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Expression of epidermal growth factor receptors in four histologic cell types of lung cancer
46
Expression of epidermal growth factor receptors in four histologic cell types of lung cancer Kaseda S, Ueda M, Ozawa S, Ishihara T, Abe 0 ,Shirmzu N. Departmen1 of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160. J Surg Oncol 1989;42:16-20.
Lung cancer tissues from 68 patients were examined for epidermal growth factor (EGF) receptor lcvcls and EGF receptor gene copy numbers. Histologic cell types of these lung cancer tissues included squamous-cell carcinoma (n = 30). adenocarcinoma (n = 28), large-cell carcinoma (n = 4). and small-cell carcinoma (n = 6). Tissues of squamous-cell carcinoma exhibIted exceptionally high l=I-EGF binding activity, and those of small-cell carcinoma showed no EGF binding activity. Southern blot hybridization analysis revealed EGF receptor gene amplification in the squamous-cell carcmomas with high EGF binding activity. The EGF receptor lcvcls m squamous-ccl1 carcmomas and adcnocarcinomas wcrc compared with lhctr pathological staging groupingandpathological findings, mcludmgdcgrcc ofdifferentiation, diamctcr of tumor, and lymph node mct;Lslilsls. Howcvcr, unlike previous reports on breast and bladder cancers, there was no obvious correlation between thcsc pathological characteristics and the EGF rcccplor lcvcls of lung cancer.
Carcinogen metabolism studies in human bronchial and lung parenchymal tissues Peuuzzclli S, De Flora S, Bagnasco M CLal. CNR lnslirule ofC/inical Phynology, Universiry of Pisa. 56100 Piss. Am Rev Rcspir Dis 1989;140:417-22. The pulmonary melabolism of xenobiotics was investigated by measuring the glutathione content and the activity of the aryl hydrocarbon hydroxylase, epoxide hydrolasc, glutathionc S-transferase, and uridine 5’-diphosphoglucuronosyl uansferase enzymes m S-12 fractions of bronchial tree and pcrcphcral lung parenchyma obtained at surgery from 21 paticna. In parallel, the same preparation were used to assess either the activation of promulagens, i.e., bcnyo(a)pyrcnc, 2aminofluorenc, cyclophosphamidc, and a cigarcttc smoke condensate, to mclabohtes revcrtmg his Salmonella lyphymurlum strains, or the dccrcasc of direct-acting mutagens, i.e., sodium dichromatc, 4-mtroquinoline N-oxide, cptchlorohydrm. and ICR 191. As compared to bronchus preparations. parcnchymal preparations contained considcrably higher concenuations of reduced glulati~onc, had a significantly higher cpox,xldc hydrolaac aclivlty, and, as &sscsscd by means of a quantilativc mdcx, were more cfllclcm m activating ?-ammofluorcne and in reducing the mutagcmcliy of dlchromatc and 4.nitroquinoline Noxldc. These data may suggest that parcnchymal lung lissue is more capable than bronchial hssuc to dctoxlfy reaclivc inrermcdiatcs of xenobiotics, posstbly explammg the grcaLcrsusceplihlllly of bronchi to clgarcuc smoke-induced cancers.
Sterically hindered analogues ofdiacylglycerols. Synthesis, binding to the phorbol ester receptor and metabolism in A549 human lung carcinoma cells Laughton CA, Bradshaw TD, Gcscher A. Cancer Research Campaign Experimental Chemotherapy Group. Pharmaceutical Sciences Instirule, Aston University, Birmingham B4 7ET. Int J Cancer 1989;44:320-
4. The 5 following compounds were synrheslded m order IO investigate the relationship between structure and ability of glyceride-type molecules to bind to the phorbol ester receptor: oncdioctanoyl cyclohexaneI ,2,4-triol. 2 isomeric methyl analogucs of I ,2-dioclanoyl-v-glycerol (diCX), one dlmcthyl and one cyclohcxyl analoguc of diC8. Their ability lo compete with ‘H-Iabcllcd phorbo-12,13-dibutyratc (13H]PDBu) for spcclfic binding sites in intact AS49 human-derived lung carcinoma cells and in a cytosolic cell cxtracr was compared with that of diCX and l2-0-tcuadccanoylphorbol-13.acctale (TPA). The affinity of diC8 for
the phorbol ester receptor was much wcakcr than that of TPA. The analogues in turn were less able than drC8 to compete with L3H]PDBu for receptor sites. Like diC8 and unlike TPA, the synthesized compounds inhibited cell growth only at those concenuations at which cytotoxicity was also apparent. DiCX and its methyl and dimethyl derivatives, but not rhc cyclohcxyl derivative or the cyclohcxanetriol diestcr, were metabolically removed from cellular incubales as measured by gas liquid chromatography. The results suggest that the binding of glyceride-type molecules to the phorbol ester rcccptor exhibitc stringent specificity and that the design of novel potent agonists of phorbol esters might reqmre the placcmcnt of the molcculx features of diacylglycerolsimponantforbiologicalactiv~tyintoamolecularframework which is more comphcaled than glycerol.
Bombesin: A potent mitogen for small cell lung cancer Camcy DN, Moody T, Cuttltta F. Department of Medical Oncology, Maler Misericordiae I-lospiml, Dublin 7. Ann New York Acad Sci
1989;547:303-9. While advances in the diagnosis and staging of SCLC have been made over the past decade, overall thcrapcutic results remain essentially unchanged. However, during this time period thcrc have been major advances in understanding the biology of this tumor cell type. The recognition ofconsidcrable heterogcncity among SCLC cells may be of prognostic importance, while rhe demonstration of specific growth factors, including bombcsin, for this tumor type may open up new means for endocrine therapy of lung carcmoma in viva. Over the next 5-10 yr, studies of clinical trials using specific antibodies or analogs of bombesin-like growth factors in patients with SCLC will define more clearly the role of BLI and GRP in patients with this disease.
A tyrosine protein kinase a&bated lasts and small cell carcinomas
by bombesin in normal fibrob-
Gaudino G, Cilli M, Gandino L, Rossino P, Mondino A, Comoglio PM. DepartmentofBiomedicalS~:ience.~andOnrolo~y, UniversilyofTorino Medical School, 10126 Torino. Ann New York Acad Sci 1989;547:293-
302. In Swiss 3T3 fibroblasts, anubodics which recognize a phosphotyrosincrcsiduc(P-Tyrandbodics) identify a 115.kDaccll surface protein (~115) that becomes phosphorylatcd on tyrosinc as a response LO bombcsin stimulation of quiescent cells. The cxtcnt ofphosphorylation is dose-dcpendcm and corrclatcs wilh the miiogenic effect induced by bomb&n, mcaured by [‘H]thymidmc incorporation. Tyrosine phosphorylation of p115 is delcctablc minutes aficr addition of bombcsin and preccdcs the acuvation of c-fos and c-myc gent transcription. Immunocomplcxes ofphosphorylatcd ~115 with P-Tyrantibodies bind ‘zl-labclcd [TySlbombcsm m a spcciflc and aaturablc manner and display an associated tyrosinc protein kmasc activily enhanced by bombcsin. P-Tyr antibodies also rccognix a protein of I I5 kDa, phosphorylatcd a[ lyrosme, in four human SCLC lines producmg bomb&n but not m a non-producer ‘variant’ Imc. Phosphorylation of SCLC ~115 does not require the ad&bon of exogenous bombesin. As in the cast of the pIIS immunoprecipitalcd from mouse fibroblasls, the SCLC pl IS is phosphorylatcd m an immunocomplcx kinase assay. Thcsc observations arc m agrccmeni wilh the hypothesis of autocrinc activation of bombcsin reccplors m human small cell lung carcinoma CCliS.
“Tc”-labeled meso-HMPAO lung tumours RowelI
NT’,
and glutathione content of human
McCrcady VR, Cronin B eta]. Academic
ofRadiotherapy,
1989:10:503-8.
Royal Marsden Ilospital.
C/nit. Department Surton. Nucl Med Commun
Expression of epidermal growth factor receptors in four histologic cell types of lung cancer Kaseda S, Ueda M, Ozawa S, Ishihara T, Abe 0 ,Shirmzu N. Departmen1 of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160. J Surg Oncol 1989;42:16-20.
Lung cancer tissues from 68 patients were examined for epidermal growth factor (EGF) receptor lcvcls and EGF receptor gene copy numbers. Histologic cell types of these lung cancer tissues included squamous-cell carcinoma (n = 30). adenocarcinoma (n = 28), large-cell carcinoma (n = 4). and small-cell carcinoma (n = 6). Tissues of squamous-cell carcinoma exhibIted exceptionally high l=I-EGF binding activity, and those of small-cell carcinoma showed no EGF binding activity. Southern blot hybridization analysis revealed EGF receptor gene amplification in the squamous-cell carcmomas with high EGF binding activity. The EGF receptor lcvcls m squamous-ccl1 carcmomas and adcnocarcinomas wcrc compared with lhctr pathological staging groupingandpathological findings, mcludmgdcgrcc ofdifferentiation, diamctcr of tumor, and lymph node mct;Lslilsls. Howcvcr, unlike previous reports on breast and bladder cancers, there was no obvious correlation between thcsc pathological characteristics and the EGF rcccplor lcvcls of lung cancer.
Carcinogen metabolism studies in human bronchial and lung parenchymal tissues Peuuzzclli S, De Flora S, Bagnasco M CLal. CNR lnslirule ofC/inical Phynology, Universiry of Pisa. 56100 Piss. Am Rev Rcspir Dis 1989;140:417-22. The pulmonary melabolism of xenobiotics was investigated by measuring the glutathione content and the activity of the aryl hydrocarbon hydroxylase, epoxide hydrolasc, glutathionc S-transferase, and uridine 5’-diphosphoglucuronosyl uansferase enzymes m S-12 fractions of bronchial tree and pcrcphcral lung parenchyma obtained at surgery from 21 paticna. In parallel, the same preparation were used to assess either the activation of promulagens, i.e., bcnyo(a)pyrcnc, 2aminofluorenc, cyclophosphamidc, and a cigarcttc smoke condensate, to mclabohtes revcrtmg his Salmonella lyphymurlum strains, or the dccrcasc of direct-acting mutagens, i.e., sodium dichromatc, 4-mtroquinoline N-oxide, cptchlorohydrm. and ICR 191. As compared to bronchus preparations. parcnchymal preparations contained considcrably higher concenuations of reduced glulati~onc, had a significantly higher cpox,xldc hydrolaac aclivlty, and, as &sscsscd by means of a quantilativc mdcx, were more cfllclcm m activating ?-ammofluorcne and in reducing the mutagcmcliy of dlchromatc and 4.nitroquinoline Noxldc. These data may suggest that parcnchymal lung lissue is more capable than bronchial hssuc to dctoxlfy reaclivc inrermcdiatcs of xenobiotics, posstbly explammg the grcaLcrsusceplihlllly of bronchi to clgarcuc smoke-induced cancers.
Sterically hindered analogues ofdiacylglycerols. Synthesis, binding to the phorbol ester receptor and metabolism in A549 human lung carcinoma cells Laughton CA, Bradshaw TD, Gcscher A. Cancer Research Campaign Experimental Chemotherapy Group. Pharmaceutical Sciences Instirule, Aston University, Birmingham B4 7ET. Int J Cancer 1989;44:320-
4. The 5 following compounds were synrheslded m order IO investigate the relationship between structure and ability of glyceride-type molecules to bind to the phorbol ester receptor: oncdioctanoyl cyclohexaneI ,2,4-triol. 2 isomeric methyl analogucs of I ,2-dioclanoyl-v-glycerol (diCX), one dlmcthyl and one cyclohcxyl analoguc of diC8. Their ability lo compete with ‘H-Iabcllcd phorbo-12,13-dibutyratc (13H]PDBu) for spcclfic binding sites in intact AS49 human-derived lung carcinoma cells and in a cytosolic cell cxtracr was compared with that of diCX and l2-0-tcuadccanoylphorbol-13.acctale (TPA). The affinity of diC8 for
the phorbol ester receptor was much wcakcr than that of TPA. The analogues in turn were less able than drC8 to compete with L3H]PDBu for receptor sites. Like diC8 and unlike TPA, the synthesized compounds inhibited cell growth only at those concenuations at which cytotoxicity was also apparent. DiCX and its methyl and dimethyl derivatives, but not rhc cyclohcxyl derivative or the cyclohcxanetriol diestcr, were metabolically removed from cellular incubales as measured by gas liquid chromatography. The results suggest that the binding of glyceride-type molecules to the phorbol ester rcccptor exhibitc stringent specificity and that the design of novel potent agonists of phorbol esters might reqmre the placcmcnt of the molcculx features of diacylglycerolsimponantforbiologicalactiv~tyintoamolecularframework which is more comphcaled than glycerol.
Bombesin: A potent mitogen for small cell lung cancer Camcy DN, Moody T, Cuttltta F. Department of Medical Oncology, Maler Misericordiae I-lospiml, Dublin 7. Ann New York Acad Sci
1989;547:303-9. While advances in the diagnosis and staging of SCLC have been made over the past decade, overall thcrapcutic results remain essentially unchanged. However, during this time period thcrc have been major advances in understanding the biology of this tumor cell type. The recognition ofconsidcrable heterogcncity among SCLC cells may be of prognostic importance, while rhe demonstration of specific growth factors, including bombcsin, for this tumor type may open up new means for endocrine therapy of lung carcmoma in viva. Over the next 5-10 yr, studies of clinical trials using specific antibodies or analogs of bombesin-like growth factors in patients with SCLC will define more clearly the role of BLI and GRP in patients with this disease.
A tyrosine protein kinase a&bated lasts and small cell carcinomas
by bombesin in normal fibrob-
Gaudino G, Cilli M, Gandino L, Rossino P, Mondino A, Comoglio PM. DepartmentofBiomedicalS~:ience.~andOnrolo~y, UniversilyofTorino Medical School, 10126 Torino. Ann New York Acad Sci 1989;547:293-
302. In Swiss 3T3 fibroblasts, anubodics which recognize a phosphotyrosincrcsiduc(P-Tyrandbodics) identify a 115.kDaccll surface protein (~115) that becomes phosphorylatcd on tyrosinc as a response LO bombcsin stimulation of quiescent cells. The cxtcnt ofphosphorylation is dose-dcpendcm and corrclatcs wilh the miiogenic effect induced by bomb&n, mcaured by [‘H]thymidmc incorporation. Tyrosine phosphorylation of p115 is delcctablc minutes aficr addition of bombcsin and preccdcs the acuvation of c-fos and c-myc gent transcription. Immunocomplcxes ofphosphorylatcd ~115 with P-Tyrantibodies bind ‘zl-labclcd [TySlbombcsm m a spcciflc and aaturablc manner and display an associated tyrosinc protein kmasc activily enhanced by bombcsin. P-Tyr antibodies also rccognix a protein of I I5 kDa, phosphorylatcd a[ lyrosme, in four human SCLC lines producmg bomb&n but not m a non-producer ‘variant’ Imc. Phosphorylation of SCLC ~115 does not require the ad&bon of exogenous bombesin. As in the cast of the pIIS immunoprecipitalcd from mouse fibroblasls, the SCLC pl IS is phosphorylatcd m an immunocomplcx kinase assay. Thcsc observations arc m agrccmeni wilh the hypothesis of autocrinc activation of bombcsin reccplors m human small cell lung carcinoma CCliS.
“Tc”-labeled meso-HMPAO lung tumours RowelI
NT’,
and glutathione content of human
McCrcady VR, Cronin B eta]. Academic
ofRadiotherapy,
1989:10:503-8.
Royal Marsden Ilospital.
C/nit. Department Surton. Nucl Med Commun