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'patient': [260, 1116], 'need': [261, 418, 1362, 1560], 'exacerbated': [263], 'costs,': [267], 'putting': [268], 'many': [269, 457, 470, 1087, 1172], 'treatments': [271, 291, 908, 991, 1599], 'out': [272], 'reach': [274], 'patients': [276, 1437, 1580, 1647, 2296], 'imposing': [278], 'strains': [279], 'local': [281], 'health': [282, 515, 1312], 'systems': [283, 1077], '[3].An': [284], 'alternative': [285], 'approach': [286], 'seeking': [288, 1597], 'not': [295, 410, 417, 556, 658, 771, 781, 1057, 1104, 1301, 1401, 1418, 1546, 1668, 2563], 'start': [297], 'targets': [300, 634, 2124], 'mind,': [302], 'but': [303, 439, 561, 654, 1066], 'assess': [305], 'those': [306, 576, 1733, 2628], '–': [308, 313, 682, 716, 909, 938, 1907, 1935], 'approved': [309], 'any': [311, 1709, 2604], 'indication': [312], 'existing': [316, 368, 907, 989, 1006, 1573, 1639, 1853, 2096, 2280], 'armamentarium': [317], 'which': [318, 701, 768], 'show': [319, 1449], 'some': [320, 1409], 'evidence': [321, 580, 712, 735, 758, 1160, 2499], 'anticancer': [323, 348, 714, 760, 883, 990], 'activity.': [324], 'This': [325, 381, 408, 475], 'field': [328], 'repurposing': [331, 463, 544, 1094, 1179, 1589, 2210, 2502], 'oncology': [333, 546, 628, 1594, 1678, 1933, 2101, 2573], 'there': [335, 1033, 1196, 1237, 1327, 1458, 1556], 'now': [337], 'an': [338, 602, 652, 787, 841, 882, 1021, 1035, 1198, 1298, 1484, 1522, 1558, 1910, 1938], 'increasing': [339], 'interest': [340, 1716, 2611], 'use': [343, 668, 2198, 2353], 'non-cancer': [345, 1591, 1640], 'therapeutics.There': [349], 'are': [350, 464, 471, 631, 657, 825, 1081, 1095, 1180, 1191, 1205, 1417, 1471, 1565, 1596, 1665, 1756, 1765, 2560], 'two': [351], 'main': [352, 696], 'advantages': [353], 'repurposing.': [355], 'Firstly,': [356], 'starting': [358], 'well-known': [360, 642], 'well-characterized': [362], 'we': [364, 572, 972, 1595, 1627, 1757, 1766], 'can': [365, 391, 1255, 1383, 1438], 'draw': [366], 'detailed': [370], 'knowledge': [371, 384], 'pharmacodynamics,': [373], 'pharmacokinetics,': [374], 'bioavailability,': [375], 'toxicities,': [376], 'established': [377, 1509], 'protocols': [378, 1049, 1129], 'dosing.': [380], 'body': [382], 'far': [386], 'excess': [388], 'what': [390, 1295], 'gained': [393], 'early': [395], 'phase': [396, 449], 'trials': [398, 831, 1155, 1348, 1366, 1393, 1407, 1416, 1508], 'particularly': [402], 'first': [404], 'class': [406], 'drugs.': [407, 1800, 1854], 'say': [412], 'repurposed': [414, 527, 851, 980, 984, 997, 1395, 1423, 2318], 'do': [416, 1103, 1397], 'Phase': [419, 1216, 1219, 1345, 2000], 'I': [420, 1217], 'trials,': [421, 1222], 'since': [422, 1468], 'they': [423, 535, 636, 898], 'may': [424, 573, 875, 879, 1012], 'used': [426, 645, 1001, 1014, 1482], 'schedules': [430], 'combinations': [432], 'differ': [434], 'from': [435, 491, 1732, 2627], 'their': [436, 1187], 'accepted': [437, 686], 'use,': [438], 'it': [440, 508, 684, 1465, 1645], 'does': [441], 'represent': [442], 'considerable': [444, 1206, 1248], 'short-circuiting': [445], 'preclinical': [448, 734], 'life': [454], 'cycle': [455], '[4].Secondly,': [456], 'candidate': [460, 541, 559, 609], 'available': [465, 472, 1135, 1193], 'at': [466, 583, 591, 762, 766, 1100, 1612], 'low': [467, 588, 592, 1038, 2155], 'cost;': [468], 'indeed': [469], 'generics.': [474], 'stark': [478], 'contrast': [479, 1041], 'very': [482], 'associated': [485, 774, 1666, 2355, 2561], 'newest': [488], 'emerging': [490], 'current': [492], 'pharmaceutical': [493, 1243], 'pipelines.': [494], 'While': [495], 'secondary': [499], 'concern': [500, 512], 'compared': [501], 'question': [504, 1480], 'efficacy,': [507], 'key': [511, 901, 935, 1330], 'stressed': [514], 'systems,': [516], 'insurers': [517, 1313], 'ultimately': [519], 'patients.': [520], 'It': [521, 967], 'suggests': [522], 'cost–utility': [525], 'calculations,': [526], 'would': [529], 'score': [530], 'highly': [532, 749], 'assuming': [533], 'demonstrate': [536], 'efficacy.The': [538], 'range': [539], 'actually': [548], 'extremely': [549], 'wide.': [550], 'In': [551, 1030, 1083, 1353, 1587], 'fact,': [552], 'difficulty': [554], 'find': [558], 'filter': [563], 'long': [565], 'list': [566], 'potential': [568, 615, 978, 1634, 2107, 2310], 'so': [570, 1367], 'focus': [574, 1055], 'efficacy': [582, 761, 1164, 1263], 'physiologically': [584], 'doses,': [586], 'toxicity': [589, 664, 1110], 'cost.': [593], 'Repurposing': [595, 1879, 1902, 1930, 2048, 2175, 2385], 'Drugs': [596, 1880, 1903, 2261], 'Oncology': [598, 1882, 1905, 2383], '(ReDO)': [599, 1883, 1906, 1934], 'Project': [600], 'international': [603], 'collaboration': [604], 'aiming': [605], 'identify': [607], 'highest': [613], 'bring': [618], 'them': [619, 1277], 'attention': [622], 'research': [625], 'communities': [629], '[5].Drugs': [630], 'considered': [632, 1257], 'high-potential': [633, 802, 863, 1121], 'if': [635, 1421, 1432], 'meet': [637, 1601], 'following': [639], 'criteria:•': [640], 'Are': [641], 'widely': [644, 784], 'clinically.': [646], 'Availability': [647], 'generic': [650], 'advantage,': [653], 'on-patent': [655], 'excluded;•': [659], 'Have': [660, 675], 'good': [661], 'toxicology.': [662], 'Low': [663], 'even': [665], 'long-term': [667], 'seen': [670], 'distinct': [673], 'advantage;•': [674], 'putative': [678, 870], 'mechanism': [679, 697], 'action': [681, 699], 'although': [683, 1400], 'sometimes': [688], 'have': [690, 865, 1545, 1628, 1700, 2595], 'off-target': [691], 'effects': [692, 1107], 'independent': [693], 'has': [704, 799, 848, 1340, 1357], 'been': [705, 850, 1341, 1358, 1547], 'developed;•': [706], 'Show': [707, 757], 'level': [710], 'activity': [715], 'vitro,': [718], 'vivo': [720, 755], 'human': [722], 'data.': [723], 'Human': [724, 1826], 'data': [725, 1134, 1455], 'particular': [727], 'scored': [729], 'significantly': [730], 'highly.': [732], 'For': [733, 896], 'results': [736, 1544], 'syngeneic,': [738], 'orthotopic': [739], 'transplantable': [740], 'models': [741], 'or': [742, 765, 878, 889, 915, 924, 1008, 1018, 1190, 1270, 1375, 1431, 1705, 1711, 1718, 1725, 1764, 2600, 2606, 2613, 2620], 'genetically': [743], 'engineered': [744], 'mice,': [745], 'rated': [747], 'than': [750], 'other': [751, 916, 1702, 2597], 'models;•': [756], 'standard': [763, 1051, 1488], 'dosing': [764, 767], 'known': [770, 1262], 'significant': [776], 'toxicity;•': [777], 'currently': [782], 'being': [783, 826, 1091, 1176], 'pursued': [785], 'active': [788], 'agent': [789], 'oncology.Examples': [791], 'ReDO': [797], 'project': [798], 'identified': [800, 1440], 'includes': [804], 'mebendazole': [805, 1908], '(anthelminthic)': [806], '[6],': [807], 'cimetidine': [808, 1502, 1514, 1936], '(H2-receptor': [809], 'antagonist)': [810], '[7],': [811], 'nitroglycerin': [812], '(vasodilator),': [813], 'diclofenac': [814], '(NSAID),': [815], 'itraconazole': [816], '(antifungal)': [817], 'clarithromycin': [819], '(antibiotic).': [820], 'Other': [821], 'noncancer': [822, 845], 'actively': [827], 'investigated': [828, 1092, 1177], 'include': [834], 'metformin,': [835], 'aspirin': [836], 'hydroxychloroquine.': [838], 'Thalidomide': [839], 'example': [842], 'successfully': [849], 'treatment': [854, 1099, 1563, 2034, 2203], 'multiple': [856], 'myeloma.It': [857], 'should': [858, 944, 1317], 'noted': [860], 'diverse': [866], 'initial': [867], 'indications': [868], 'mechanisms': [871, 917, 952], 'action.': [873, 1334], 'They': [874], 'cytotoxic': [877, 1060], 'instead': [880], 'exert': [881], 'effect': [884, 1061], 'acting': [886], 'one': [888], 'aspects': [891], 'microenvironment.': [895], 'example,': [897, 911, 940], 'might:•': [899], 'Disrupt': [900, 934], 'mediate': [904], 'resistance': [905], 'affecting': [912], 'efflux': [914], 'resistance;•': [919], 'Interfere': [920], 'neo-angiogenesis': [923], 'vascularization;•': [926], 'Stimulate': [927], 'host': [928], 'immunity': [929], 'and/or': [930], 'reverse': [931], 'cancer-associated': [932], 'immunosuppression;•': [933], 'proliferative': [936], 'disrupting': [941], 'microtubule': [942], 'dynamics.It': [943], 'apparent': [946], 'individually': [948], 'none': [949], 'likely': [954, 1447], 'sufficient': [957], 'attack': [959], 'multifaceted': [961], 'disease': [962], 'process': [963, 1211], 'cancer.': [966, 2038], 'imperative,': [969], 'therefore,': [970], 'think': [973], 'systemically': [974], 'when': [975, 1519], 'exploring': [976], 'consider': [983], 'combination': [987, 993, 1004, 1128, 2403], 'andin': [992], 'each': [995], 'other.Some': [996], 'might': [999], 'short-term': [1002], 'chemotherapies': [1007], 'therapies.': [1010], 'Others': [1011], 'chronic': [1017, 1098], 'continuous': [1019], 'dosing,': [1020], 'obvious': [1022, 1199], 'overlap': [1023], 'movement': [1026], 'towards': [1027, 1955], 'metronomic': [1028, 2157], 'chemotherapy.': [1029], 'case': [1032, 1496], 'emphasis': [1036], 'toxicity,': [1039], 'classical': [1044], 'dose-dense': [1045], 'Maximum': [1046], 'Tolerated': [1047], 'Dose': [1048], 'chemotherapy': [1052], '[8].': [1053], 'maximum': [1059], 'massive': [1063], 'kill,': [1065], 'altering': [1068], 'microenvironment': [1071], 'such': [1072, 1323, 1454], '‘life': [1075], 'support’': [1076], 'attacked.': [1082], 'common': [1084], 'metronomics,': [1086], 'suitable': [1096], 'doses': [1101], 'cause': [1105], 'adverse': [1106], 'consequent': [1109], 'negative': [1113], 'impact': [1114], 'quality': [1117], 'life.Identifying': [1119], 'summarizing': [1123], 'data,': [1125], 'identifying': [1126, 1847], 'probable': [1127], 'making': [1131, 1758], 'all': [1132], 'researchers': [1137], 'clinicians': [1139], 'relatively': [1141], 'straightforward.': [1142], 'However,': [1143, 1540], 'intractable': [1146], 'task': [1147], 'move': [1150], 'into': [1153, 1549], 'definitive': [1154], 'provide': [1157], 'necessary': [1159], 'safety': [1162], 'order': [1166], 'change': [1168], 'practice.Given': [1170], 'either': [1181], 'coming': [1182], 'end': [1185], 'patent': [1188], 'lifetime': [1189], 'already': [1192], 'generics,': [1195], 'issue': [1200, 1286], 'economic': [1202, 1240, 1299, 1651], 'incentives.': [1203], 'There': [1204], 'attached': [1208], 'taking': [1213], 'through': [1215], 'III': [1220, 1346, 2001], 'beyond': [1224], 'statutory': [1227], 'approval': [1228], 'adoption': [1230, 1267], 'practice.': [1233], 'Without': [1234], 'IP': [1235], 'protection,': [1236], 'no': [1239, 1701, 2596], 'incentive': [1241, 1274], 'make': [1246], 'process.': [1252], 'These': [1253], '‘financial': [1258], 'orphans,’': [1259], 'languish': [1265], 'without': [1266], 'agencies': [1269], 'take': [1276, 1398], 'market': [1279], '[9].': [1280], 'Clearly': [1281], 'social': [1285, 1653, 2528], 'utmost': [1289], 'importance': [1290, 2099], 'requiring': [1291], 'innovative': [1292], 'solutions': [1293], 'essentially': [1297], 'issue,': [1300], 'medical': [1303], 'one.': [1304], 'Collaborations': [1305], 'between': [1306], 'nonprofit': [1307], 'organizations,': [1308], 'governments,': [1309], 'agencies,': [1311], 'patients’': [1315], 'organizations': [1316, 1671, 2566], 'encouraged': [1319], 'lead': [1321, 1425], 'paradigm': [1325], 'shift.Finally,': [1326], 'exists': [1328], 'another': [1329], 'impediment': [1331], 'demands': [1333], 'trend': [1336, 1356], 'recent': [1338], 'years': [1339], 'ever': [1343], 'larger': [1344], 'agents.': [1352, 1414], 'part,': [1354], 'driven': [1359], 'adequately': [1364, 1390], 'power': [1365], 'often': [1370], 'incremental': [1371], 'improvements': [1372, 1428], 'progression-free': [1376], 'wrought': [1378], 'measured': [1385], '[10].': [1386], 'Well-designed,': [1387], 'well-run': [1388], 'powered': [1391], 'place,': [1399], 'scale': [1404], 'Large': [1415], 'necessarily': [1419], 'needed': [1420], 'drug(s)': [1424], 'substantial': [1427], 'outcomes': [1430, 2004], 'specific': [1434], 'population': [1435], 'whom': [1442], 'benefit.': [1451], 'Even': [1452], 'after': [1453], 'becomes': [1456], 'available,': [1457], 'will': [1459], 'challenge': [1462, 1569], '‘marketing’': [1464], 'practitioners,': [1467], 'commercial': [1469, 1494], 'entities': [1470], 'unlikely': [1472], 'get': [1474], 'involved,': [1475], 'unless': [1476], 'intervention': [1478, 2433], 'adjunct': [1485, 1523], 'care': [1490], 'carries': [1493], 'interest.A': [1495], 'point': [1498], 'H2RA': [1501], '(Tagamet).': [1503], 'A': [1504, 2267, 2362], 'number': [1505], 'peri-operative': [1511], 'postoperative': [1513], 'provided': [1515], 'benefit': [1518], 'given': [1520], 'curative': [1525], 'surgical': [1526], 'resection': [1527], 'colorectal': [1529, 2037], 'cancers,': [1530], 'finding': [1532], 'confirmed': [1533], 'subsequent': [1536], 'Cochrane': [1537, 2039], 'review': [1538, 2343], '[11].': [1539], 'date,': [1542], 'translated': [1548], 'practice,': [1551], 'fact': [1554], 'acknowledged': [1559], 'strategies.We': [1564], 'faced': [1566], 'meeting': [1571], 'future': [1575, 2077], 'needs': [1577, 1603], 'both': [1582, 1618], 'advanced': [1583, 2006], 'economies.': [1586], 'short': [1606], 'time-frame': [1608], 'possible': [1610], 'cost': [1614], 'affordable': [1617], 'developed': [1620], 'countries.': [1623], 'As': [1624], 'society': [1626], 'chance': [1630], 'mine': [1632], 'therapeutic': [1635], 'gold': [1636], 'supply.': [1642], 'We': [1643], 'owe': [1644], 'overcome': [1649], 'impediments': [1654], 'stand': [1656], 'path.Financial': [1659], 'competing': [1661, 2556], 'interests': [1662, 2557], 'disclosureThe': [1663, 2558], 'authors': [1664, 1699, 2559, 2594], 'profit': [1670, 2565], 'aim': [1673, 2568], 'repurpose': [1675, 2570], 'treatments.': [1679, 2574], 'VP': [1680, 2575], 'also': [1683, 2578], 'Scientific': [1686, 2581], 'Advisory': [1687, 2582], 'Boards': [1688, 2583], 'consultant': [1691, 2586], 'Berg': [1693, 2588], 'Pharma': [1694, 2589], 'Mitra': [1696, 2591], 'Biotech.': [1697, 2592], 'affiliations': [1704, 2599], 'financial': [1706, 1715, 1719, 2601, 2610, 2614], 'involvement': [1707, 2602], 'organization': [1710, 2605], 'entity': [1712, 2607], 'conflict': [1720, 2615], 'subject': [1723, 2618], 'matter': [1724, 2619], 'materials': [1726, 2621], 'discussed': [1727, 2622], 'manuscript': [1730, 2625], 'apart': [1731, 2626], 'disclosed.No': [1734, 2629], 'writing': [1735, 2630], 'assistance': [1736, 2631], 'was': [1737, 2632], 'utilized': [1738, 2633], 'production': [1741, 2636], 'manuscript.References1': [1744], 'Fojo': [1745], 'T,': [1746], 'Parkinson': [1747], 'DR.': [1748], 'Biologically': [1749], 'therapy': [1752, 2158], 'marginal': [1754], 'benefits:': [1755], 'too': [1759, 1762, 1768, 1772], 'much': [1760], 'little': [1763, 1769], 'achieving': [1767], 'giving': [1771], 'much?': [1773], 'Clin.': [1774, 1960, 2015], 'Cancer': [1775, 2055, 2062, 2068, 2141], 'Res.': [1776], '16(24),': [1777], '5972–5980': [1778], '(2010).Crossref,': [1779], 'Medline,': [1780, 1806, 1838, 1862, 1889, 1917, 1945, 1965, 2020], 'CAS,': [1781, 1807, 1863, 1966], 'Google': [1782, 1808, 1839, 1864, 1890, 1918, 1946, 1967, 2021], 'Scholar2': [1783], 'Hay': [1784], 'M,': [1785, 1951], 'Thomas': [1786], 'DW,': [1787], 'Craighead': [1788], 'JL,': [1789], 'Economides': [1790], 'C,': [1791], 'Rosenthal': [1792], 'J.': [1793, 2014], 'Clinical': [1794, 2115, 2130, 2188, 2226, 2270], 'success': [1796], 'rates': [1797], 'investigational': [1799], 'Nat.': [1801, 1855, 1958], 'Biotechnol.': [1802], '32(1),': [1803], '40–51': [1804], '(2014).Crossref,': [1805, 1888, 1916, 1944, 1964, 2019], 'Scholar3': [1809], 'Bray': [1810], 'F,': [1811], 'Jemal': [1812], 'A,': [1813, 1974], 'Grey': [1814], 'N,': [1815, 1949], 'Ferlay': [1816], 'J,': [1817], 'Forman': [1818], 'D.': [1819], 'Global': [1820], 'transitions': [1822], 'according': [1823], 'Development': [1827], 'Index': [1828], '(2008-2030):': [1829], 'population-based': [1831, 2364], 'study.': [1832], 'Lancet': [1833], 'Oncol..': [1834], '13(8),': [1835], '790–801': [1836], '(2012).Crossref,': [1837], 'Scholar4': [1840], 'Ashburn': [1841], 'TT,': [1842], 'Thor': [1843], 'KB.': [1844], 'Drug': [1845, 1857, 2174, 2232, 2271, 2320, 2484], 'repositioning:': [1846], 'uses': [1851], 'Rev.': [1856, 1959, 2042], 'Discov.': [1858], '3(8),': [1859], '673–683': [1860], '(2004).Crossref,': [1861], 'Scholar5': [1865], 'P,': [1867, 1893, 1921], 'G,': [1869, 1895, 1923], 'L,': [1871, 1897, 1925], 'V,': [1873, 1899, 1927], 'VP,': [1875, 1970], 'P.': [1877], 'Project.': [1884], 'Ecancermedicalscience': [1885, 1913, 1941], '8,': [1886, 1914, 1942, 2419], '442': [1887], 'Scholar6': [1891], 'VP.': [1901, 1929], 'anti-cancer': [1911, 1939], 'agent.': [1912, 1940], '443': [1915], 'Scholar7': [1919], '445': [1943], 'Scholar8': [1947], 'André': [1948], 'Carré': [1950], 'Pasquier': [1952], 'E.': [1953], 'Metronomics:': [1954], 'personalized': [1956], 'chemotherapy?': [1957], 'Oncol.': [1961, 2016], '11(7),': [1962], '413–431': [1963], 'Scholar9': [1968], 'Fang': [1971], 'K,': 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