;PMID: 9820175 ;source_file_1757.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..35] = [t:0..35] ;1)sentence:[e:41..132] = [t:41..132] ;2)section:[e:136..213] = [t:136..213] ;3)section:[e:217..319] = [t:217..319] ;4)sentence:[e:323..473] = [t:323..473] ;5)sentence:[e:474..556] = [t:474..556] ;6)sentence:[e:558..647] = [t:558..647] ;7)sentence:[e:648..838] = [t:648..838] ;8)sentence:[e:839..1036] = [t:839..1036] ;9)sentence:[e:1037..1094] = [t:1037..1094] ;10)sentence:[e:1095..1215] = [t:1095..1215] ;11)sentence:[e:1216..1380] = [t:1216..1380] ;12)sentence:[e:1381..1523] = [t:1381..1523] ;13)section:[e:1527..1571] = [t:1527..1571] ;section 0 Span:0..35 ;Br J Cancer. 1998 Nov;78(9):1170-4. (SEC (FRAG (NNP:[0..2] Br) (NNP:[3..4] J) (NNP:[5..11] Cancer) (.:[11..12] .) (CD:[13..17] 1998) (VBD:[18..24] Nov;78) (-LRB-:[24..25] -LRB-) (CD:[25..26] 9) (-RRB-:[26..27] -RRB-) (::[27..28] :) (CD:[28..32] 1170) (CD:[32..35] -4.))) ;sentence 1 Span:41..132 ;Potent and non-specific inhibition of cytochrome P450 by JM216, a new oral ;platinum agent. ;[79..94]:cyp450:"cytochrome P450" ;[98..103]:substance:"JM216" ;[117..131]:substance:"platinum agent" (SENT (NP-HLN (NP (ADJP (ADJP (JJ:[41..47] Potent)) (CC:[48..51] and) (ADJP (AFX:[52..55] non) (HYPH:[55..56] -) (JJ:[56..64] specific))) (NN:[65..75] inhibition)) (PP (IN:[76..78] of) (NP (NN:[79..89] cytochrome) (NN:[90..94] P450))) (PP (IN:[95..97] by) (NP (NP (NN:[98..103] JM216)) (,:[103..104] ,) (NP (DT:[105..106] a) (JJ:[107..110] new) (JJ:[111..115] oral) (NN:[117..125] platinum) (NN:[126..131] agent)))) (.:[131..132] .))) ;section 2 Span:136..213 ;Ando Y, Shimizu T, Nakamura K, Mushiroda T, Nakagawa T, Kodama T, Kamataki ;T. (SEC (FRAG (NNP:[136..140] Ando) (NNP:[141..142] Y) (,:[142..143] ,) (NNP:[144..151] Shimizu) (NNP:[152..153] T) (,:[153..154] ,) (NNP:[155..163] Nakamura) (NNP:[164..166] K,) (NNP:[167..176] Mushiroda) (NNP:[177..178] T) (,:[178..179] ,) (NNP:[180..188] Nakagawa) (NNP:[189..190] T) (,:[190..191] ,) (NNP:[192..198] Kodama) (NNP:[199..200] T) (,:[200..201] ,) (NNP:[202..210] Kamataki) (NNP:[211..213] T.))) ;section 3 Span:217..319 ;Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido ;University, Sapporo, Japan. (SEC (FRAG (NNP:[217..225] Division) (IN:[226..228] of) (NNP:[229..233] Drug) (NNP:[234..244] Metabolism) (,:[244..245] ,) (NNP:[246..253] Faculty) (IN:[254..256] of) (NNP:[257..271] Pharmaceutical) (NNPS:[272..280] Sciences) (,:[280..281] ,) (NNP:[282..290] Hokkaido) (NNP:[292..302] University) (,:[302..303] ,) (NNP:[304..311] Sapporo) (,:[311..312] ,) (NNP:[313..318] Japan) (.:[318..319] .))) ;sentence 4 Span:323..473 ;Bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV), JM216, is the ;first antineoplastic platinum compound that can be given to patients ;orally. ;[323..380]:substance:"Bis-acetato-ammine-dichloro-cyclohexylamine-platinum ;(IV)" ;[382..387]:substance:"JM216" ;[403..435]:substance:"antineoplastic platinum compound" (SENT (S (NP-SBJ (NP (NN:[323..375] Bis-acetato-ammine-dichloro-cyclohexylamine-platinum) (-LRB-:[376..377] -LRB-) (CD:[377..379] IV) (-RRB-:[379..380] -RRB-)) (,:[380..381] ,) (NP (NN:[382..387] JM216))) (,:[387..388] ,) (VP (VBZ:[389..391] is) (NP-PRD (NP (DT:[392..395] the) (JJ:[396..401] first) (JJ:[403..417] antineoplastic) (NN:[418..426] platinum) (NN:[427..435] compound)) (SBAR (WHNP-1 (WDT:[436..440] that)) (S (NP-SBJ-1 (-NONE-:[440..440] *T*)) (VP (MD:[441..444] can) (VP (VB:[445..447] be) (VP (VBN:[448..453] given) (NP-1 (-NONE-:[453..453] *)) (PP-DTV (TO:[454..456] to) (NP (NNS:[457..465] patients))) (ADVP-MNR (RB:[466..472] orally))))))))) (.:[472..473] .))) ;sentence 5 Span:474..556 ;Several phase II clinical trials of JM216 monotherapy have already been ;reported. ;[511..516]:substance:"JM216" (SENT (S (NP-SBJ-1 (NP (JJ:[474..481] Several) (NML (NN:[483..488] phase) (CD:[489..491] II)) (JJ:[492..500] clinical) (NNS:[501..507] trials)) (PP (IN:[508..510] of) (NP (NN:[511..516] JM216) (NN:[517..528] monotherapy)))) (VP (VBP:[529..533] have) (ADVP-TMP (RB:[534..541] already)) (VP (VBN:[542..546] been) (VP (VBN:[547..555] reported) (NP-1 (-NONE-:[555..555] *))))) (.:[555..556] .))) ;sentence 6 Span:558..647 ;However, no information on the potential drug interactions caused by JM216 is ; available. ;[599..603]:substance:"drug" ;[627..632]:substance:"JM216" (SENT (S (ADVP (RB:[558..565] However)) (,:[565..566] ,) (NP-SBJ (NP (DT:[567..569] no) (NN:[570..581] information)) (PP (IN:[582..584] on) (NP (NP (DT:[585..588] the) (JJ:[589..598] potential) (NN:[599..603] drug) (NNS:[604..616] interactions)) (VP (VBN:[617..623] caused) (NP (-NONE-:[623..623] *)) (PP (IN:[624..626] by) (NP-LGS (NN:[627..632] JM216))))))) (VP (VBZ:[633..635] is) (ADJP-PRD (JJ:[637..646] available))) (.:[646..647] .))) ;sentence 7 Span:648..838 ;In this study, the capacity of JM216 to inhibit cytochrome P450 (CYP) in ;human liver microsomes was investigated by measuring the inhibition potential ; (IC50 and Ki) on prototype reactions. ;[679..684]:substance:"JM216" ;[696..711]:cyp450:"cytochrome P450" ;[713..716]:cyp450:"CYP" ;[802..806]:quantitative-name:"IC50" ;[811..813]:quantitative-name:"Ki" (SENT (S (PP-LOC (IN:[648..650] In) (NP (DT:[651..655] this) (NN:[656..661] study))) (,:[661..662] ,) (NP-SBJ-1 (NP (DT:[663..666] the) (NN:[667..675] capacity) (S-3 (-NONE-:[675..675] *ICH*))) (PP (IN:[676..678] of) (NP (NN:[679..684] JM216))) (S-3 (NP-SBJ (-NONE-:[684..684] *)) (VP (TO:[685..687] to) (VP (VB:[688..695] inhibit) (NP (NP (NN:[696..706] cytochrome) (NN:[707..711] P450)) (NP (-LRB-:[712..713] -LRB-) (NN:[713..716] CYP) (-RRB-:[716..717] -RRB-))) (PP-LOC (IN:[719..721] in) (NP (JJ:[722..727] human) (NN:[728..733] liver) (NNS:[734..744] microsomes))))))) (VP (VBD:[745..748] was) (VP (VBN:[749..761] investigated) (NP-1 (-NONE-:[761..761] *)) (PP-MNR (IN:[762..764] by) (S-NOM (NP-SBJ (-NONE-:[764..764] *)) (VP (VBG:[765..774] measuring) (NP (NP (DT:[775..778] the) (NN:[779..789] inhibition) (NN:[790..799] potential)) (NP (-LRB-:[801..802] -LRB-) (NN:[802..806] IC50) (CC:[807..810] and) (NN:[811..813] Ki) (-RRB-:[813..814] -RRB-))) (PP (IN:[815..817] on) (NP (NN:[818..827] prototype) (NNS:[828..837] reactions)))))))) (.:[837..838] .))) ;sentence 8 Span:839..1036 ;Specific substrates of CYP included testosterone (catalysed by CYP3A4), ;paclitaxel (CYP2C8), 7-ethoxyresorufin (CYP1A1, CYP1A2), coumarin (CYP2A6), ;aniline (CYP2E1) and (+/-)-bufuralol (CYP2D6). ;[848..858]:substance:"substrates" ;[862..865]:cyp450:"CYP" ;[876..888]:substance:"testosterone" ;[903..909]:cyp450:"CYP3A4" ;[912..922]:substance:"paclitaxel" ;[924..930]:cyp450:"CYP2C8" ;[933..950]:substance:"7-ethoxyresorufin" ;[953..959]:cyp450:"CYP1A1" ;[961..967]:cyp450:"CYP1A2" ;[970..978]:substance:"coumarin" ;[980..986]:cyp450:"CYP2A6" ;[989..996]:substance:"aniline" ;[998..1004]:cyp450:"CYP2E1" ;[1010..1025]:substance:"(+/-)-bufuralol" ;[1028..1034]:cyp450:"CYP2D6" (SENT (S (NP-SBJ (NP (JJ:[839..847] Specific) (NNS:[848..858] substrates)) (PP (IN:[859..861] of) (NP (NN:[862..865] CYP)))) (VP (VBD:[866..874] included) (NP (NP (NN:[876..888] testosterone) (PRN (-LRB-:[889..890] -LRB-) (VP (VBN:[890..899] catalysed) (NP (-NONE-:[899..899] *)) (PP (IN:[900..902] by) (NP-LGS (NN:[903..909] CYP3A4)))) (-RRB-:[909..910] -RRB-))) (,:[910..911] ,) (NP (NN:[912..922] paclitaxel) (PRN (-LRB-:[923..924] -LRB-) (NP (NN:[924..930] CYP2C8)) (-RRB-:[930..931] -RRB-))) (,:[931..932] ,) (NP (NN:[933..950] 7-ethoxyresorufin) (PRN (-LRB-:[952..953] -LRB-) (NP (NN:[953..959] CYP1A1) (,:[959..960] ,) (NN:[961..967] CYP1A2)) (-RRB-:[967..968] -RRB-))) (,:[968..969] ,) (NP (NN:[970..978] coumarin) (PRN (-LRB-:[979..980] -LRB-) (NP (NN:[980..986] CYP2A6)) (-RRB-:[986..987] -RRB-))) (,:[987..988] ,) (NP (NN:[989..996] aniline) (PRN (-LRB-:[997..998] -LRB-) (NP (NN:[998..1004] CYP2E1)) (-RRB-:[1004..1005] -RRB-))) (CC:[1006..1009] and) (NP (NN:[1010..1025] -LRB-+/--RRB--bufuralol) (PRN (-LRB-:[1027..1028] -LRB-) (NP (NN:[1028..1034] CYP2D6)) (-RRB-:[1034..1035] -RRB-))))) (.:[1035..1036] .))) ;sentence 9 Span:1037..1094 ;JM216 inhibited the catalytic activities of CYP isozymes. ;[1037..1042]:substance:"JM216" ;[1081..1093]:cyp450:"CYP isozymes" (SENT (S (NP-SBJ (NN:[1037..1042] JM216)) (VP (VBD:[1043..1052] inhibited) (NP (NP (DT:[1053..1056] the) (JJ:[1057..1066] catalytic) (NNS:[1067..1077] activities)) (PP (IN:[1078..1080] of) (NP (NN:[1081..1084] CYP) (NNS:[1085..1093] isozymes))))) (.:[1093..1094] .))) ;sentence 10 Span:1095..1215 ;The IC50 values were between 0.3 microM and 10 microM, indicating strong and ;non-specific inhibitory effects of JM216. ;[1099..1103]:quantitative-name:"IC50" ;[1125..1128]:quantitative-value:"0.3" ;[1129..1135]:quantitative-units:"microM" ;[1140..1142]:quantitative-value:"10" ;[1143..1149]:quantitative-units:"microM" ;[1209..1214]:substance:"JM216" (SENT (S (NP-SBJ (DT:[1095..1098] The) (NN:[1099..1103] IC50) (NNS:[1105..1111] values)) (VP (VBD:[1112..1116] were) (PP-PRD (IN:[1117..1124] between) (NP (NP (CD:[1125..1128] 0.3) (NN:[1129..1135] microM)) (CC:[1136..1139] and) (NP (CD:[1140..1142] 10) (NN:[1143..1149] microM)))) (,:[1149..1150] ,) (S-ADV (NP-SBJ (-NONE-:[1150..1150] *)) (VP (VBG:[1151..1161] indicating) (NP (NP (ADJP (ADJP (JJ:[1162..1168] strong)) (CC:[1169..1172] and) (ADJP (AFX:[1173..1176] non) (HYPH:[1176..1177] -) (JJ:[1177..1185] specific))) (JJ:[1187..1197] inhibitory) (NNS:[1198..1205] effects)) (PP (IN:[1206..1208] of) (NP (NN:[1209..1214] JM216))))))) (.:[1214..1215] .))) ;sentence 11 Span:1216..1380 ;The inhibition occurred in a non-competitive manner, and the Ki value was ;1.0 and 0.9 microM for metabolite formation of testosterone and paclitaxel ;respectively. ;[1278..1280]:quantitative-name:"Ki" ;[1291..1294]:quantitative-value:"1.0" ;[1299..1302]:quantitative-value:"0.9" ;[1303..1309]:quantitative-units:"microM" ;[1314..1324]:substance:"metabolite" ;[1339..1351]:substance:"testosterone" ;[1356..1366]:substance:"paclitaxel" (SENT (S (S (NP-SBJ (DT:[1216..1219] The) (NN:[1220..1230] inhibition)) (VP (VBD:[1231..1239] occurred) (PP-MNR (IN:[1240..1242] in) (NP (DT:[1243..1244] a) (ADJP (AFX:[1245..1248] non) (HYPH:[1248..1249] -) (JJ:[1249..1260] competitive)) (NN:[1262..1268] manner))))) (,:[1268..1269] ,) (CC:[1270..1273] and) (S (NP-SBJ (DT:[1274..1277] the) (NN:[1278..1280] Ki) (NN:[1281..1286] value)) (VP (VBD:[1287..1290] was) (NP-PRD (NP (CD:[1291..1294] 1.0) (NML-1 (-NONE-:[1294..1294] *P*))) (CC:[1295..1298] and) (NP (CD:[1299..1302] 0.9) (NML-1 (NN:[1303..1309] microM)))) (PP (IN:[1310..1313] for) (NP (NP (NN:[1314..1324] metabolite) (NN:[1325..1334] formation)) (PP (IN:[1335..1337] of) (NP (NN:[1339..1351] testosterone) (CC:[1352..1355] and) (NN:[1356..1366] paclitaxel))))) (ADVP (RB:[1367..1379] respectively)))) (.:[1379..1380] .))) ;sentence 12 Span:1381..1523 ;Therefore, some in vivo studies should be conducted to determine whether or ;not there is a correlation between in vivo and in vitro results. (SENT (S (ADVP (RB:[1381..1390] Therefore)) (,:[1390..1391] ,) (NP-SBJ-2 (DT:[1392..1396] some) (ADJP (FW:[1397..1399] in) (FW:[1400..1404] vivo)) (NNS:[1405..1412] studies)) (VP (MD:[1413..1419] should) (VP (VB:[1421..1423] be) (VP (VBN:[1424..1433] conducted) (NP-2 (-NONE-:[1433..1433] *)) (S-PRP (NP-SBJ (-NONE-:[1433..1433] *)) (VP (TO:[1434..1436] to) (VP (VB:[1437..1446] determine) (SBAR (IN:[1447..1454] whether) (CC:[1455..1457] or) (RB:[1458..1461] not) (S (NP-SBJ (EX:[1462..1467] there)) (PP (VBZ:[1468..1470] is) (NP-PRD (NP (DT:[1471..1472] a) (NN:[1473..1484] correlation)) (PP (IN:[1485..1492] between) (NP (NP (ADJP (FW:[1493..1495] in) (FW:[1496..1500] vivo)) (NML-1 (-NONE-:[1500..1500] *P*))) (CC:[1502..1505] and) (NP (ADJP (FW:[1506..1508] in) (FW:[1509..1514] vitro)) (NML-1 (NNS:[1515..1522] results))))))))))))))) (.:[1522..1523] .))) ;section 13 Span:1527..1571 ;PMID: 9820175 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1527..1531] PMID) (::[1531..1532] :) (CD:[1533..1540] 9820175) (NN:[1541..1542] -LSB-) (NNP:[1542..1548] PubMed) (::[1549..1550] -) (NN:[1551..1558] indexed) (IN:[1559..1562] for) (NNP:[1563..1571] MEDLINE-RSB-)))