0 15 Differentiation Differentiation NNP 16 18 of of IN 19 24 U-937 u-937 NN 25 37 promonocytic promonocytic JJ 38 43 cells cell NNS 44 46 by by IN 47 56 etoposide etoposide NN 57 60 and and CC 61 69 ICRF-193 ICRF-193 NNP 69 70 , , , 71 74 two two CD 75 85 antitumour antitumour JJ 86 89 DNA dna NN 90 103 topoisomerase topoisomerase NN 104 106 II ii CD 107 117 inhibitors inhibitor NNS 118 122 with with IN 123 132 different different JJ 133 143 mechanisms mechanism NNS 144 146 of of IN 147 153 action action NN 153 154 . . . 156 158 We we PRP 159 163 have have VBP 164 172 compared compare VBN 173 176 the the DT 177 183 action action NN 184 186 on on IN 187 192 U-937 u-937 NN 193 198 human human JJ 199 211 promonocytic promonocytic JJ 212 220 leukemia leukemia NN 221 226 cells cell NNS 227 229 of of IN 230 233 two two CD 234 237 DNA dna NN 238 251 topoisomerase topoisomerase NN 252 254 II ii CD 255 265 inhibitors inhibitor NNS 265 266 , , , 267 273 namely namely RB 274 277 the the DT 278 296 epipodophyllotoxin epipodophyllotoxin NN 297 306 etoposide etoposide NN 307 310 and and CC 311 314 the the DT 315 333 bisdioxopiperazine bisdioxopiperazine NN 334 342 ICRF-193 icrf-193 NN 342 343 . . . 344 347 One one CD 348 352 hour hour NN 353 368 pulse-treatment pulse-treatment NN 369 373 with with IN 374 375 3 3 CD 376 382 microM microm NN 383 392 etoposide etoposide NN 393 399 caused cause VBD 400 413 topoisomerase topoisomerase NN 414 424 associated associate VBN 424 425 , , , 426 433 primary primary JJ 434 437 DNA dna NN 438 446 breakage breakage NN 446 447 , , , 448 453 which which WDT 454 457 was be VBD 458 465 rapidly rapidly RB 466 474 followed follow VBN 475 477 by by IN 478 487 apoptosis apoptosis NN 487 488 . . . 489 491 By by IN 492 500 contrast contrast NN 500 501 , , , 502 507 these these DT 508 515 effects effect NNS 516 520 were be VBD 521 524 not not RB 525 533 observed observe VBN 534 538 upon upon IN 539 554 pulse-treatment pulse-treatment NN 555 559 with with IN 560 561 6 6 CD 562 568 microM microm NN 569 577 ICRF-193 icrf-193 NN 577 578 . . . 579 586 However however RB 586 587 , , , 588 598 continuous continuous JJ 599 609 treatments treatment NNS 610 614 with with IN 615 627 subcytotoxic subcytotoxic JJ 628 642 concentrations concentration NNS 643 645 of of IN 646 655 etoposide etoposide NN 656 657 ( ( ( 657 661 0.15 0.15 CD 662 668 microM microM NNP 668 669 ) ) ) 670 673 and and CC 674 682 ICRF-193 ICRF-193 NNP 683 684 ( ( ( 684 687 0.3 0.3 CD 688 694 microM microM NNP 694 695 ) ) ) 696 704 produced produce VBD 705 712 several several JJ 713 720 similar similar JJ 721 728 effects effect NNS 728 729 , , , 730 736 namely namely RB 737 746 decreased decrease VBD 747 751 cell cell NN 752 765 proliferation proliferation NN 765 766 , , , 767 779 accumulation accumulation NN 780 782 of of IN 783 788 cells cell NNS 789 791 at at IN 792 794 G2 g2 NN 794 795 , , , 796 804 increase increase NN 805 807 in in IN 808 812 cell cell NN 813 817 mass mass NN 817 818 , , , 819 822 and and CC 823 832 induction induction NN 833 835 of of IN 836 851 differentiation differentiation NN 851 852 . . . 853 858 Under under IN 859 864 these these DT 865 875 conditions condition NNS 875 876 , , , 877 886 etoposide etoposide NN 887 895 produced produce VBD 896 897 a a DT 898 906 biphasic biphasic JJ 907 917 activation activation NN 918 920 of of IN 921 928 protein protein NN 929 935 kinase kinase NNP 936 937 C C NNP 937 938 , , , 939 944 which which WDT 945 954 consisted consist VBD 955 957 in in IN 958 960 an an DT 961 966 early early JJ 967 976 transient transient JJ 977 987 activation activation NN 988 989 ( ( ( 989 993 from from IN 994 999 hours hour NNS 1000 1001 1 1 CD 1002 1004 to to TO 1005 1006 6 6 CD 1006 1007 ) ) ) 1008 1010 of of IN 1011 1014 the the DT 1015 1029 membrane-bound membrane-bound JJ 1030 1036 enzyme enzyme NN 1037 1045 followed follow VBN 1046 1048 by by IN 1049 1050 a a DT 1051 1056 later later JJ 1057 1067 activation activation NN 1068 1069 ( ( ( 1069 1073 hour hour NN 1074 1076 48 48 CD 1076 1077 ) ) ) 1078 1080 of of IN 1081 1084 the the DT 1085 1090 total total JJ 1090 1091 , , , 1092 1106 membrane-bound membrane-bound JJ 1107 1110 and and CC 1111 1120 cytosolic cytosolic JJ 1121 1127 enzyme enzyme NN 1127 1128 . . . 1129 1131 By by IN 1132 1140 contrast contrast NN 1140 1141 , , , 1142 1150 ICRF-193 ICRF-193 NNP 1151 1155 only only RB 1156 1164 provoked provoke VBD 1165 1166 a a DT 1167 1171 late late JJ 1172 1182 activation activation NN 1183 1184 ( ( ( 1184 1188 from from IN 1189 1194 hours hour NNS 1195 1197 72 72 CD 1198 1200 to to TO 1201 1203 96 96 CD 1203 1204 ) ) ) 1205 1207 of of IN 1208 1211 the the DT 1212 1217 total total JJ 1218 1224 enzyme enzyme NN 1224 1225 . . . 1226 1230 When when WRB 1231 1235 used use VBN 1236 1238 at at IN 1239 1263 differentiation-inducing differentiation-inducing JJ 1264 1278 concentrations concentration NNS 1278 1279 , , , 1280 1284 both both DT 1285 1298 topoisomerase topoisomerase NN 1299 1309 inhibitors inhibitor NNS 1310 1316 caused cause VBD 1317 1318 a a DT 1319 1324 great great JJ 1325 1336 stimulation stimulation NN 1337 1339 of of IN 1340 1344 AP-1 ap-1 NN 1345 1352 binding binding NN 1353 1361 activity activity NN 1361 1362 , , , 1363 1367 with with IN 1368 1375 maximum maximum JJ 1376 1381 value value NN 1382 1384 at at IN 1385 1389 hour hour NN 1390 1392 12 12 CD 1393 1395 in in IN 1396 1413 etoposide-treated etoposide-treated JJ 1414 1419 cells cell NNS 1420 1423 and and CC 1424 1426 at at IN 1427 1431 hour hour NN 1432 1434 48 48 CD 1435 1437 in in IN 1438 1454 ICRF-193-treated icrf-193-treated JJ 1455 1460 cells cell NNS 1460 1461 . . . 1462 1464 By by IN 1465 1473 contrast contrast NN 1473 1474 , , , 1475 1478 the the DT 1479 1486 binding binding NN 1487 1495 activity activity NN 1496 1498 of of IN 1499 1502 the the DT 1503 1514 NF-kappa(B) nf-kappa(b) NN 1515 1518 and and CC 1519 1524 EGR-1 egr-1 NN 1525 1538 transcription transcription NN 1539 1546 factors factor NNS 1547 1550 was be VBD 1551 1557 little little RB 1558 1566 affected affect VBN 1566 1567 . . . 1568 1570 It it PRP 1571 1573 is be VBZ 1574 1583 concluded conclude VBN 1584 1588 that that IN 1589 1602 topoisomerase topoisomerase NN 1603 1605 II ii CD 1606 1616 inhibitors inhibitor NNS 1617 1620 may may MD 1621 1627 induce induce VB 1628 1631 the the DT 1632 1647 differentiation differentiation NN 1648 1650 of of IN 1651 1663 promonocytic promonocytic JJ 1664 1669 cells cell NNS 1669 1670 , , , 1671 1684 independently independently RB 1685 1687 of of IN 1688 1693 their their PRP$ 1694 1702 capacity capacity NN 1703 1705 to to TO 1706 1711 cause cause VB 1712 1715 DNA DNA NNP 1716 1722 strand strand NN 1723 1729 breaks break NNS 1729 1730 . . . 1731 1738 However however RB 1738 1739 , , , 1740 1745 there there EX 1746 1749 are be VBP 1750 1755 other other JJ 1756 1763 effects effect NNS 1763 1764 , , , 1765 1769 such such JJ 1770 1772 as as IN 1773 1776 the the DT 1777 1782 early early JJ 1783 1793 activation activation NN 1794 1796 of of IN 1797 1804 protein protein NN 1805 1811 kinase kinase NNP 1812 1813 C C NNP 1813 1814 , , , 1815 1820 which which WDT 1821 1824 are be VBP 1825 1833 probably probably RB 1834 1841 derived derive VBN 1842 1846 from from IN 1847 1850 the the DT 1851 1861 production production NN 1862 1864 of of IN 1865 1872 primary primary JJ 1873 1876 DNA dna NN 1877 1885 breakage breakage NN 1886 1888 by by IN 1889 1893 some some DT 1894 1912 anti-topoisomerase anti-topoisomerase JJ 1913 1918 drugs drug NNS 1918 1919 . . .