Apoptosis and p53 status predict the efficacy of postoperative administration of UFT in non-small cell lung cancer

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1 doi: / bjoc , vilble online t on Apoptosis nd p53 sttus predict the efficcy of postopertive dministrtion of UFT in non-smll cell lung cncer F Tnk, Y Otke, K Yngihr, T Ymd, R Miyhr, Y Kwno, M Li, K Inui nd H Wd Deprtment of Thorcic Surgery, Fculty of Medicine, Kyoto University; Shogoin-kwhr-cho 54, Skyo-ku, Kyoto, , Jpn Summry To exmine whether efficcy of postopertive orl dministrtion of UFT, 5-fluorourcil derivtive chemotherpeutic gent, my be influenced by incidence of poptosis (poptosis index) or poptosis-relted gene sttus (p53 nd bcl-2) of the tumour, totl of 162 ptients with pthologic stge I non-smll cell lung cncer were retrospectively reviewed. UFT ws dministrted postopertively to 44 ptients (UFT group), nd not to the other 118 ptients (Control group). For ll ptients, 5-yer survivl rte of the UFT group (79.9%) seemed higher thn tht of the Control group (69.8%), lthough without significnt difference (P = 54). For ptients with higher poptotic index, 5-yer survivl rte of the UFT group (83.3%) ws significntly higher thn tht of the Control group (67.6%, P = 39); for ptients with lower poptotic index, however, there ws no difference in the prognosis between these two groups. Similrly, UFT ws effective for ptients without p53 berrnt expression (5-yer survivl rtes: 95.2% for the UFT group nd 74.3% for the Control group, P = 22), wheres not effective for ptients with p53 berrnt expression. Bcl-2 sttus did not influence the efficcy of UFT. In conclusion, poptotic index nd p53 sttus re useful fctors to predict the efficcy of postopertive djuvnt therpy using UFT Cncer Reserch Cmpign Keywords: p53; bcl-2; poptosis; djuvnt therpy; 5-fluorourcil; UFT Non-smll cell lung cncer (NSCLC) is mlignnt tumour with poor prognosis, nd the postopertive survivl is not stisfctory (Mountin, 1997). Although djuvnt therpy ws introduced to improve the postopertive prognosis, it hs been concluded tht rdiotherpy cn not improve the survivl lthough it cn reduce the locl recurrence rte. Therefore, systemic chemotherpy hs been expected to improve the postopertive survivl by suppressing occurrence of distnt metstsis, nd vriety of chemotherpeutic regimens hve been ttempted. However, the efficcy of postopertive djuvnt chemotherpy hs not been estblished yet (Ihde et l, 1994). However, recent retrospective study conducted by Kyoto University suggested tht UFT dministrtion ws effective s postopertive djuvnt therpy for NSCLC (Tnk et l, 1998). UFT is n orl 5-fluorourcil (5-FU) derivtive drug composed of tegfur (1-[2-tetrhydrofuryl]-5-fluoroircil, FT) nd urci (U); tegfur is pro-drug tht persistently releses 5-FU, nd urcil is dded to inhibit degrdtion of the relesed 5-FU (Fujii et l, 1978; Ikenk et l, 1979). As result, when UFT is dministrted, certin 5-FU concentrtion in blood nd tumour tissues cn be mintined for long time. The efficcy of postopertive orl dministrtion of UFT ws confirmed by prospective rndomized study conducted by The West Jpn Study Group for lung cncer surgery ; 5-yer survivl rtes of pthologic (p-) stge I III, NSCLC were 64.1%, 6% nd 49.0% in ptients who received postopertive UFT dministrtion (400 mg body 1 dy 1 for one yer fter surgery, UFT group), in those who received the sme Received 24 August 2000 Revised 9 October 2000 Accepted 18 October 2000 Correspondence to: H Wd UFT dministrtion following intrvenous infusion of CDDP (50 mg/m 2 body surfce for one course) + VDS (2 3 mg kg body weight 1 for 3 courses) (CVUft group), nd in those who received no djuvnt therpy (Control group), respectively (P = 44 mong 3 groups, nd P = 19 between the UFT group nd the Control group) (Wd et l, 1996). The efficcy of postopertive UFT dministrtion in NSCLC ws demonstrted in other prospective rndomized studies (The Study Group of Adjuvnt Chemotherpy for Lung Cncer (Chubu, Jpn), 1995; Wd et l, 1999). Although these results suggest the efficcy of postopertive UFT dministrtion, postopertive recurrence my pper in some cses even if UFT dministrtion is performed. Thus, if whether UFT dministrtion is effective or not cn be predicted in n individul ptient before the dministrtion, postopertive prognosis cn be improved when efficcy of UFT dministrtion is expected, nd medicl nd finncil disdvntge of UFT dministrtion cn be relieved when the efficcy is not expected. The p53 tumour suppressor gene protects the genome ginst vriety of dmges, nd suppresses occurrence of mlignnt tumour (Levine et l, 1991). The p53 gene induces poptosis s well s regultes the cell cycle (Clrke et l, 1993; Lowe et l, 1993). Apoptosis is kind of cell deth distinct from necrosis, showing morphologicl fetures such s cell shrinkge, loss of cell cell contct, chromtin condenstion nd intrnucleosoml degrdtion of DNA (Kerr et l, 1972). Apoptosis is n essentil phenomenon for norml development nd mintennce of homeostsis, nd lso plys n importnt role in suppressing prolifertion of mlignnt tumour cells (Symonds et l, 1994; Holmgren et l, 1995). It is known tht poptosis is induced by vrious Prts of this rticle ws presented t the 34th nnul meeting of ASCO (Los Angeles, CA, bstrct No. 2110) nd the 35th nnul meeting of ASCO (Atlnt, GA, bstrct No. 2393). 263

2 264 F Tnk et l nticncer gents nd rdiotherpy. Therefore, it hs been reported tht sensitivity to nticncer gents nd rdiotherpy cn be influenced by the sttus of some genes ssocited with poptosis such s the p53 gene (Clrke et l, 1993; Lowe et l, 1993). In preliminry study, we hve lredy reported tht the efficcy of orl dministrtion of FT nd UFT fter surgery for NSCLC my be influenced by p53 sttus (Tnk et l, 1999). Moreover, we hve lredy reported tht blnce between incidence poptotic cell deth nd tumour-cell prolifertion is n importnt fctor to predict postopertive survivl in resected NSCLC (Tnk et l, 1999b). In the present study, whether the efficcy of postopertive UFT dministrtion ws influenced by incidence of poptosis (poptotic index: AI) nd by sttus of p53 nd bcl-2 regulting poptosis in more homogeneous ptients (p-stge I ptients) ws exmined. PATIENTS AND METHODS A totl of 163 consecutive ptients with p-stge I, NSCLC who underwent complete tumour resection nd medistinl lymph node dissection without ny preopertive therpy t the Deprtment of Thorcic Surgery, Kyoto University between Jnury 1, 1987 nd December 31, 1992, were reviewed. P-stge nd histologicl typing were re-evluted nd determined ccording to the current TNM clssifiction (Mountin, 1997) nd the current clssifiction by World Helth Orgniztion (Trvis et l, 1999), respectively. One ptient ws excluded from the study due to opertion-relted deth, nd thus finl totl of 162 ptients (122 mles nd 40 femles) were evluted. For ll these ptients, the inptient medicl records, chest X-ry films, whole-body CT films, bone nd gllium scnning dt nd records of surgery were reviewed without knowledge of the results of immunohistochemicl stining. Follow-up of the postopertive clinicl course ws conducted by outptient medicl records nd by inquiries by telephone or letter. The dy of thorcotomy ws considered the strting dy for counting postopertive survivl dys. Clinicl chrcteristics of ptients UFT ws dministrted to ll ptients in whom n informed consent hd been tken; UFT ws not dministrted if not. As result, mong ll 162 ptients, UFT (Tiho Phrmceuticl Co, Tokyo, Jpn) ws dministered to 44 ptients (UFT group), nd not dministered to the other 118 ptients (control group). Administrtion dose of UFT ws 300 mg dy 1 body 1 (body weight < 50 kg) or 400 mg dy 1 body 1 (body weight 50 kg). Orl dministrtion of UFT ws initited within one month fter surgery. UFT ws dministered for t lest one yer if the ptients were live; for decesed ptients, UFT ws dministered until orl dministrtion becme impossible. There were no significnt differences in clinicl chrcteristics of ptients between the UFT group nt the control group (Tble 1). No other preopertive, intropertive, or postopertive therpy ws performed in ny cse. Tissue preprtion Detection of poptotic cells ws performed with the terminl deoxynucleotidyl trnsferse-medited dutp-biotin nick endlbelling (TUNEL) method. Expression of PCNA (proliferting cell nucler ntigen), which ws expressed in nucleus t the lte G1 phse nd S phse of the cell cycle, ws exmined immunohistochemiclly s n index of cell prolifertion. Aberrnt expression of p53 nd expression of bcl-2 were lso exmined immunohistochemiclly. Seril 4-µm sections were prepred from ech formlin-fixed nd prffin-embedded tumour specimen, nd served for routine hemtoxylin nd eosin (H&E) stining, the TUNEL stining nd immunohistochemicl stining (IHS). Dewxed sections were digested with 20 µg ml 1 proteinse K (Boehringer Mnheim, Mnheim, Germny) for 20 minutes t 25 C for the TUNEL stining, nd were heted in microwve oven for 5 minutes three times for IHS. Endogenous peroxidse ws inctivted by incubting the sections with 3% H 2 O 2 in methnol for 30 minutes t 25 C. To reduce unspecific lbelling, the sections were incubted with norml clf serum (DAKO Jpn, Kyoto, Jpn). Detection of poptosis The TUNEL stining ws performed using In Situ Deth Detection Kit, POD (Boehringer Mnheim, Mnheim, Germny) following the mnufctured protocol s described previously (Tnk et l, 1999b). The specificity of the TUNEL stining of poptotic cells ws confirmed by mking the negtive nd the positive control slides t every stining. As negtive control slides, sections incubted with the TUNEL rection mixture without TdT were used. As positive control slides, sections treted with DNse 1 (0.7 mg ml 1, Strtgene, L Joll, CA) for 10 minutes t 25 C before the TUNEL rection were used. Apoptotic cells were determined with creful observtion of TUNEL-stining sections nd seril H&E-stining sections. TUNEL-positive stining cells tht represent histologicl fetures of necrosis in H&E-stining sections were not considered to be poptotic cells. In ech cse, totl of tumour cells, 1000 tumour cells ech in 10 different fields, were evluted t high mgnifiction ( 400) by two uthors independently (F.T. nd Y.O) without knowledge of clinicl dt. When different evlution of poptotic cells ws mde, the field ws re-evluted until the evlution coincided. The poptotic index (AI) ws defined s the number of poptotic cells per 1000 tumour cells. IHS Procedure of IHS using streptovidin-biotinylted horserdishperoxidse complex method (LSAB kit; DAKO JAPAN, Kyoto, Jpn) ws described previously (Tnk et l, 1998b, 1999, 1999b). Mouse nti-humn PCNA, monoclonl ntibody (MoAb) PC-10 (mouse IgG2, kpp 400 µg ml 1 DAKO Jpn) diluted t 1:50, nti-humn p53 MoAb, clone DO-7 (mouse IgG2b, kpp, 250 µg ml 1, DAKO Jpn) diluted t 1:50, nd nti-humn bc1-2 MoAb, clone 124 (mouse IgG, kpp, 200 µg ml 1, DAKO Jpn) diluted t 1:50 nd mouse were used s the primry ntibody. Stined tissue slides were evluted by two of the uthors (F.T. nd Y.O.) independently without knowledge of clinicl dt. A totl of 1000 tumour cells were counted, nd the percentges of positive cells were determined. When the percentge of positive-stining cells exceeded 5%, the slide ws judged to exhibit berrnt expression of p53 or positive expression of bcl-2. The frction of prolifertive cells ws represented by the percentge of PCNA-positive tumour cells (prolifertive index: PI). Sttisticl methods Counts were compred by the chi-squre test, nd trends in counts were nlysed by the chi-squre test for trends. Continuous dt

3 Apoptosis nd p53 sttus predict the efficcy of UFT 265 were compred using Student s t-test if the distribution of smples ws norml, or using Mnn-Whitney U-test if the smple distribution ws symmetricl. Postopertive survivl rte ws nlysed by the Kpln-Meier method, nd the difference ws ssessed by the log-rnk test. Multivrite nlysis of prognostic fctors ws performed using Cox s regression model. Differences were considered significnt when P- vlue ws less thn 5. All sttisticl mnipultions were performed using the SPSS for Windows softwre system (SPSS Inc, Chicgo, IL, USA, 1993). RESULTS Incidence of poptosis (AI), berrnt expression of p53 nd expression of bcl-2 The men AI for ll ptients ws 19.2 ± 2.0 (men ± stndrd error: SE), nd the medin AI ws There ws no difference in the men AI between the UFT group nd the Control group (Tble 1). Even if the ptients were divided to ptients with higher AI (AI 10.9) nd those with lower AI (AI < 10.9), there ws no difference in rtios of higher nd lower AI ptients between the UFT group nd the Control group. In 67 of 162 (41.4%) ptients, p53 berrnt expression ws demonstrted. In only 33 (2%) ptients, bcl-2 ws expressed. There ws no significnt difference in rtios of ptients with p53 berrnt expression or in rtios of bcl-2-positive ptients between the UFT group nd the Control group (Tble 1). Correltion of AI with cell prolifertion, berrnt expression of p53 nd expression of bcl-2 Correltion between AI nd frction of prolifertive cncer cells (PI) ws exmined (Tble 2). The men PI in higher-ai ptients ws 53.5%, which ws significntly higher thn tht in lower-ai ptients (31.6%). Moreover, the number of ptients showing Tble 2 Correltion between poptotic index (AI) nd poptosis-relted gene (p53, bcl-2) sttus Lower-AI b Higher-AI b P vlue Prolifertive index (PI, men) 31.6% 53.5% <01 Lower-PI c 58 (71.6%) 24 (29.6%) <01 Higher-PI c 23 (28.4%) 57 (7%) p-53 berrnt expression Negtive 50 (61.7%) 45 (55.6%) 25 Positive 31 (38.3%) 36 (44.4%) Negtive 62 (76.5%) 67 (82.7%) Positive 19 (23.5%) 14 (17.3%) P vlue: Comprison of ptients chrcteristics between ptients with Lower-AI nd those with Higher-AI. b Lower-AI: AI < 10.9 (medin AI). Higher-AI: AI 10.9 (medin AI). c Lower-PI: PI < 44% (medin PI). Higher- PI: PI 44% (medin PI). higher PI (PI 44%) ws lrger in higher-ai ptients thn in lower-ai ptients. These results demonstrted tht more cncer cells showing ctive prolifertion hve more chnces of undergoing poptosis. On the other hnd, no significnt correltion of AI with p53 berrnt expression or ws observed. AI, berrnt expression of p53 expression of bcl-2 nd postopertive prognosis According to univrite nlysis of prognostic fctors, 5-yer survivl rtes of ptients with nd those without p53 berrnt expression were 6% nd 80.1%, suggesting p53 berrnt expression ws significnt fctor to predict poor prognosis (P = 11). In contrst, no significnt difference ws observed in the prognosis between ptients with nd those without, or between ptients with higher AI nd those with lower AI (Tble 3). Multivrite nlysis lso confirmed tht p53 berrnt Tble 1 Chrcteristics of ptients, poptotic index (AI) nd poptosis-relted gene (p53, bcl-2) sttus in ptients with nd without postopertive orl dministrtion of UFT All ptients Ptients with Ptients without P vlue UFT dministrtion UFT dministrtion Gender Mle 122 (75.3%) 31 (70.5%) 91 (77.1%) Femle 40 (24.7%) 13 (29.5%) 27 (22.9%) Age (men, yers) Performnce sttus (90.7%) 40 (90.9%) 107 (90.7%) (9.3%) 4 (9.1%) 11 (9.3%) Pthologic T1 (stge IA) 84 (51.9%) 23 (52.3%) 61 (51.7%) T2 (stge IB) 78 (48.1%) 21 (47.7%) 57 (48.3%) Histology Squmous cell 55 (34.0%) 14 (31.8%) 41 (34.7%) Adenocrcinom 93 (57.4%) 27 (61.4%) 66 (55.9%) Lrge cell 11 (6.8%) 2 (4.5%) 9 (7.6%) Others Apoptotic index (AI, men) 19.2/1000 cncer cells Lower-AI (<10.9) 81 (5%) 23 (52.3%) 58 (49.2%) Higher-AI ( 10.9) 81 (5%) 21 (47.7%) 60 (5%) p53 berrnt expression Negtive 95 (58.6%) 25 (56.8%) 70 (59.3%) Positive 67 (41.4%) 19 (43.2%) 48 (40.7%) Negtive 129 (79.6%) 32 (72.7%) 97 (82.2%) Positive 33 (2%) 12 (27.3%) 21 (17.8%) P vlue: Comprison of ptients chrcteristics between ptients with nd without postopertive dministrtion of UFT.

4 266 F Tnk et l Tble 3 Unvrite nlysis of prognostic fctors Prognostic fctors 5-yer survivl rte P vlue Gender Mle/Femle 66.9%/82.7% 67 Age Lower ge / Higher ge 76.3%/64.7% 86 Performnce Sttus 0 / %/46.2% Pthologic-T fctor T1 (IA) / T2 (IB) 71.9%/69.4% Histology Squmous cell / Adenocrcinom 67.9%/73.1% p53 berrnt expression Negtive / Positive 80.1%/6% 11 Negtive / Positive 71.2%/75.9% Apoptotic index (AI) b Lower / Higher 72.1%/71.5% 84 Prolifertive index (PI) c Lower/Higher 74.0% / 75.6% 61 Postopertive UFT dministrtion No / Yes 79.9% / 69.8% 54 Lower ge: Age < 64.0 yers (medin ge). Higher ge: Age 64.0 yers (medin ge). b Lower-AI: AI < 10.9 (medin AI). Higher-AI: AI 10.9 (medin AI). c Lower-PI: PI < 44% (medin PI). Higher-PI: PI 44% (medin PI). expression ws significnt fctor to predict poor postopertive, nd tht or AI could not be significnt prognostic fctor (Tble 4). Efficcy of postopertive UFT dministrtion nd AI, berrnt expression of p53 nd expression of bcl-2 5-yer survivl rtes of the UFT group nd the Control group were 79.9% nd 69.8%, respectively. Although the UFT group seemed to show fvourble prognosis s compred with the Control group, the difference proved not be significnt (P = 54, Figure 1). The efficcy of the UFT dministrtion ws compred between ptients without nd those with p53 berrnt expression. In ptients without p53 berrnt expression, the UFT group showed significntly better prognosis thn the Control group (95.2% nd 74.3%, respectively, P = 22, Figure 2), demonstrting tht UFT dministrtion could improve the postopertive prognosis. In ptients with p53 berrnt expression, however, there ws no significnt difference in the prognosis between the UFT group nd the Control group (55.8% nd 62.8%, respectively, P = 34, Figure 2b), demonstrting tht UFT dministrtion ws not effective in such cses. In contrst, there ws no difference demonstrted in the efficcy of the UFT dministrtion between ptients with nd those without, showing the efficcy of UFT ws not influenced by the sttus of bcl-2 (Tble 5). Concerning AI nd the efficcy of UFT, in ptients with lower AI, there ws no significnt difference in the prognosis between the UFT group nd the Control group (5-yer survivl rtes: 74.6% nd 71.6%, respectively, P = 0.592, Figure 3), showing tht UFT dministrtion ws not effective in lower-ai ptients. On the other hnd, in ptients with higher AI, the UFT group showed significntly better prognosis thn the Control group (5-yer survivl rtes: 83.3% nd 67.6%, respectively, P = 39, Figure 3b), suggesting tht UFT dministrtion ws effective in higher-ai ptients. To confirm the efficcy of UFT dministrtion in ptients without p53 expression nd those with higher AI, multivrite nlysis ws performed mong ech ptient-group. As result, UFT dministrtion proved to be n independent prognostic fctor to improve the prognosis mong ptients without p53 berrnt expression (P = 30, reltive risk (RR) nd the 95% confidence intervl (CI): 94 ( )), wheres not mong ptients with p53 berrnt expression (P = 30, RR nd the 95% CI: ( )). Similrly, UFT dministrtion proved to be n independent prognostic fctor to improve the prognosis mong higher-ai (P = 32, RR nd the 95% CI: 55 ( )), wheres not mong lower-ai ptients (P = 0.311, RR nd the 95% CI: ( )). DISCUSSION In the present study, it ws suggested tht efficcy of UFT dministrtion s postopertive djuvnt therpy for NSCLC might be influenced by incidence of poptosis (AI) nd sttus of p53 regulting poptosis. UFT is 5-FU derivtive chemotherpeutic gent developed in Jpn, nd hs been widely used in Jpn Tble 4 Multivrite nlysis of prognostic fctors (Cox s proportionl hzrd model) Prognostic fctors β P vlue Reltive hzrd (95% confidence intervl) Gender (Mle/Femle) ( ) Age ( ) Performnce sttus (0/1) ( ) Pthologic-T fctor (1/2) ( ) Histology (Adenocrcinom or not) ( ) p53 berrnt expression (Negtive/Positive) ( ) (Negtive/Positive) ( ) Apoptotic index (AI) (Lower/Higher) ( ) Prolifertive index (PI) b (Lower/Higher) (21 13) Postopertive UFT ( /+) ( ) Lower-AI: AI < 10.9 (medin AI). Higher-AI: AI 10.9 (medin AI). b Lower-PI: PI < 44% (medin PI). Higher-PI: PI 44% (medin PI).

5 Apoptosis nd p53 sttus predict the efficcy of UFT 267 P = 54 (log-rnk test) UFT dministrtion (+) 5-yer survivl rte: 79.9% UFT dministrtion ( ) 5-yer survivl rte: 69.8% Figure 1 fter complete tumour resection with lymph node dissection for p-stge I, non-smll cell lung cncer (NSCLC). Comprison between ptients with postopertive UFT dministrtion nd those without postopertive UFT dministrtion Tble 5 Postopertive survivl nd influence of UFT dministrtion 5-yer survivl rte (%) Ptients with UFT Ptients without P vlue dministrtion UFT dministrtion All ptients Strtified by poptosis nd poptosis-relted gene sttus Apoptosis index (AI) b Lower-AI Higher-AI p53 sttus Aberrnt expression: negtive Aberrnt expression: positive bcl-2 sttus Expression: negtive Expression: positive P-vlue: Comprison of ptients chrcteristics between ptients with nd without postopertive dministrtion of UFT. b Lower-AI: AI < 10.9 (medin AI). Higher-AI: AI 10.9 (medin AI). minly for mlignnt tumours originting from the digestive system. Recently, UFT hs been introduced to clinicl trils conducted in the United Sttes. Pzdur nd coworkers hve lredy reported tht UFT is effective to metsttic colorectl cncer when dministrted with leucovorin (Pzdur et l, 1994). Although 5-FU hs been used s bsic chemotherpeutic gent for vriety of solid tumours, it hs been reported tht 5-FU is not effective to primry lung cncer. However, ll these reports re bsed on results obtined by n intrvenous bolus injection. Mny experimentl nd clinicl studies hve reveled tht 5-FU is not dose-dependent but time-dependent gent (Pinedo nd Peter, 1988; Lokich et l, 1989). Orl dministrtion of 5- FU nd the derivtives which cn continuously mintin 5-FU concentrtion is n extremely useful method when the phrmcologicl fetures of 5-FU re considered (Fujii et l, 1978; Ikenk et l, 1979). UFT is inferior to other chemotherpeutic gents such s CDDP in terms of potency of direct nticncer ctivity. However, these chemotherpeutic gents with potent ntitumour effect hve not improved postopertive survivl of NSCLC. The most importnt fctor tht worsens the prognosis of completely resected NSCLC ptients is high incidence of distnt metstsis fter opertion. Recently, it hs been reveled experimentlly tht tumour growth ws suppressed with induction of poptosis in micrometsttic lesion (Holmgren et l, 1995). We hve lso reveled cliniclly tht the blnce of poptosis nd prolifertion of cncer cells influences on postopertive survivl of NSCLC (Tnk et l, 1999b). Postopertive orl dministrtion of UFT mintins certin blood concentrtion of 5-FU, which my ccelerte poptosis of cncer cells in micrometsttic lesions without suppression of ptients immunity, resulting in improving the postopertive prognosis. Assocition of the efficcy of UFT with poptosis is supported by the results obtined in the present study. In ptients with higher AI, tht is ptients whose cncer cells cn be esily induced to poptotic deth without tretment, UFT is effective s postopertive dministrtion of UFT cn suppress recurrence by ccelerting poptosis of cncer cells. On the other hnd, in ptients with lower AI, tht is ptients whose cncer cells cn not be esily induced to poptotic deth, UFT dministrtion cn not regulte micrometstses by filure to induce such cncer cells to poptosis. This specultion is consistent with results of bsic experiments demonstrting tht mny nticncer drugs such s CDDP nd 5-FU induce cncer cells to poptosis (Sen nd D Incki, 1992). The p53 gene is n importnt gene tht regultes poptosis. It hs been demonstrted experimentlly nd cliniclly tht the ntitumour effect of chemotherpeutic gents ws remrkbly decresed if the p53 gene is mutted (Fujiwr et l, 1994; Lowe et l, 1994; Bergh et l, 1995). These results re consistent with our results demonstrting tht the efficcy of postopertive orl dministrtion of UFT ws diminished in ptients with berrnt expression of p53, nd re resonbly understndble when the function of p53 gene nd poptosis re considered. IHS employed in the present study to determine p53 sttus is cliniclly useful, becuse it is very esy nd inexpensive s well s it cn be performed on prffin-embedded slides. However, ccurte detection of p53 gene muttion cn be chieved only when complete sequence of the p53 gene is determined (Crbone et l, 1994). In future study, correltion between efficcy of UFT nd the presence of p53 gene muttion should be exmined. The bcl-2 gene ws cloned s gene tht prolongs cellulr life by inhibiting poptosis. Although there hs been mny reports on significnce of in NSCLC, definite conclusion hs not yet been estblished (Pezzell et l, 1993; Pstorino et l, 1997). Becuse the incidence of in NSCLC is s low s bout 20%, the significnce of bcl-2 expression s prognostic fctor nd predictive fctor of therpeutic effect my not be importnt. In future, to clrify significnce of p53 berrnt expression detected with IHS nd incidence of poptosis (AI) in ssocition with the efficcy of postopertive orl dministrtion of UFT, prospective rndomized study on the UFT dministrtion strtified by the p53 sttus nd AI should be conducted.

6 268 F Tnk et l (A) UFT dministrtion (+) 5-yer survivl rte: 95.2% UFT dministrtion ( ) 5-yer survivl rte: 74.3% (B) UFT dministrtion ( ) 5-yer survivl rte: 62.8% UFT dministrtion (+) 5-yer survivl rte: 55.8% P = 22 (log-rnk test) P = 34 (log-rnk test) Figure 2 (A) Postopertive survivl of ptients demonstrting no berrnt p53 expression. Comprison between ptients with postopertive UFT dministrtion nd those without postopertive UFT dministrtion. (B) Postopertive survivl of ptients demonstrting berrnt p53 expression. Comprison between ptients with postopertive UFT dministrtion nd those without postopertive UFT dministrtion (A) UFT dministrtion (+) (B) UFT dministrtion (+) 5-yer survivl rte: 74.6% 5-yer survivl rte: 83.3% UFT dministrtion ( ) 5-yer survivl rte: 71.6% UFT dministrtion ( ) 5-yer survivl rte: 67.6% P = log-rnk test) P = 39 (log-rnk test) Figure 3 (A) Postopertive survivl of ptients demonstrting lower poptotic index (AI). Comprison between ptients with postopertive UFT dministrtion nd those without postopertive UFT dministrtion. (B) Postopertive survivl of ptients demonstrting higher poptotic index (AI). Comprison between ptients with postopertive UFT dministrtion nd those without postopertive UFT dministrtion ACKNOWLEDGEMENT We thnk Dr Mskzu Fukushim (Tiho Phrmceuticl Co Ltd, Sitm, Jpn) for helpful discussion. REFERENCES Bergh J, Norberg N, Sjogren S, Lindgre A nd Holmberg L (1995) Complete sequencing of the p53 gene provides prognostic informtion in brest cncer ptients, prticulrly in reltion to djuvnt systemic therpy nd rdiotherpy. Nture Med 1: Crbone DP, Mitsudomi T, Chib I, Pintdosi S, Rusch V, Nowk JA, McIntire D, Slmon D, Gzdr A nd Minn J (1994) p53 immunostining positivity is ssocited with reduced survivl nd imperfectly correlted with gene muttions in resected non-smll cell lung cncer. A preliminry report of LCSG 871. Chest 106: 377s 381s Clrke AR, Purdie CA, Hrrison DJ, Morris RG, Bird CC, Hooper ML nd Wyllie AH (1993) Thymocyte poptosis induced by p53-dependent nd independent pthwys. Nture 362: Fujii S, Ikenk K, Fukushim M nd Shirsk T (1978) Effect of urcil nd its derivtives on ntitumor ctivity of 5-fluorourcil nd 1-(2-tetrhydrofuryl)- 5-fluorourcil. Gnn (Jpn J Cncer Res) 69: Fujiwr T, Grim EA, Mukhopdhyy T, Zhng W, Own-Schub LB nd Roth JA (1994) Induction of chemosensitivity in humn lung cncer cells in vivo by denovirus-medited trnsfer of the wild-type p53 gene. Cncer Res 54: Gsprini G, Brbreschi M, Doglioni C, Plm PD, Mruri FA, Borcchi P, Bevilcqu P, Cffo O, Morelli L, Verderio P, Pezzell F nd Hrris AL (1995) Expression of bcl-2 protein predicts efficcy of djuvnt tretment in operble node-positive brest cncer. Clin Cncer Res 1: Holmgren L, O Reilly MS nd Folkmn J (1995) Dormncy of micrometstsis: blnced prolifertion nd poptosis in the presence of ngiogenesis suppression. Nture Med 1:

7 Apoptosis nd p53 sttus predict the efficcy of UFT 269 Ihde D, Bll D, Arrigd R, Bthelemy N, Benner S, Bonner J, Bureu G, Crino L, Deneffe G, Emmi B, Feld R, Joseph D, Pccgnell A, Rocmns P nd vn Houtte P (1994) Postopertive djuvnt therpy for non-smll cell lung cncer: consensus report. Lung Cncer 11s: Ikenk K, Shirsk T nd Kitno S (1979) Effect of urcil on metbolism of 5-fluorourcil in vitro. Gnn (Jpn J Cncer Res) 70: Kerr JF, Wyllie AH nd Currie AR (1972) Apoptosis: bsic biologicl phenomenon with wide-rnging impliction in tissue kinetics. Br J Cncer 26: Levine AJ, Monmnd J nd Finly CA (1991) The p53 tumor suppressor gene. Nture 351: Lokich J, Ahlgren JD, Gullo JJ, Philips JA nd Fryer JG (1989) A prospective rndomised comprison of continuous infusion fluorourcil with conventionl bolus schedule in metsttic colorectl crcinom: A mid-tlntic oncology progrm study. J Clin Oncol 7: Lowe SW, Schmitt EM, Smith SW, Osborne BA nd Jcks T (1993) p53 is required for rdition-induced poptosis in mouse thymocytes. Nture 362: Lowe SW, Bodis S, McCltchey A, Remington L, Ruley HE, Fisher DE, Housmn DE nd Jcks T (1994) p53 sttus nd the efficcy of cncer therpy. Science 266: Mountin CF (1997) Revisions in the interntionl system for stging lung cncer. Chest 116: Pstorino U, Andreol S, Tglibue E, Pezzell F, Incrbone M, Sozzi G, Buyse M, Menrd S, Pierotti M nd Rilke F (1997) Immunocytochemicl mrkers in stge I lung cncer: relevnce to prognosis. J Clin Oncol 15: Pzdur R, Lssere Y, Rhodes V, Ajni JA, Sugrmn SM, Ptt YZ, Jones Jr. DV, Mrkowitz AB, Abbruzzese JL, Bredy B nd Levin B (1994) Phse II tril of urcil nd tegfur plus orl leucovorin: effective orl regimen in the tretment of metsttic colorectl crcinom. J Clin Oncol 12: Pezzell F, Turley H, Kuzu I, Tungekr MF, Dunnill MS, Pierce CB, Hrris A, Gtter KC nd Mson DM (1993) Bcl-2 protein in non-smll cell lung crcinom. N Eng J Med 329: Pinedo HM nd Peter FJ (1988) Fluorourcil: biochemistry nd phrmcology. J Clin Oncol 6: Sen S nd D Inclci M (1992) Apoptosis. Biochemicl events nd relevnce to cncer chemotherpy. FEBS lett 307: Symonds H, Krll L, Remington L, Senz-Robles M, Lowe S, Jcks T nd Dyke TV (1994) p53-dependent poptosis suppresses tumor growth nd progression in vivo. Cell 78: Tnk F, Miyhr R, Ohtke Y, Yngihr K, Fukuse T, Hitomi S nd Wd H (1998) Advntge of postopertive orl dministrtion of UFT (Tegfur nd Urcil) for completely resected p-stge I-III non-smll cell lung cncer (NSCLC). Eur J Crdiothorc Surg 14: Tnk F, Miyhr R, Ohtke Y, Yngihr K, Fukuse T, Hitomi S nd Wd H (1998b) Lewis Y ntigen expression nd postopertive survivl in nonsmll cell lung cncer. Ann Thorc Surg 66: Tnk F, Yngihr K, Ohtke Y, Miyhr R, Kwno Y, Fukuse T, Hitomi S nd Wd H (1999) p53 sttus predicts the efficcy of postopertive orl dministrtion of tegfur for completely respected non-smll cell lung cncer. Jpn J Cncer Res 90: Tnk F, Kwno Y, Li M, Tkt T, Miyhr R, Yngihr K, Ohtke Y, Fukuse T nd Wd H (1999b) Prognostic significnce of poptotic index in completely resected non-smll cell lung cncer. J Clin Oncol 17: The Study Group of Adjuvnt Chemotherpy for Lung Cncer (Chubu, Jpn) (1995) A rndomised tril of postopertive djuvnt chemotherpy in non-smll cell lung cncer (the second coopertive study). Eur J Surg Oncol 21: Trvis WD, Colby TV, Corrin B, Shimosto Y nd Brmbill E (1999) World Helth Orgniztion Interntionl Histologicl Clssifiction of Tumors. Histologicl Typing of Lung nd Pleurl Tumors. Third edition. Springer: Berlin Wd H, Hitomi S, Termtsu T, West Jpn Study Group for Lung Cncer Surgery (1996) Adjuvnt chemotherpy fter complete resection in non-smll-cell lung cncer. J Clin Oncol 14: Wd H, Miyhr R, Tnk F nd Hitomi S (1999) Postopertive djuvnt chemotherpy with PVM (Cispltin + Vindesine + Mitomycin C) nd UFT (Urcil + Tegfur) in resected stge I II NSCLC (non-smll cell lung cncer): rndomized clinicl tril. West Jpn Study Group for lung cncer surgery (WJSG) Eur J Crdiothorc Surg 15:

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