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Abstmcts/Lung Cancer 13 (1995) 81-104 detected 7 mutatvx~s in 17 mcsolhchomas (41%) nnlnn Ihc ccdmg regton of NE but none III 75 lung cancer cell lmcs (3X small ccl1 lung cancers. 34 non-small cell lung cancers. and 3 carcmmds) Thcsc mulalmns were found to bc somatic when normal lrssw uas aadablc for testing Four mcsothclioma ccl1 hncs had rclan\cl) large delcwns (-10-50 khbascs) mtbcNF2 gcnedncnabk~ Soulhcrn blot anal>srs Two mcsothehoma cell hncs had nonsense mulanons a, codons 57 and 341, respectively Anolhcr mcsolhclionla obaamcdasa spccmle~r dlrcctl! from a palrent. had a IO-base pmr mrcrodclcuon from nuclcoc~dc llWI4 10 nucleonde 1013 causing a framcshrn mutatron Thcsc rcsuI,s suggcs, that the NFZ gene parlrcrpalcs rn the oncogcncrw III a subscl of mcsothchomas bu, no, III lung cancers Transforming growth factor il, as Ypmgnosfic faclur in pulmunrr’! ndenocrrvinoma Takanam~ I. lmamura T. HashrrumcT. K,kucb K. Yamanwlo Y. Kodarra S Rrs, Depa,0nenr o/Suge~. Te,@o ~~n,vcrs,!v oj,\fed,c,nr. II-l Kogo 2.Chome, Ilaha.sh+ku. 7b@o 173 J Chn Palhol 1994.47 109R- I IO0 Arm -Tocvalualc lkcflicacyofvansformll~ggmuth fanorD (TCF- 0) for the prognosis of pulmonary adenocaranoma .tLlhadv - TCF-0 was detcctcd immunohis~ochcnncally uung the awdm-bwun-pcrovdasc complex tcchmque m rcscctcd pulmonary adcnocarcmomas irom 88 pa,& Resulrs-- Of the 88 pat&. 39 were TGF-O negau\e and 45 TGF-0 msitrve The 8ve war survwl ra,c was 56% for ,hc TGF-O negalivf and 16% for the ‘fGF-0 pornwe group Conclusions - TGF-O can bc used as a progncmic factor m pulmonar) adcnoclrcmorna New short-chain analogs of l substance-P antagonist inhibit proliferation of human small-cell lung-cancer ceils in vitro and in viva Omu A. Schren 1. Nagy 1. Bathe L. Schon 1. Nyekr PG. Bmchenml Department, Nat Kormyt Ins, TBC/Pubw~nologv POE 1. H-1529 Budapest. In, 1 Cancer 1995:6@82-7 Human smallccll lung-cancer cells (SCLC) produce and sccrelc gasbin-rcJeasingpide (GRP). the mammalian equivalent of bomb&n (BN). There is some cvidaa to suggest that GRP is an autocrine regulator of SCLC all gmwh. In the search for potent BN antagonisls. several substance-P (SP) analogs were found ,o inhabit the growth of SCLC cells. WC found that a known showchain SP antagonia, pHOPA- DTrp-Phe-DTrp-La-La-~ (NY3238). inhibits Ihe binding of “‘I- Tyr’-BN on Swiss 3T3 ccl1 line expressing BN recep(ors. as well as the pmlifcralion of NCI-H69 SCLC alls In lhrs study we lested several analogs of NY3238 and we found that NY3521 and NY3460 arc more effectwe m ,nlnb,tmn ofproliferatwn of SCLC cells but less potent in inhrbilmn of binding of “‘I-Ty+BN on Swiss 3T3 cells than NY3238. Furlhennorc, we de(glcd spccdic bindmg of mdiolabcllcd NY3238 cvcn below I nM on NC&H69 cells that could have been inhibiled by SP and NY346OralhcrlhanbyBN. Inadditiontothereinv,vonudics.NY3460 proved 10 be effective in inhibiting the growth of NCI-H69 SCLC xenografb in nude mice in viva These analogs of NY3238 could be promising (herapeulic &gents m Ihe treatment of SCLC Clonal dominance behveen subpopulations of mixed small cell lung cancer xenoprafts implanted ectopicllly in nu& mice Aaba K. Vindclw LL, Spang=Thornscn M. Univ. Ins,. ofP&ologrcal An,,,o,,ry, “~ivc,s,,y of Copenhagen. Fmdmk Vb !&J II. DK-2100 Copenhagen. Eur J Cancer Part A Gcn Top 1995;3 L:222-9. Clonalcvolution dncoplasticausduringsolidtumourgrauth leads to the cmcrgcncc of new ,umour cell subpop&dions with diverging phenc+ypiccharaEtrrinicrwhich mayaltuthckbatiourofamaligMnt discasc Cellular mtcmction was studied in mixed xenogr& in nude mice and during in vitro gmwh of twu sets of small cell lung cancer (SCLC) subuouulatmns f54A. 54B and NYH. NYHZ). The tumour ccl1 lines d&r& in cell&DNA content enabling flow cylomelric DNA analysis (FCM) to be used 10 monilor changes in the fraclional compm~tlon of the mixed all populations. The progeny clone 54B was found 10 dominate the parent 54A clone when grown as mixed subctrmeous xemgrafts in nude mia, whereas no dominance was exerted during in vitro growth. The in viva dominance add not be explained by diffcrcnccs in growth kinetics between the two tumour cell bnes, and the interaction was not dependent on 548 being in excess in mixed turnours. The dominance was dependent on close ,n wvo contact as no remofe e&cl on the growth of 54A was found when ,hc dominating 54B cells wrc graving in the opposite flank of tunwur- bearing mice. Irradiation inactivated 548 alls were unable lo exert the dominating effect. indicating that the interaction required viable and pmlifcraling cells. Clone1 dombumcc was not found in mixed NYH- NYHZ tutnours indicating that Ihe dominance mechanism(s) may not always te operational between subpptdatiotu in hdcrogencous hunours Recognition of interaction between lumour cell populatwns may result in a belter understanding of the bcbwiow of hc,cmgcnwus human malignancies. lmmunohistochemical locdiation of cytochrume P450 3A in human pulmonary carcinomas and normal bronchial tissue Kivisto KT, Frilz P, Linder A. Frxdel G. Bcaunc P, Krocmer HK Porhologrsches InsNfuI. Robe,,-Bosh-Kr~“kenhrrus. Auerbochslrosse 110, D-70376Slu,tgar, Hismchem Cell Biol 1995;103:25-9. The cytochrome P450 (CW) enzymes metabolize drugs and olher xenobiotics in liver and alsc in some earahepatic tissues. We have studzd the expression and localization of CYF’3A in primary lung lum~tus and normal lung tissue from the same patients. Thiny-two patients undcgoing pardal or total lung rescctwn for therapy of primary pulmonary carcinoma were inch&cd in lhis study Immunohismchcnucal staining for CYP3A was pcrfonncd wilh a modification of the ABC lahniquc. Eightofthe 32 cascsofprbnarypulmonarycarcinomashmved expression of CYPSA. In 12 of the 32 cases of normal tissue. ,he seronwwus glands were posn,vc for CYP3A. The bronchial epilhebum was positive for CYP3A in I I cases. We obscwcd no conelation beween CYP3A expression in tutnwr tissue and that in serotnucow glands or bmnchialepithclium Wemncludc1hatCYP3Aisprcscnt inbothnornml and cancerous lung tissue. Our findings suggest, however. no co- expression of CYP3A in lung cancer. Investigation of grow kinetics in non-small lung cancer in relation to bcl-2 oncopn expnssion Vermes I, Van Den Bcmh FAJTM. Van Dcr Sluijs Uxr G. Gmsc WFA. Ollhuis FMFG. Haane;C. Klinmch Chmiscb ioboromrium. Mrdisch Swctrum Twente. Poslbus 50000, 7500 KA Enschcde Ned Tiidrhr Klin Chem 1995:20:38-43. Expression of ,he bcl-2 oncogcne has been described to bc a prog- nostic marker in non-small cell lung cancer (NSCLC) demonstrated by a longer 5-years survival rate B&&c bcl-2 expression was found 10 prevent apopwsis in follicular lymphomas and hematopoielx cell lines, we wondered if lhe c~prcssion of bcl-2 rn NSCLC would Imply a distincl ncoplan~c mechanism. m which nunor growh II the result ofdiminished cell loss and no, the consequence of mcrcased cell prcduaion. To invertigate ,o what ewn, the mpnxsmn ofbcl-2 m NSCLC really affects the growth lanetics oflhesc tumor cells. we inlend 10 measure in tumor spximens ofNSCLC p&rents the cxlcnl ofbcl-2 expressron m relatmn topmlifcratmn andapcptarcirrdices These indrccs. related lothecx~en, ofbcl-2 expression. wdl possrbly prowde the answer to the hypothcrw that b&2 eprcssmn in NSCLC rmphes a drstinct tumor biology ofbcl- 2 protein positive lung cancers compared IobcI-2 protern negatweones Changes in expression of neural cell adhesion molecule and desmoplakin associated with phcnotypic transitions in cloned cell lines from a non-small cell lung carcinamn Wright-Perkins S. Daniel MR. Walker C. Clorlerbrtdge Comer Research Trusr. J.K Douglas Cancer Researrh Lob., Clarterbndge H~~prlo/, Bebington. W& L63 41,‘. In, 1 Oncol 1995;6: 617-23. - I Ff and I F’f vanant A clonal cell lines. both derived from the same neuroendocrrne posrtwe. undillcremiated large cell lung carcinoma. shaved ddferences m Iheir morphology, DNA conlent, presence of desmosnmes and expression of NCAM and desmoplakm Colonies ofcells which morphologically resembled I F’f variant A cells arosc In cultures oftk 1 Ff clocal line followirw prolonacd cullwation. Such transilmns in cloned cells of NSCLC ori& havenot previously been reported Tlw lransnmn was arsocmtcd wrth incrcascd expression of dcsmoplakm and downregulauon of NCAM A converse transition of I PT vanant A cells 10 I PT-like cells wld not bc demonstrated

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Page 1: New short-chain analogs of a substance-P antagonist inhibit proliferation of human small-cell lung-cancer cells in vitro and in vivo

Abstmcts/Lung Cancer 13 (1995) 81-104

detected 7 mutatvx~s in 17 mcsolhchomas (41%) nnlnn Ihc ccdmg regton of NE but none III 75 lung cancer cell lmcs (3X small ccl1 lung cancers. 34 non-small cell lung cancers. and 3 carcmmds) Thcsc mulalmns were found to bc somatic when normal lrssw uas aadablc for testing Four mcsothclioma ccl1 hncs had rclan\cl) large delcwns (-10-50 khbascs) mtbcNF2 gcnedncnabk~ Soulhcrn blot anal>srs Two mcsothehoma cell hncs had nonsense mulanons a, codons 57 and 341, respectively Anolhcr mcsolhclionla obaamcdasa spccmle~r dlrcctl! from a palrent. had a IO-base pmr mrcrodclcuon from nuclcoc~dc llWI4 10 nucleonde 1013 causing a framcshrn mutatron Thcsc rcsuI,s suggcs, that the NFZ gene parlrcrpalcs rn the oncogcncrw III a subscl of mcsothchomas bu, no, III lung cancers

Transforming growth factor il, as Y pmgnosfic faclur in pulmunrr’! ndenocrrvinoma Takanam~ I. lmamura T . HashrrumcT. K,kucb K. Yamanwlo Y. Kodarra S Rrs, Depa,0nenr o/Suge~. Te,@o ~~n,vcrs,!v oj,\fed,c,nr. II-l Kogo 2.Chome, Ilaha.sh+ku. 7b@o 173 J Chn Palhol 1994.47 109R- I IO0

Arm -Tocvalualc lkcflicacyofvansformll~ggmuth fanorD (TCF- 0) for the prognosis of pulmonary adenocaranoma .tLlhadv - TCF-0 was detcctcd immunohis~ochcnncally uung the awdm-bwun-pcrovdasc complex tcchmque m rcscctcd pulmonary adcnocarcmomas irom 88 pa,& Resulrs-- Of the 88 pat&. 39 were TGF-O negau\e and 45 TGF-0 msitrve The 8ve war survwl ra,c was 56% for ,hc TGF-O negalivf and 16% for the ‘fGF-0 pornwe group Conclusions - TGF-O can bc used as a progncmic factor m pulmonar) adcnoclrcmorna

New short-chain analogs of l substance-P antagonist inhibit proliferation of human small-cell lung-cancer ceils in vitro and in viva Omu A. Schren 1. Nagy 1. Bathe L. Schon 1. Nyekr PG. Bmchenml Department, Nat Kormyt Ins, TBC/Pubw~nologv POE 1. H-1529 Budapest. In, 1 Cancer 1995:6@82-7

Human smallccll lung-cancer cells (SCLC) produce and sccrelc gasbin-rcJeasingpide (GRP). the mammalian equivalent of bomb&n (BN). There is some cvidaa to suggest that GRP is an autocrine regulator of SCLC all gmwh. In the search for potent BN antagonisls. several substance-P (SP) analogs were found ,o inhabit the growth of SCLC cells. WC found that a known showchain SP antagonia, pHOPA- DTrp-Phe-DTrp-La-La-~ (NY3238). inhibits Ihe binding of “‘I- Tyr’-BN on Swiss 3T3 ccl1 line expressing BN recep(ors. as well as the pmlifcralion of NCI-H69 SCLC alls In lhrs study we lested several analogs of NY3238 and we found that NY3521 and NY3460 arc more effectwe m ,nlnb,tmn ofproliferatwn of SCLC cells but less potent in inhrbilmn of binding of “‘I-Ty+BN on Swiss 3T3 cells than NY3238. Furlhennorc, we de(glcd spccdic bindmg of mdiolabcllcd NY3238 cvcn below I nM on NC&H69 cells that could have been inhibiled by SP and NY346OralhcrlhanbyBN. Inadditiontothereinv,vonudics.NY3460 proved 10 be effective in inhibiting the growth of NCI-H69 SCLC xenografb in nude mice in viva These analogs of NY3238 could be promising (herapeulic &gents m Ihe treatment of SCLC

Clonal dominance behveen subpopulations of mixed small cell lung cancer xenoprafts implanted ectopicllly in nu& mice Aaba K. Vindclw LL, Spang=Thornscn M. Univ. Ins,. ofP&ologrcal An,,,o,,ry, “~ivc,s,,y of Copenhagen. Fmdmk Vb !&J I I . DK-2100 Copenhagen. Eur J Cancer Part A Gcn Top 1995;3 L:222-9.

Clonalcvolution dncoplasticausduringsolidtumourgrauth leads to the cmcrgcncc of new ,umour cell subpop&dions with diverging phenc+ypiccharaEtrrinicrwhich mayaltuthckbatiourofamaligMnt discasc Cellular mtcmction was studied in mixed xenogr& in nude mice and during in vitro gmwh of twu sets of small cell lung cancer (SCLC) subuouulatmns f54A. 54B and NYH. NYHZ). The tumour ccl1 lines d&r& in cell&DNA content enabling flow cylomelric DNA analysis (FCM) to be used 10 monilor changes in the fraclional compm~tlon of the mixed all populations. The progeny clone 54B was found 10 dominate the parent 54A clone when grown as mixed subctrmeous xemgrafts in nude mia, whereas no dominance was exerted during in vitro growth. The in viva dominance add not be explained by diffcrcnccs in growth kinetics between the two tumour cell bnes, and the interaction was not dependent on 548 being in excess

in mixed turnours. The dominance was dependent on close ,n wvo contact as no remofe e&cl on the growth of 54A was found when ,hc dominating 54B cells wrc graving in the opposite flank of tunwur- bearing mice. Irradiation inactivated 548 alls were unable lo exert the dominating effect. indicating that the interaction required viable and pmlifcraling cells. Clone1 dombumcc was not found in mixed NYH- NYHZ tutnours indicating that Ihe dominance mechanism(s) may not always te operational between subpptdatiotu in hdcrogencous hunours Recognition of interaction between lumour cell populatwns may result in a belter understanding of the bcbwiow of hc,cmgcnwus human malignancies.

lmmunohistochemical locdiation of cytochrume P450 3A in human pulmonary carcinomas and normal bronchial tissue Kivisto KT, Frilz P, Linder A. Frxdel G. Bcaunc P, Krocmer HK Porhologrsches InsNfuI. Robe,,-Bosh-Kr~“kenhrrus. Auerbochslrosse 110, D-70376Slu,tgar, Hismchem Cell Biol 1995;103:25-9.

The cytochrome P450 (CW) enzymes metabolize drugs and olher xenobiotics in liver and alsc in some earahepatic tissues. We have studzd the expression and localization of CYF’3A in primary lung lum~tus and normal lung tissue from the same patients. Thiny-two patients undcgoing pardal or total lung rescctwn for therapy of primary pulmonary carcinoma were inch&cd in lhis study Immunohismchcnucal staining for CYP3A was pcrfonncd wilh a modification of the ABC lahniquc. Eightofthe 32 cascsofprbnarypulmonarycarcinomashmved expression of CYPSA. In 12 of the 32 cases of normal tissue. ,he seronwwus glands were posn,vc for CYP3A. The bronchial epilhebum was positive for CYP3A in I I cases. We obscwcd no conelation beween CYP3A expression in tutnwr tissue and that in serotnucow glands or bmnchialepithclium Wemncludc1hatCYP3Aisprcscnt inbothnornml and cancerous lung tissue. Our findings suggest, however. no co- expression of CYP3A in lung cancer.

Investigation of grow kinetics in non-small lung cancer in relation to bcl-2 oncopn expnssion Vermes I, Van Den Bcmh FAJTM. Van Dcr Sluijs Uxr G. Gmsc WFA. Ollhuis FMFG. Haane;C. Klinmch Chmiscb ioboromrium. Mrdisch Swctrum Twente. Poslbus 50000, 7500 KA Enschcde Ned Tiidrhr Klin Chem 1995:20:38-43.

Expression of ,he bcl-2 oncogcne has been described to bc a prog- nostic marker in non-small cell lung cancer (NSCLC) demonstrated by a longer 5-years survival rate B&&c bcl-2 expression was found 10 prevent apopwsis in follicular lymphomas and hematopoielx cell lines, we wondered if lhe c~prcssion of bcl-2 rn NSCLC would Imply a distincl ncoplan~c mechanism. m which nunor growh II the result ofdiminished cell loss and no, the consequence of mcrcased cell prcduaion. To invertigate ,o what ewn, the mpnxsmn ofbcl-2 m NSCLC really affects the growth lanetics oflhesc tumor cells. we inlend 10 measure in tumor spximens ofNSCLC p&rents the cxlcnl ofbcl-2 expressron m relatmn topmlifcratmn andapcptarcirrdices These indrccs. related lothecx~en, ofbcl-2 expression. wdl possrbly prowde the answer to the hypothcrw that b&2 eprcssmn in NSCLC rmphes a drstinct tumor biology ofbcl- 2 protein positive lung cancers compared IobcI-2 protern negatweones

Changes in expression of neural cell adhesion molecule and

desmoplakin associated with phcnotypic transitions in cloned cell lines from a non-small cell lung carcinamn Wright-Perkins S. Daniel MR. Walker C. Clorlerbrtdge Comer Research Trusr. J.K Douglas Cancer Researrh Lob., Clarterbndge H~~prlo/, Bebington. W& L63 41,‘. In, 1 Oncol 1995;6: 617-23. -

I Ff and I F’f vanant A clonal cell lines. both derived from the same neuroendocrrne posrtwe. undillcremiated large cell lung carcinoma. shaved ddferences m Iheir morphology, DNA conlent, presence of desmosnmes and expression of NCAM and desmoplakm Colonies ofcells which morphologically resembled I F’f variant A cells arosc In cultures oftk 1 Ff clocal line followirw prolonacd cullwation. Such transilmns in cloned cells of NSCLC ori& havenot previously been reported Tlw lransnmn was arsocmtcd wrth incrcascd expression of dcsmoplakm and downregulauon of NCAM A converse transition of I PT vanant A cells 10 I PT-like cells wld not bc demonstrated