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Dietary β-carotene, cigarette smoking, and lung cancer in men
Abstracts /Lung
141
Cancer IO (1993) 123-150
Prevention Dietary Resmtene, cigarette smoking. and lung cancer in men Shibate A. Pagaoioi-Hill A. Ross R.K. YU MC. Hmderson B.E. ofSouthern California. Departmetu of Preventive Medicine, Uniwsity School of Medicine, 1721 Grt#in Avenue, Los Angeles, CA 90031. Cancer Causes Control 1992;3:207-14. A cohort of 5,080 mea living in s retiremeat community in California (United States) sod initially free. From lung cancer were followed FromJune 1981 toDewmbe.r 1989. At recruitment. each study participPntco~letedamPiledquestionnaire~ch~Rquestedformstion on thesuhject’smedicslhistory, useofcigwettes, andusoalconsumption Frequencies during the preceding 12 months of 44 vegetable and Fruit items. Men who had never smoked hsd the highest mao daily intake of &carotene (8,505 g). followed by ppst smokers (7,761 g) and then by current smokers (6,178 g). &Carotene intake of the subject’s wife ws.s correlated significantly with that of the husbaad in the 4,018 spouse pairs (r = 0.46; P = 0.0001). Among mea with similar smoking habits, dietary B-carotene intake significantly decreased with the spouse’s smoking habit: aever, past, sod current smokers (P = 0.004; test for linear trend). During 31,477 person-years of follow-up, 12.5 incident cases of lung cancer were observed among tbe cohort of 5,080 me”. Age-adjusted relative risks for long caocer were below o&y (i.e., demonstrating s reduced risk) for higher relative to lower consumption of R-carotene, of all vegetables sod fruits, and of yellow vegetables alone. However, these relative risks approached or cmssed the null value when adjusted for personal smoking. The natural history of lung rawer estimated from the results of a randcmized trial of screening Walter SD, K&ii A, Parkin DM, Reissigovn I, Adamec M, Khlat M. L4RC. 150 Cows Alben-l71omnr. F-69372 Lyon Cedez. Cancer Causes Control 1992;3:115-23. The results from a randomized controlled trial of screening forlongcaaccrinCzechoslovskinhavebeenasedtoestimateparameters of the natural history, using a model to simulate the disease prows sod the effects of screening. The results suggest that the period before cliical prweutatioo during which lesions CM be detected by screening is very short (seven to eight months). This implies thst to detect threequarters of all long cancers by scrwning, hvo examinations per year are necessary, snd that such P program would advance diagnosis by six months iftherewerecompleteparticipstion. Therestdtsofthe trial itself suggest that the benefit, in terms of a reduction in mortality from lung cancer, is likely to be very small.
Chemotherapy Intensive etoposide and carboplatin chemotherapy for advanced non-small- cell lung cancer: A phase II trial of the Cancer and Leukemia Gmup B Lyss AI’, Perry MC, Goutsou M, Propert K, Hemdoo JE II, MssonCoughlin K. Green MR. Depanment of Medicine, Jewish Hospital. Washington
University
Louis, MO 63110.
Medical
Center.
216 S. Kingshighway,
St.
Am J Clin Oacol Cancer Clin Trials 1992;15:399-
404. From April 2 to July 9, 1989, Caocer aod Leukemia Group B (CALGB) conducted s Phase II study of etoposide and carboplatin in advanced (AJC Stage IIIb-IV) non-small-cell lung csncer (NSCLC) patients whose performance statas (PS) wss O-2. The combination was givenat themaximum tolerateddosessdefinedinapriorCALGBstody. Of 76 eligible patients with follow-up data, complete responses were achieved in three patients (4%) and partial responses, in five patients (7%). One patient (1%) with evdoable disease showed improvement. There wss only one partial response in the PS 2 patients. Perfomwu status was a predictive factor for response or improvement (p = 0.0368). Ahighincidence(74W)ofsevereorlife-threatinghemstologic toxicity and fatal sepsis in four patients was B reflection of the intensity of the chemotherapeutic regime. The median survival From study entry was 7.4 months. Thirty-seven percent of the patients survived beyond
1 year; the mediao survival for the PS 0-l patients wss 11.7 months for thePS2patieots,4.1 months. Mediaa timetotreptmeatfailurewas 3.9 months, but treatment had not failed in 9 96of the patients after 1 year, all of whom were PS O-l at time of study entry. Although the respoose rate with this dose- intensive chemotherapy regimen w~lsdissppointiog, the median survival of PS O-l ptients wss equivalent to that of Stage III NSCLC patients in prior CALGB stodies. In patients with NSCLC who are treated with chemotherapy. PS may be as importaot a prognostic factor ss stage, when median survival is used ss so endpoint. Elevated DTdiaphorw activity and messenger RNA content in hunan non- snail cell lung tnmimmx Relationship to the response of lung tumor xenografts to mitomycin C Meikinmn AM, Siegel D, Forrest GL, Gwdar AP, Oie HK, Cbao DC et al. MTBHSP, School ofPharmacy, University ofColorado. Boulder, CO 80309. Csnwr Res 1992;52:4752-7. TbeenzymeDTdiaphor(DTD; NAD(P)H:quinoneoxido-redoctsse, EC 1.6.99.2), is sn obligate hvo electma redo&se which catalyze reduction of P broad range of substrates, includiag qttinones. We report here variations in DTD concentrations nmong different classes of lung hlmors known also to vary in their responsiveaess to cytotoxic agents. Small cell long cxcinomas (SCLCs) pod cell lines derived from them hwethelowDTDactivitiessndmRNAwntentcharacteristicofnorma1 homao lung, wherw non-small cell lung carcinomw (NSCLCs) have greatly elevated levels. DTD activity was incressed up to SO-fold m NSCLC tumors relative to norms1 long and 20-35-fold i NSCLC relative to SCLC cell lines. Incnzased DTD activity sppwred to be a function of the NSCLC phenotype rsther than P result of derivation from s cell type rich in DTD, siace all histological classes of NSCLC showed tbis phenotype. Ia addition, where traasfection of SCLC cell lines with the v-Ha-ras protooncogene caused a transition to IINSCLC phenotype, DTD activity was also elevated. Neuroendocrine-positive cells (SCLC. carcinoids, sod s few NSCLC lines) typically had far lower DTD activities than did cell limes which lacked neoroendoctie markers (most NSCLC cells and mesotheliomas). High DTD activity msy be exploited in the design of drugs which undergo bioreductive activation by this enzyme. Consistent with this, xenogrsfts derived from NSCLC cell lines with high DTD thst were grown in athymic nude mice were more susceptible to thenntitomor qoinone, mitomycin C, thanwerexenogmfts derived fmm SCLC cells cootpining low DTD. These data provide s mechanistic basis for the rational design of more effective bioreductive antitumor agents for use against NSCLC. Cytogenetic alterations associated with P-glycoprotein- and non-Pglycopmtein-mediated multidrug resistance in SW-1573 human lung tlrmor cell lines NieuwiatA.W.M. BsssF. WiegsntJ. JoeajeH. CytogenericsLaborarory, Free University Hospital, P. 0. Box 7057, NL-1007 MB Amsterdam. Cancer Res 1992;52:4361-71. Multidrug resistance can be induced ia msmmsliao cells by selection with a single cytotoxic agent. Overpmductioa of the energy-dependent drug eftlux pump P-glycoproteio, encoded by the mdrl gene, hss been identified as the cause of one form of multidrug resistance. Tbe molecular b&s of other forms of multidrug resistawe is unknown. Doxorubicio selection ofthe humsn squamous lung cnocer cell line SW1573 resulted io multidrug-resistsot sublines in which a non-Pglycoprotein-mediated Form of multidrug resistance precedes mdrl expression. Here we present a cytogenetic analysis of both non- Pglycopmtein-mediimultidrog-resis&otadP-glycoprotein-medi&d multidrug-resistsntsubliaesderivedFromSW-1573. Threeindependently derived non-P-glycoproteia-mediated multidrug-resistant sublines showed s heterozygoos deletion of the short arm of chromosome 2 @23pter), whereas alterations of chromosome 7 were present in the Pglycopmtein-mediated multidrug-resistsat cell lines. In one series of cl~nallyderivedP- glycoprotein-mediatedmultidlug-resIstant soblines, mdrl overexpression was accompanied by various markers of chromosome 7 with breakpoiats at 7q22, the mdrl gene being known to belocptedat7q21.1. ChIrdatasuggestthatinSW- 1573cellsacqu~sit1on of non-P-glycopmtein-mediated multidrug resistaxe is accompsmed by s specific deletion or s trsoslocation involving the short arm of
141
Cancer IO (1993) 123-150
Prevention Dietary Resmtene, cigarette smoking. and lung cancer in men Shibate A. Pagaoioi-Hill A. Ross R.K. YU MC. Hmderson B.E. ofSouthern California. Departmetu of Preventive Medicine, Uniwsity School of Medicine, 1721 Grt#in Avenue, Los Angeles, CA 90031. Cancer Causes Control 1992;3:207-14. A cohort of 5,080 mea living in s retiremeat community in California (United States) sod initially free. From lung cancer were followed FromJune 1981 toDewmbe.r 1989. At recruitment. each study participPntco~letedamPiledquestionnaire~ch~Rquestedformstion on thesuhject’smedicslhistory, useofcigwettes, andusoalconsumption Frequencies during the preceding 12 months of 44 vegetable and Fruit items. Men who had never smoked hsd the highest mao daily intake of &carotene (8,505 g). followed by ppst smokers (7,761 g) and then by current smokers (6,178 g). &Carotene intake of the subject’s wife ws.s correlated significantly with that of the husbaad in the 4,018 spouse pairs (r = 0.46; P = 0.0001). Among mea with similar smoking habits, dietary B-carotene intake significantly decreased with the spouse’s smoking habit: aever, past, sod current smokers (P = 0.004; test for linear trend). During 31,477 person-years of follow-up, 12.5 incident cases of lung cancer were observed among tbe cohort of 5,080 me”. Age-adjusted relative risks for long caocer were below o&y (i.e., demonstrating s reduced risk) for higher relative to lower consumption of R-carotene, of all vegetables sod fruits, and of yellow vegetables alone. However, these relative risks approached or cmssed the null value when adjusted for personal smoking. The natural history of lung rawer estimated from the results of a randcmized trial of screening Walter SD, K&ii A, Parkin DM, Reissigovn I, Adamec M, Khlat M. L4RC. 150 Cows Alben-l71omnr. F-69372 Lyon Cedez. Cancer Causes Control 1992;3:115-23. The results from a randomized controlled trial of screening forlongcaaccrinCzechoslovskinhavebeenasedtoestimateparameters of the natural history, using a model to simulate the disease prows sod the effects of screening. The results suggest that the period before cliical prweutatioo during which lesions CM be detected by screening is very short (seven to eight months). This implies thst to detect threequarters of all long cancers by scrwning, hvo examinations per year are necessary, snd that such P program would advance diagnosis by six months iftherewerecompleteparticipstion. Therestdtsofthe trial itself suggest that the benefit, in terms of a reduction in mortality from lung cancer, is likely to be very small.
Chemotherapy Intensive etoposide and carboplatin chemotherapy for advanced non-small- cell lung cancer: A phase II trial of the Cancer and Leukemia Gmup B Lyss AI’, Perry MC, Goutsou M, Propert K, Hemdoo JE II, MssonCoughlin K. Green MR. Depanment of Medicine, Jewish Hospital. Washington
University
Louis, MO 63110.
Medical
Center.
216 S. Kingshighway,
St.
Am J Clin Oacol Cancer Clin Trials 1992;15:399-
404. From April 2 to July 9, 1989, Caocer aod Leukemia Group B (CALGB) conducted s Phase II study of etoposide and carboplatin in advanced (AJC Stage IIIb-IV) non-small-cell lung csncer (NSCLC) patients whose performance statas (PS) wss O-2. The combination was givenat themaximum tolerateddosessdefinedinapriorCALGBstody. Of 76 eligible patients with follow-up data, complete responses were achieved in three patients (4%) and partial responses, in five patients (7%). One patient (1%) with evdoable disease showed improvement. There wss only one partial response in the PS 2 patients. Perfomwu status was a predictive factor for response or improvement (p = 0.0368). Ahighincidence(74W)ofsevereorlife-threatinghemstologic toxicity and fatal sepsis in four patients was B reflection of the intensity of the chemotherapeutic regime. The median survival From study entry was 7.4 months. Thirty-seven percent of the patients survived beyond
1 year; the mediao survival for the PS 0-l patients wss 11.7 months for thePS2patieots,4.1 months. Mediaa timetotreptmeatfailurewas 3.9 months, but treatment had not failed in 9 96of the patients after 1 year, all of whom were PS O-l at time of study entry. Although the respoose rate with this dose- intensive chemotherapy regimen w~lsdissppointiog, the median survival of PS O-l ptients wss equivalent to that of Stage III NSCLC patients in prior CALGB stodies. In patients with NSCLC who are treated with chemotherapy. PS may be as importaot a prognostic factor ss stage, when median survival is used ss so endpoint. Elevated DTdiaphorw activity and messenger RNA content in hunan non- snail cell lung tnmimmx Relationship to the response of lung tumor xenografts to mitomycin C Meikinmn AM, Siegel D, Forrest GL, Gwdar AP, Oie HK, Cbao DC et al. MTBHSP, School ofPharmacy, University ofColorado. Boulder, CO 80309. Csnwr Res 1992;52:4752-7. TbeenzymeDTdiaphor(DTD; NAD(P)H:quinoneoxido-redoctsse, EC 1.6.99.2), is sn obligate hvo electma redo&se which catalyze reduction of P broad range of substrates, includiag qttinones. We report here variations in DTD concentrations nmong different classes of lung hlmors known also to vary in their responsiveaess to cytotoxic agents. Small cell long cxcinomas (SCLCs) pod cell lines derived from them hwethelowDTDactivitiessndmRNAwntentcharacteristicofnorma1 homao lung, wherw non-small cell lung carcinomw (NSCLCs) have greatly elevated levels. DTD activity was incressed up to SO-fold m NSCLC tumors relative to norms1 long and 20-35-fold i NSCLC relative to SCLC cell lines. Incnzased DTD activity sppwred to be a function of the NSCLC phenotype rsther than P result of derivation from s cell type rich in DTD, siace all histological classes of NSCLC showed tbis phenotype. Ia addition, where traasfection of SCLC cell lines with the v-Ha-ras protooncogene caused a transition to IINSCLC phenotype, DTD activity was also elevated. Neuroendocrine-positive cells (SCLC. carcinoids, sod s few NSCLC lines) typically had far lower DTD activities than did cell limes which lacked neoroendoctie markers (most NSCLC cells and mesotheliomas). High DTD activity msy be exploited in the design of drugs which undergo bioreductive activation by this enzyme. Consistent with this, xenogrsfts derived from NSCLC cell lines with high DTD thst were grown in athymic nude mice were more susceptible to thenntitomor qoinone, mitomycin C, thanwerexenogmfts derived fmm SCLC cells cootpining low DTD. These data provide s mechanistic basis for the rational design of more effective bioreductive antitumor agents for use against NSCLC. Cytogenetic alterations associated with P-glycoprotein- and non-Pglycopmtein-mediated multidrug resistance in SW-1573 human lung tlrmor cell lines NieuwiatA.W.M. BsssF. WiegsntJ. JoeajeH. CytogenericsLaborarory, Free University Hospital, P. 0. Box 7057, NL-1007 MB Amsterdam. Cancer Res 1992;52:4361-71. Multidrug resistance can be induced ia msmmsliao cells by selection with a single cytotoxic agent. Overpmductioa of the energy-dependent drug eftlux pump P-glycoproteio, encoded by the mdrl gene, hss been identified as the cause of one form of multidrug resistance. Tbe molecular b&s of other forms of multidrug resistawe is unknown. Doxorubicio selection ofthe humsn squamous lung cnocer cell line SW1573 resulted io multidrug-resistsot sublines in which a non-Pglycoprotein-mediated Form of multidrug resistance precedes mdrl expression. Here we present a cytogenetic analysis of both non- Pglycopmtein-mediimultidrog-resis&otadP-glycoprotein-medi&d multidrug-resistsntsubliaesderivedFromSW-1573. Threeindependently derived non-P-glycoproteia-mediated multidrug-resistant sublines showed s heterozygoos deletion of the short arm of chromosome 2 @23pter), whereas alterations of chromosome 7 were present in the Pglycopmtein-mediated multidrug-resistsat cell lines. In one series of cl~nallyderivedP- glycoprotein-mediatedmultidlug-resIstant soblines, mdrl overexpression was accompanied by various markers of chromosome 7 with breakpoiats at 7q22, the mdrl gene being known to belocptedat7q21.1. ChIrdatasuggestthatinSW- 1573cellsacqu~sit1on of non-P-glycopmtein-mediated multidrug resistaxe is accompsmed by s specific deletion or s trsoslocation involving the short arm of