Types of Lung Cancer

be฀identiied฀ [17,฀59] .฀Whereas฀SCC฀used฀to฀be฀the฀predominant฀type,฀for฀about฀the฀last฀10฀ years,฀it฀has฀been฀overtaken฀by฀AC,฀with฀small฀cell฀and฀undifferentiated฀carcinoma฀in฀third฀ and฀fourth฀positions฀ [60] .฀The฀change฀in฀incidence฀is฀thought฀to฀be฀due฀to฀the฀switch฀to฀low- tar฀and฀low-nicotine฀cigarette฀brands฀ [61] ฀where฀inhalation฀depth฀and฀frequency฀and฀nitro- samine฀ exposure฀ are฀ increased฀ [62] .฀ As฀ a฀ result,฀ smaller,฀ less฀ well-protected฀ bronchial฀ 0.6 0.5 0.4 0.3 0.2 0.1 0.0 I-Hydroxypyrene [µg24 h] All subjects Nonsmokers Smokers 42 27 27 15 15 12 suburban rural a 0.00 0.05 0.10 0.15 0.20 0.25 All subjects [fmolmg] Nonsmokers Smokers b c All subjects Nonsmokers Smokers 0.00 0.03 0.06 0.09 0.12 0.15 Fig. 5.4 ฀฀฀Renal฀excretion฀of฀ von฀1-hydroxypyrene฀a,฀ benzo[a]pyrene฀adducts฀of฀ haemoglobin฀b฀and฀of฀ albumin฀c฀in฀42฀ ฀non-smokers฀and฀27฀ smokers,฀classiied฀by฀ suburban฀or฀rural฀location฀of฀ residence.฀The฀vertical฀lines฀ show฀the฀standard฀error฀of฀ the฀mean.฀p฀=฀0.056฀ [55] regions฀come฀into฀contact฀with฀smoke฀constituents,฀and฀this฀may฀be฀one฀reason฀for฀the฀ change฀in฀predominant฀tumour฀type.

5.2.3 Genetic Factors That Increase the Risk for Bronchial Carcinoma

Shifts฀are฀plainly฀occurring฀in฀the฀presentation฀of฀different฀lung฀cancer฀types.฀While฀there฀ has฀been฀a฀proportional฀decrease฀in฀SCC,฀AC฀has฀become฀more฀common,฀possibly฀due฀to฀ the฀reduction฀in฀polynuclear฀aromatic฀hydrocarbons฀PAH฀in฀inhaled฀smoke฀from฀iltered฀ low-yield฀cigarettes฀ [27] .฀The฀enzymes฀CYP1A1฀and฀GSTM1฀play฀a฀major฀role฀in฀the฀ metabolic฀activation฀and฀detoxiication฀of฀PAH,฀while฀CYP2E1฀is฀responsible฀more฀for฀the฀ metabolic฀activation฀of฀nitrosamines.฀One฀case-control฀study฀conducted฀in฀341฀incident฀ lung฀cancer฀cases฀compared฀with฀456฀healthy฀controls฀conirmed฀a฀2.4-fold฀increase฀in฀the฀ risk฀for฀SCC฀where฀the฀CYP1A1฀MspI฀variant฀allele฀was฀present,฀and฀a฀3.1-fold฀increase฀ when฀this฀was฀combined฀with฀a฀GSTM1฀deletion฀ [63] .฀In฀contrast,฀CYP2E1฀RsaI฀and฀DraI฀ polymorphisms฀did฀not฀correlate฀with฀SCC฀risk;฀however,฀the฀presence฀of฀these฀enzyme฀ variants฀ was฀ associated฀ with฀ a฀ tenfold฀ reduction฀ in฀ the฀ risk฀ for฀ small฀ cell฀ lung฀ cancer฀ SCLC,฀while฀AC฀development฀was฀encouraged฀by฀CYP2E1฀mutants฀ [63] . On฀ stratiied฀ analysis,฀ it฀ is฀ found฀ that฀ the฀ polymorphic฀ metabolicoxidative฀ enzyme฀ myeloperoxidase฀MPO฀genotypes฀modiied฀the฀effect฀of฀asbestos฀exposure฀on฀lung฀cancer฀ risk.฀Speciically,฀GG฀carriers฀who฀were฀exposed฀to฀asbestos฀had฀a฀higher฀risk,฀while฀A-allele฀ carriers฀GA฀+฀AA฀showed฀a฀reduced฀OR฀of฀0.89฀95฀CI;฀0.56–1.44.฀The฀A-allele฀geno- types,฀therefore,฀demonstrated฀protective฀effects฀on฀the฀development฀of฀lung฀cancer.

5.2.3.1 Tobacco-Specific Carcinogens

Several฀products฀have฀been฀implicated฀in฀the฀development฀of฀cancer฀in฀smokers:฀PAH,฀ tobacco-speciic฀ nitrosamines฀ TSNA฀ und฀ aromatic฀ amines฀ AA.฀ The฀ metabolism฀ of฀ these฀toxic฀substances฀plays฀a฀crucial฀role,฀and฀this฀process฀may฀be฀inluenced฀to฀a฀major฀ extent฀by฀genetic฀differences฀in฀the฀metabolising฀cytochrome฀P450฀CYP฀enzymes฀and฀by฀ the฀glutathione฀S-transferase฀GST฀system. Benzo[a]pyrene฀activates฀oncogenes฀and฀interacts฀with฀DNA;฀it฀also฀promotes฀the฀for- mation฀of฀diol-epoxides฀as฀key฀reactive฀substances.฀Benzo[a]pyrene฀undergoes฀transfor- mation฀to฀phenol฀metabolites฀and฀benzo[a]pyrene-7,8-diole฀by฀the฀action฀of฀cytochrome฀ enzymes฀such฀as฀epoxide฀hydrolases฀and฀other฀isoenzymes;฀the฀latter฀form฀the฀highly฀reac- tive฀+-anti-benzo[a]pyrene฀diol-epoxide฀BPDE,฀which฀is฀a฀good฀substrate฀for฀GST฀M1,฀ M2,฀M3฀and฀an฀even฀better฀substrate฀for฀GSTPI฀ [39] .฀These฀metabolic฀products฀have฀also฀ been฀detected฀in฀lung฀tissue฀and฀in฀lymphocytes฀ [36] . 4-Methylnitrosoamino-1,3-pyridyl-1-butanone฀NNK฀and฀N′-nitrosonornicotine฀NNN฀ cf.฀Box฀3.1in฀ Chap.฀3 ฀are฀the฀most฀important฀TSNA;฀they฀are฀formed฀in฀unburned฀tobacco฀ and฀during฀combustion.฀Smokers฀are฀principally฀confronted฀with฀both฀substances,฀though฀ NNK฀in฀particular฀produces฀cancer฀in฀the฀upper฀respiratory฀tract.฀The฀metabolic฀pathways฀ of฀NNK฀in฀humans฀and฀animals฀are฀identical.฀NNK฀doses฀absorbed฀by฀humans฀are฀dei- nitely฀carcinogenic฀in฀animal฀experiments.฀Prior฀to฀binding฀to฀DNA,฀both฀nitrosamines฀ require฀ activation฀ a-methyl฀ or฀ a-methylene฀ hydroxylation,฀ pyridine-N-oxidation฀ by฀ CYP-mediated฀reactions฀and฀glucuronidation฀ [64,฀65] .฀The฀alcohol฀from฀NNK฀is฀excreted฀ in฀the฀urine฀and฀serves฀as฀an฀indicator฀for฀NNK฀exposure. The฀AA,฀including฀4-aminobiphenyl,฀are฀compounds฀that฀play฀a฀particular฀role฀in฀the฀ development฀of฀carcinoma฀of฀the฀bladder฀ [66] ฀and฀therefore,฀will฀not฀be฀discussed฀further฀ in฀the฀present฀context. DNA฀damage฀is฀also฀produced฀as฀a฀result฀of฀oxidation฀processes฀and฀by฀lipid฀peroxida- tion.฀Inhaled฀material฀from฀tobacco฀contains฀oxygen฀and฀nitrogen฀groups,฀which฀react฀with฀ the฀various฀body฀tissues฀in฀smokers.฀Consequently,฀oxidative฀DNA฀damage฀due฀to฀prod- ucts฀formed฀by฀lipid฀peroxidation฀malondialdehyde,฀crotonaldehyde,฀trans-4-OH-2-฀nonenal฀ is฀commonly฀found฀in฀the฀respiratory฀tract฀tissues฀of฀smokers.฀These฀metabolites฀are฀epoxi- dised฀by฀CYP-mediated฀reactions฀and฀form฀promutagenic฀DNA฀adducts฀in฀human฀tissue฀ [40,฀ 67,฀ 68] ,฀ leading฀ to฀ an฀ increased฀ cancer฀ risk฀ for฀ the฀ upper฀ respiratory฀ tract฀ [41] .฀ Chewing฀tobacco฀with฀or฀without฀betel฀produces฀cancers฀in฀the฀oral฀cavity฀ [69] .

5.2.3.2 The Cytochrome P450 and GST System and Carcinogenesis

Current฀epidemiological฀research฀into฀carcinogenesis฀in฀the฀lung฀indicates฀that฀several฀pop- ulations฀are฀at฀risk฀for฀the฀development฀of฀lung฀cancer,฀especially฀smokers฀and฀workers฀ exposed฀to฀toxic฀substances.฀One฀genetic฀factor฀that฀deserves฀particular฀mention฀in฀this฀ context฀is฀the฀induction฀of฀aryl฀hydrocarbon฀hydroxylase฀CYP1A1;฀AHH.฀This฀enzyme฀ transforms฀the฀PAH฀produced฀by฀cigarette฀smoke฀into฀compounds฀that฀are฀highly฀carcino- genic฀ [70] .฀In฀addition,฀oxidation฀processes฀are฀catalysed฀by฀the฀CYP450฀system฀and฀using฀ debrisoquine-4-hydroxylation฀ CYP2D6฀ as฀ a฀ model฀ reaction,฀ a฀ clear฀ distinction฀ can฀ be฀ drawn฀between฀lung฀cancer฀patients฀and฀matched฀controls฀ [71–73] .฀Where฀there฀is฀extensive฀ hydroxylation฀of฀the฀“model฀substance”฀debrisoquine,฀the฀risk฀for฀the฀development฀of฀lung฀ cancer฀is฀simultaneously฀increased.฀To฀date,฀however,฀there฀are฀no฀routine฀tests฀for฀the฀pro- phylactic฀identiication฀of฀such฀risk฀factors.฀As฀shown฀by฀the฀data฀summarised฀in฀Fig.฀ 5.4 ,฀ the฀renal฀excretion฀of฀carcinogens฀is฀higher฀in฀smokers฀than฀in฀non-smokers,฀with฀slight฀dif- ferences฀detected฀in฀terms฀of฀residential฀environment฀suburban฀or฀rural฀ [56] .฀Several฀stud- ies฀have฀been฀conducted฀in฀patients฀affected฀by฀these฀problems฀ [66] ฀and฀the฀key฀inding฀is฀ that฀metabolites฀of฀these฀inhaled฀tobacco฀products฀form฀adducts฀with฀DNA฀Fig.฀ 5.4 . The฀CYP฀system฀plays฀a฀central฀role฀in฀the฀metabolism฀or฀activation฀of฀carcinogens฀ [68,฀ 74–77] .฀Case-control฀studies฀have฀revealed฀associations฀between฀tobacco฀smoke฀and฀can- cer฀risks฀for฀the฀lungs,฀larynx,฀mouth,฀oesophagus,฀kidneys,฀urinary฀system฀and฀breasts. CYP1A1:฀PAH฀and฀AA฀are฀activated฀by฀the฀enzyme.฀Approximately฀10฀of฀Caucasians฀ have฀a฀highly฀inducible฀form฀of฀CYP1A1฀also฀known฀as฀B[a]P-hydroxylase,฀in฀conjunc- tion฀with฀an฀increased฀risk฀for฀tumours฀of฀the฀bronchi,฀larynx฀and฀oral฀cavity฀ [78] .฀Four฀ different฀forms฀of฀the฀cytochrome฀enzyme฀1A1฀have฀been฀described฀to฀date฀Table฀ 5.2 ,฀ though฀regrettably฀several฀nomenclatures฀are฀in฀use.฀The฀inducibility฀of฀CYP1A1฀corre- lates฀with฀the฀occurrence฀of฀bronchial฀carcinoma฀ [80] ,฀with฀the฀m2฀mutant฀Ile-→−Val฀