consequently, Topolsomerase I-targeting anticancer agents such as 7-ethyl-lO-[4-(l- NB-506 is considered an interesting anticancer agent, and single pipendyl)-1-pipendyljcarbonyloxy-eamptothecin (CPT-11) and 6-N- dosing schedule Phase I studies of NB-506 are now conducted in formylamlno-12,13-dihydro-1,11-dihydroxy-13-(fi-D-glucopyranosyl)-5H- indolo[2@-a]pyr@lo[3,4-c]carbazole-5,7(6H)-dione(NB-506)have been Japan. CDDP is a key agent for cancer chemotherapy, and some developedandshowstrong antitumor activity againstvariouscancers.We combination chemotherapy regimens have been prompted by a ther examinedthe interaction of thesedrugs and cisplatin (CDDP), and bio apeutic synergy between CDDP and etoposide (7—9)or CPT-l 1 chemicalmechanismsofsynergismbetweenthem.Interactionofdrugsin (10—12).CPT-ll is active against various human cancer patients; humansmallcelllungcancercells,SBC-3,wasanalyzedusingtheisobo however, preclinical and clinical studies suggest it behaves as a logram method. Combinations of CDDP with NB-506, CPT-11, and an prodrug in vivo, and the majority of antitumor activity may be attrib active metabolite of CPT-11, 7-ethyl-1O-hydroxy-CPT (SN-38), showed utable to its more active metabolite SN-38. In vitro, SN-38 is 250— synergistic effects. Formation of DNA interstrand cross-links (ICLs) on 1000-fold more potent than CVF-ll in the inhibition of topoisomerase thecellswasanalyzedusinganalkalineelutionassayandincreasedICLs I activity. wereobservedbysimultaneousexposuretoCDDP (1.5 gtM)and NB-506 Demonstration of supraadditive cell killing would imply an inter (10flM)comparedwiththatinresponsetoCDDPalone.DNArepairafter ICL formationInducedby3-hexposuretoCDDP(1.5gtM)wasreducedby action between two agents at a cellular level and have profound NB-506 (10 nM) exposure.On the other hand, a higher concentration of implications for biochemical study. In this study, we demonstrated CDDP (150 ELM)enhancedthetopolsomeraseIinhibitoryactivityof that the cytotoxic effects of CDDP combined with NB-506, CPT-11, NB-506 and SN-38determined by relaxation of supercoiledEscherichia and SN-38 were synergistic and elucidated the mechanisms respon coli DNA. These biological interactions might result in synergistic inter sible for the synergistic effects. actions between CDDP and NB-506 or SN-38. Topolsomerase I inhibitors and CDDP may be a key regimen for cancer chemotherapy and merit further examination. MATERIALS AND METHODS INTRODUCTION Drugs and Chemicals. CVF-l 1 and SN-38 were provided by Daiichi Co. Ltd. (Tokyo, Japan),NB-506wasprovidedby the BanyuTsukubaResearch The DNA topoisomerases are enzymes that can alter the topology Institute (Tsukuba, Japan), CDDP was purchased from Nippon Kayaku Co. of DNA by transiently breaking one or two strands of DNA, passing Ltd. (Tokyo, Japan),paclitaxel and etoposidewere obtainedfrom Bristol a single- or double-stranded DNA through the break, and finally MyersSquibbCo.Ltd. (Tokyo,Japan),vindesinewasobtainedfromShionogi resealing the breaks. These enzymes are involved in a number of Co. Ltd. (Osaka,Japan),and plasmid DNA pBR322 was purchasedfrom crucial cellular processes, including replication, transcription, and ToyoboCo. Ltd. (Osaka,Japan). Cell Line and CUltUre. The human small cell lung cancer cell line SBC.3, recombination, and they are now viewed as important therapeutic originally established at the Okayama University School of Medicine, was targets for cancer chemotherapy. In particular, after demonstrating donatedby the JapaneseCancerResearchResourcesCellBank.The SBC-3 that CPT-l l@, a semisynthetic derivative of CPT, showed strong cellsweregrownasattachedculturesin RPM! 1640medium(GIBCO,Grand antitumor activity against leukemia, lymphoma (1), small cell lung Island,NY) supplementedwith10%v/v heat-inactivatedfetalbovineserum (2), non-small-cell lung (3), colorectal (4), and ovarian and cervical (SigmaChemicalCo. SL Louis, MO), penicillin (100 units/mI),andstrepto (5) cancers. It is therefore probable that topoisomerase I inhibitors are mycin (100 @.&g/ml)ina humidified atmosphere of 5% CO2 in air at 37°C.The promising anticancer agents. NB-506 is a novel indolocarbazole cells wereharvestedroutinelyby trypsinizationanddiluted with the medium anticancer agent. The primary target of this agent is considered to be to the appropriateconcentrations.Thecell sizesandnumbersweremeasured topoisomerase I. The indolocarbazole structure of NB-506 is unique by a CoulterChannalyzerC-256system(CoulterElectronics,Hialeah,FL). Growth Inhibition Assay. We used the tetrazoliumdye (MU) assay described previously (13) to evaluate the growth inhibitory effects of the Received 8/14/95; accepted 12/6/95. The costsof publicationof this article weredefrayedin part by the paymentof page cytotoxic agents. In brief, l60-@d aliquots of an exponentially growing cell charges. This article must therefore be hereby marked advertisement in accordance with suspension(6.3X l0@cells/mI)wereseededinto96-wellmicrotiterplates,and 18 U.S.C. Section 1734 solely to indicate this fact. thecellswereincubatedfor 12h, afterwhich 20-@alaliquotsof drug solutions @ This work was supported in part by Grants-in-Aid for Cancer Researchand from the of variousconcentrationswereadded.Followingexposuretothedrugsfor 72 SecondTermComprehensive10-YearStrategyforCancerControl,theMinistry of Health andWelfare,theMinistryofEducationScienceofJapan,atrustfund,theAdultDisease h, 20 p3 MTF solution(5 mg/mi in PBS)wereaddedto eachwell, andthe MemorialFoundation,andthe Bristol-MyersSquibbFoundation. plateswereincubatedat37°Cforanother4h.After centrifugationoftheplates 2 To whom requests for reprints should be addressed. Phone: 81-3-3542-251 1; Fax: at 1200X g for 8 mm,themediumwasaspiratedfromeachwell ascompletely 81-3-3542-I 886. aspossible,200pi DMSO wereaddedto eachwell to dissolvetheformazan, 3 The abbreviations used are: CPT-l 1, 7-ethyl-l0-[4-(l-piperidyl)-l-piperidyl]car andtheabsorbancewasmeasuredat562and630nmusingaDeltaSoftELISA bonyloxy-camptothecin; CPT, camptothecin; NB-506, 6-N-formylamino-l2,l3-dihydro 1,11-dihydroxy-I3-(j3-o-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole analysis program for a Macintosh computer interfaced with a Bio-Tek Micro 5,7(6H)-dione; CDDP, cis-diamminedichloroplatimum(ll); SN-38, 7-ethyl-lO-hydroxy plate Reader(EL-340; BioMetallics, Princeton,NJ). Wells containingonly camptothecin; IC50, drug concentration that inhibited cell growth by 50%; MT1', 3-(4,5- RPMI 1640-fetal bovine serum and MU were used as controls. Each exper dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; ICL, interstrand cross-link; Cl, imentwasperformedusingsix replicatewellsfor eachdrugconcentrationand cross-link index; NB, nuclear buffer, comprising 2 inst KH2PO4@5msi MgCl2, 150 inst NaCI, I mM ethyleneglycol bis(@3-aminoethylether)-N,N,N',N'-tetraacetic acid, and 1 inst carried out independently three times. The IC@ was defined as the concentra dithiothreitol (adjusted to pH 6.5). tion that reduced the absorbance in each test by 50%. The absorbance was 789 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1996 American Association for Cancer Research. SYNERGISM OF CDDP AND TOPOI5OMERA5E I INHIBITORS NB-506 AND SN-38 calculatedas(meanabsorbanceofsix wells containingdrug —absorbanceof v/v glycerol, and 50 M Iris-HCI (pH 7.4), 0.7 @.tgpBR322,and crude nuclear six control wells)/(mean absorbance of six drug-free wells —absorbance of six extract. The reactionmixtures used for measuringthe inhibition of DNA control wells) X 100. relaxationby topoisomeraseIinhibitors comprisedthe specifiedamountof Analysisof CombinationEffects.On thebasisofthegrowthinhibition nuclearextract(1.0p@g/mlprotein)anddrugsolution,or theequivalentvolume curve for each single drug, we analyzed the effects of drug combinations using of water,in addition to the abovecomponents.Thereactionmixtureswere the isobologrammethodof Steeland Peckham(14).Three isoeffectcurves incubated at 37°Cfor 10 mm, and the reactions were terminated by adding 45 (modesI, hA, andIIB) weredrawnasdescribedpreviously(15),andthetotal @ldyesolutioncomprising2.5%w/v SDS,0.01%w/v bromphenolblue,and area enclosed by these three lines represents an “envelopeofadditivity.― 50% v/v glycerol. The mixtures were applied to 0.7% w/v agarose gel and Actual IC50values,which were the concentrationsof the two drugs to electrophoresedfor4 h with a runningbuffer of Iris-acetateEDTA. The gel produce50%growth inhibition, wereobtainedfrom growthinhibition curves was stainedwith 2 @LMethidiumbromideand photographedundertransillu afterexposureof variousconcentrationsofthedrugs.Whentheexperimental minationwith 300 nm UV light. IC50concentrationofadrugcombinationplottedliesin theareaontheleft side of the envelope,thetwo-drugcombinationis
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