Topoisomerase inhibitor

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerase[1] (topoisomerase I and II), which is a type of enzyme that controls the changes in DNA structure[2] by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.

In recent years, topoisomerases have become popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently leads to apoptosis and cell death.

Topoisomerase inhibitors can also function as antibacterial agents.[3] Quinolones (including nalidixic acid and ciprofloxacin) have this function.[4] Quinolones bind to these enzymes and prevent them from decatenation replicating DNA.


Topoisomerase inhibitors are often divided according to which type of enzyme it inhibits.[5]

Numerous plant derived natural phenols (ex. EGCG,[7][8][9][10][11] genistein, quercetin, resveratrol) possess strong topoisomerase inhibitory properties affecting both types of enzymes. They may express function of phytoalexins - compounds produced by plants to combat vermin and pests.

Use of topoisomerase inhibitors for antineoplastic treatments may lead to secondary neoplasms because of DNA damaging properties of the compounds. Also plant derived polyphenols shows signs of carcinogenity, especially in fetuses and neonates who do not detoxify the compounds sufficiently.[12][13][14] An association between high intake of tea (containing polyphenols) during pregnancy and elevated risk of childhood malignant central nervous system (CNS) tumours has been found.[15][16]

Type I topoisomerase inhibitors

Human DNA topoisomerase I (Top1) is an essential enzyme that relaxes DNA supercoiling during replication and transcription. Top1 generates DNA single-strand breaks that allow rotation of the cleaved strand around the double helix axis. Top1 also religates the cleaved strand to reestablish intact duplex DNA. The Top1-DNA intermediates, known as cleavage complexes, are transient and at low levels under normal circumstances. However, treatment with Top1 inhibitors, such as the camptothecins, stabilize the cleavable complexes, prevent DNA religation and induce lethal DNA strand breaks. Cancer cells are selectively sensitive to the generation of these DNA lesions.

Top1 is a validated target for the treatment of human cancers. Camptothecins are among the most effective anticancer agents recently introduced into clinical practice. In this regard, the camptothecin derivative topotecan (Hycamtin) is approved by the U.S. FDA for the treatment of ovarian and lung cancer. Another camptothecin derivative irinotecan (CPT11) is approved for the treatment of colon cancer.

There are, however, certain clinical limitations of the camptothecin derivatives. These include: 1) spontaneous inactivation to a lactone form in blood, 2) rapid reversal of the trapped cleavable complex after drug removal, requiring prolonged infusions, 3) resistance of cancer cells overexpressing membrane transporters, and 4) dose-limiting side effects of diarrhea and neutropenia.

To circumvent these limitations, Dr. Mark Cushman at Purdue University and Dr. Yves Pommier at the National Cancer Institute developed the non-camptothecin family of indenoisoquinoline inhibitors of Top1. In contrast to the camptothecins, the indenoisoquinolines are: 1) chemically stable in blood, 2) inhibitors of Top1 cleavable complexes at distinct sites, 3) not substrates of membrane transporters, and 4) more effective as anti-tumor agents in animal models. The preclinical and IND package filed with the US Food and Drug Administration along with complete GMP production supporting the lead molecule are components of the published and non-published information covered by the license agreement with Purdue Research Foundation the National Cancer Center and Linus Oncology, Inc.

Linus Oncology has licensed the intellectual property that covers the development of these and related indenoisoquinoline derivatives. Phase I Study in Adults With Relapsed Solid Tumors and Lymphomas is ongoing (2012).

Indenoisoquinolines (green) form a ternary complexes of Top1 (brown) and DNA (blue) (Pommier et al.) and act as interfacial inhibitors.

There are several advantages of these novel non-camptothecin Top1 inhibitors as compared to the FDA-approved camptothecin analogs:

  • They are synthetic and chemically stable compounds
  • The Top1 cleavage sites trapped by the indenoisoquinolines have different genomic locations, implying differential targeting of cancer cell genomes
  • The Top1 cleavage complexes trapped by indenoisoquinolines are more stable, indicative of prolonged drug action
  • The indenoisoquinolines are seldom or not used as substrates for the multidrug resistance efflux pumps (ABCG2 and MDR-1)

Based on these highly favorable characteristics, two indenoisoquinoline derivatives (from a series of > 400 molecules), indotecan (LMP400; NSC 743400) and indimitecan (LMP776; NSC 725776) are presently under evaluation in a Phase I clinical trial being conducted at the National Cancer Institute for patients with relapsed solid tumors and lymphomas.[17]

Type II topoisomerase inhibitors

These inhibitors are split into two main classes: topoisomerase poisons, which target the topoisomerase-DNA complex, and topoisomerase inhibitors, which disrupt catalytic turnover.

Topo II poisons

Examples of topoisomerase poisons include the following:

  • eukaryotic type II topoisomerase inhibitors (topo II): amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin. These drugs are anti-cancer therapies.
  • bacterial type II topoisomerase inhibitors (gyrase and topo IV): fluoroquinolones. These are antibacterials and include fluoroquinolones such as ciprofloxacin.

Some of these poisons encourage the forward cleavage reaction (fluoroquinolones), while other poisons prevent the re-ligation of DNA (etoposide and teniposide).

Poisons of type IIA topoisomerases can target prokaryotic and eukaryotic enzymes preferentially, making them attractive drug candidates. Ciprofloxacin targets prokaryotes in excess of a thousandfold more than it targets eukaryotic topo IIs. Despite this, Ciprofloxacin is a potent dose-dependent type II poison, which is why it causes mass destruction of tissue cells.[18] This poor safety profile is one reason the FDA has advised fluoroquinolones only be used as a treatment of last resort.

Topo II inhibitors

These inhibitors target the N-terminal ATPase domain of topo II and prevent topo II from turning over.

Examples of topoisomerase inhibitors include :

  • ICRF-193.[19] The structure of this compound bound to the ATPase domain was solved by Classen (Proceedings of the National Academy of Sciences, 2004) showing that the drug binds in a non-competitive manner and locks down the dimerization of the ATPase domain.[20]
  • genistein.

Synthetic lethality with deficient WRN expression

Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in expression of only one of these genes does not. The deficiencies can arise through mutations, epigenetic alterations or inhibitors of the genes. Synthetic lethality with the topoisomerase inhibitor irinotecan appears to occur when given to cancer patients with deficient expression of the DNA repair gene WRN.

The analysis of 630 human primary tumors in 11 tissues shows that hypermethylation of the WRN CpG island promoter (with loss of expression of WRN protein) is a common event in tumorigenesis.[21] WRN is repressed in about 38% of colorectal cancers and non-small-cell lung carcinomas and in about 20% or so of stomach cancers, prostate cancers, breast cancers, non-Hodgkin lymphomas and chondrosarcomas, plus at significant levels in the other cancers evaluated. The WRN protein helicase is important in homologous recombinational DNA repair and also has roles in non-homologous end joining DNA repair and base excision DNA repair.[22]

A 2006 retrospective study, with long clinical follow-up, was made of colon cancer patients treated with the topoisomerase inhibitor irinotecan. In this study, 45 patients had hypermethylated WRN gene promoters and 43 patients had unmethylated WRN promoters.[21] Irinotecan was more strongly beneficial for patients with hypermethylated WRN promoters (39.4 months survival) than for those with unmethylated WRN promoters (20.7 months survival). Thus, a topoisomerase inhibitor appeared to be especially synthetically lethal with deficient WRN expression. Further evaluations have also indicated synthetic lethality of deficient expression of WRN and topoisomerase inhibitors.[23][24][25][26][27]


  1. "Definition of topoisomerase inhibitor - NCI Dictionary of Cancer Terms".
  2. "Dorlands Medical Dictionary:topoisomerase inhibitor".
  3. Mitscher, Lester A. (2005). "Bacterial Topoisomerase Inhibitors: Quinolone and Pyridone Antibacterial Agents". Chemical Reviews. 105 (2): 559–92. doi:10.1021/cr030101q. PMID 15700957.
  4. Fisher, L. Mark; Pan, Xiao-Su (2008), "Methods to Assay Inhibitors of DNA Gyrase and Topoisomerase IV Activities", New Antibiotic Targets, Methods In Molecular Medicine, 142, pp. 11–23, doi:10.1007/978-1-59745-246-5_2, ISBN 978-1-58829-915-4
  5. Vladimir, D'yakonov; Lilya, Dzhemileva; Usein, Dzhemilev (2017). "Advances in the Chemistry of Natural and Semisynthetic Topoisomerase I/II Inhibitors". Studies in Natural Products Chemistry. 54: 21-86. doi:10.1016/B978-0-444-63929-5.00002-4.
  6. Benchokroun, Y; Couprie, J; Larsen, AK (1995). "Aurintricarboxylic acid, a putative inhibitor of apoptosis, is a potent inhibitor of DNA topoisomerase II in vitro and in Chinese hamster fibrosarcoma cells". Biochemical Pharmacology. 49 (3): 305–13. doi:10.1016/0006-2952(94)00465-X. PMID 7857317.
  7. Neukam, Karin; Pastor, Nuria; Cortés, Felipe (2008). "Tea flavanols inhibit cell growth and DNA topoisomerase II activity and induce endoreduplication in cultured Chinese hamster cells". Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 654 (1): 8–12. doi:10.1016/j.mrgentox.2008.03.013. PMID 18541453.
  8. Berger, S; Gupta, S; Belfi, CA; Gosky, DM; Mukhtar, H (2001). "Green Tea Constituent (−)-Epigallocatechin-3-gallate Inhibits Topoisomerase I Activity in Human Colon Carcinoma Cells". Biochemical and Biophysical Research Communications. 288 (1): 101–5. doi:10.1006/bbrc.2001.5736. PMID 11594758.
  9. Suzuki, K; Yahara, S; Hashimoto, F; Uyeda, M (2001). "Inhibitory activities of (−)-epigallocatechin-3-O-gallate against topoisomerases I and II". Biological & Pharmaceutical Bulletin. 24 (9): 1088–90. doi:10.1248/bpb.24.1088. PMID 11558576.
  10. Bandele, Omari J.; Osheroff, Neil (2008). "(−)-Epigallocatechin Gallate, A Major Constituent of Green Tea, Poisons Human Type II Topoisomerases". Chemical Research in Toxicology. 21 (4): 936–43. doi:10.1021/tx700434v. PMC 2893035. PMID 18293940.
  11. Bandele, Omari J.; Osheroff, Neil (2007). "Bioflavonoids as Poisons of Human Topoisomerase IIα and IIβ". Biochemistry. 46 (20): 6097–108. doi:10.1021/bi7000664. PMC 2893030. PMID 17458941.
  12. Paolini, M; Sapone, A; Valgimigli, L (2003). "Avoidance of bioflavonoid supplements during pregnancy: a pathway to infant leukemia?". Mutation Research. 527 (1–2): 99–101. doi:10.1016/S0027-5107(03)00057-5. PMID 12787918.
  13. Strick, R.; Strissel, PL; Borgers, S; Smith, SL; Rowley, JD (2000). "Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia". Proceedings of the National Academy of Sciences. 97 (9): 4790–5. doi:10.1073/pnas.070061297. PMC 18311. PMID 10758153.
  14. Ross, JA (2000). "Dietary flavonoids and the MLL gene: A pathway to infant leukemia?". Proceedings of the National Academy of Sciences of the United States of America. 97 (9): 4411–3. doi:10.1073/pnas.97.9.4411. PMC 34309. PMID 10781030.
  15. Wang, R; Zhou, W; Jiang, X (2008). "Reaction kinetics of degradation and epimerization of epigallocatechin gallate (EGCG) in aqueous system over a wide temperature range". Journal of Agricultural and Food Chemistry. 56 (8): 2694–701. doi:10.1021/jf0730338. PMID 18361498.
  16. Plichart, Matthieu; Menegaux, Florence; Lacour, Brigitte; Hartmann, Olivier; Frappaz, Didier; Doz, François; Bertozzi, Anne-Isabelle; Defaschelles, Anne-Sophie; Pierre-Kahn, Alain (2008). "Parental smoking, maternal alcohol, coffee and tea consumption during pregnancy and childhood malignant central nervous system tumours: the ESCALE study (SFCE)". European Journal of Cancer Prevention. 17 (4): 376–83. doi:10.1097/CEJ.0b013e3282f75e6f. PMC 2746823. PMID 18562965.
  18. Mukherjee, A; Sen, S; Agarwal, K (1993). "Ciprofloxacin: Mammalian DNA topoisomerase type II poison in vivo". Mutation Research Letters. 301 (2): 87–92. doi:10.1016/0165-7992(93)90029-U. PMID 7678175.
  19. Robinson, Helen; Bratlie-Thoresen, Sigrid; Brown, Robert; Gillespie, David A.F. (2007). "Chk1 is required for G2/M Checkpoint Response Induced by the Catalytic Topoisomerase II Inhibitor ICRF-193". Cell Cycle. 6 (10): 1265–7. doi:10.4161/cc.6.10.4225. PMID 17495539.
  20. Baird, C. L.; Gordon, MS; Andrenyak, DM; Marecek, JF; Lindsley, JE (2001). "The ATPase Reaction Cycle of Yeast DNA Topoisomerase II. SLOW RATES OF ATP RESYNTHESIS AND Pi RELEASE". Journal of Biological Chemistry. 276 (30): 27893–8. doi:10.1074/jbc.M102544200. PMID 11353771.
  21. 1 2 Agrelo R, Cheng WH, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M (2006). "Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer". Proc. Natl. Acad. Sci. U.S.A. 103 (23): 8822–7. doi:10.1073/pnas.0600645103. PMC 1466544. PMID 16723399.
  22. Monnat RJ (2010). "Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology". Semin. Cancer Biol. 20 (5): 329–39. doi:10.1016/j.semcancer.2010.10.002. PMC 3040982. PMID 20934517.
  23. Wang L, Xie L, Wang J, Shen J, Liu B (2013). "Correlation between the methylation of SULF2 and WRN promoter and the irinotecan chemosensitivity in gastric cancer". BMC Gastroenterol. 13: 173. doi:10.1186/1471-230X-13-173. PMC 3877991. PMID 24359226.
  24. Bird JL, Jennert-Burston KC, Bachler MA, Mason PA, Lowe JE, Heo SJ, Campisi J, Faragher RG, Cox LS (2012). "Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease". Biogerontology. 13 (1): 49–62. doi:10.1007/s10522-011-9341-8. PMID 21786128.
  25. Masuda K, Banno K, Yanokura M, Tsuji K, Kobayashi Y, Kisu I, Ueki A, Yamagami W, Nomura H, Tominaga E, Susumu N, Aoki D (2012). "Association of epigenetic inactivation of the WRN gene with anticancer drug sensitivity in cervical cancer cells". Oncol. Rep. 28 (4): 1146–52. doi:10.3892/or.2012.1912. PMC 3583574. PMID 22797812.
  26. Futami K, Takagi M, Shimamoto A, Sugimoto M, Furuichi Y (2007). "Increased chemotherapeutic activity of camptothecin in cancer cells by siRNA-induced silencing of WRN helicase". Biol. Pharm. Bull. 30 (10): 1958–61. doi:10.1248/bpb.30.1958. PMID 17917271.
  27. Futami K, Ishikawa Y, Goto M, Furuichi Y, Sugimoto M (2008). "Role of Werner syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells". Cancer Sci. 99 (5): 843–8. doi:10.1111/j.1349-7006.2008.00778.x. PMID 18312465.


  • Antony S, Agama KK, Miao ZH, Takagi K, Wright MH, Robles AI, Varticovski L, Nagarajan M, Morrell A, Cushman M, Pommier Y (Nov 2007). "Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance". Cancer Res. 67 (21): 10397–405. doi:10.1158/0008-5472.can-07-0938. PMID 17974983. 
  • Antony S, Agama KK, Miao ZH, Hollingshead M, Holbeck SL, Wright MH, Varticovski L, Nagarajan M, Morrell A, Cushman M, Pommier Y (2006). "Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity". Mol. Pharmacol. 70: 1109–1120. doi:10.1124/mol.106.024372. 
  • Antony S, Kohlhagen G, Agama K, Jayaraman M, Cao S, Durrani FA, Rustum YM, Cushman M, Pommier Y (Feb 2005). "Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison". Mol. Pharmacol. 67 (2): 523–30. doi:10.1124/mol.104.003889. 
  • Antony S, Jayaraman M, Laco G, Kohlhagen G, Kohn KW, Cushman M, Pommier Y (Nov 2003). "Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I". Cancer Res. 63 (21): 7428–35. 
  • Bakshi RP, Sang D, Morrell A, Cushman M, Shapiro TA (Jan 2009). "Activity of indenoisoquinolines against African trypanosomes". Antimicrob. Agents Chemother. 53 (1): 123–8. doi:10.1128/aac.00650-07. PMC 2612167. 
  • Baxter J, Diffley JF (Jun 2008). "Topoisomerase II inactivation prevents the completion of DNA replication in budding yeast". Molecular Cell. 30 (6): 790–802. doi:10.1016/j.molcel.2008.04.019. 
  • Burgess DJ, Doles J, Zender L, Xue W, Ma B, McCombie WR, Hannon GJ, Lowe SW, Hemann MT (Jul 2008). "Topoisomerase levels determine chemotherapy response in vitro and in vivo". Proc. Natl. Acad. Sci. USA. 105 (26): 9053–8. doi:10.1073/pnas.0803513105. PMC 2435590. 
  • Cho WJ, Le QM, My Van HT, Youl Lee K, Kang BY, Lee ES, Lee SK, Kwon Y (Jul 2007). "Design, docking, and synthesis of novel indeno[1,2-c]isoquinolines for the development of antitumor agents as topoisomerase I inhibitors". Bioorg. Med. Chem. Lett. 17 (13): 3531–4. doi:10.1016/j.bmcl.2007.04.064. 
  • Cinelli MA, Cordero B, Dexheimer TS, Pommier Y, Cushman M (Oct 2009). "Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: investigating the hypothesis of shared structure-activity relationships". Bioorg. Med. Chem. 17 (20): 7145–55. doi:10.1016/j.bmc.2009.08.066. PMC 2769207. 
  • Cinelli MA, Morrell AE, Dexheimer TS, Agama K, Agrawal S, Pommier Y, Cushman M (Aug 2010). "The structure-activity relationships of A-ring-substituted aromathecin topoisomerase I inhibitors strongly support a camptothecin-like binding mode". Bioorg. Med. Chem. 18 (15): 5535–52. doi:10.1016/j.bmc.2010.06.040. PMC 2911012. 
  • Cinelli MA, Morrell A, Dexheimer TS, Scher ES, Pommier Y, Cushman C (Aug 2008). "Design, synthesis, and biological evaluation of 14-substituted aromathecins as Topoisomerase I inhibitors". J. Med. Chem. 51 (15): 4609–19. doi:10.1021/jm800259e. PMC 2538619. 
  • Cushman M, Jayaraman M, Vroman JA, Fukunaga AK, Fox BM, Kohlhagen G, Strumberg D, Pommier Y (Oct 2000). "Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors". J. Med. Chem. 43 (20): 3688–98. doi:10.1021/jm000029d. 
  • Holleran JL, Parise RA, Yellow-Duke AE, Egorin MJ, Eiseman JL, Covey JM, Beumer JH (Sep 2010). "Liquid chromatography-tandem mass spectrometric assay for the quantitation in human plasma of the novel indenoisoquinoline topoisomerase I inhibitors, NSC 743400 and NSC 725776". J. Pharm. Biomed. Anal. 52 (5): 714–20. doi:10.1016/j.jpba.2010.02.020. 
  • Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M (2005). "Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis". J. Med. Chem. 48: 4803–14. doi:10.1021/jm050076b. 
  • Kinders RJ, Hollingshead M, Lawrence S, Ji J, Tabb B, Bonner WM, Pommier Y, Rubinstein L, Evrard YA, Parchment RE, Tomaszewski J, Doroshow JH (Nov 2010). "Development of a validated immunofluorescence assay for yH2AX as a pharmacodynamic marker of topoisomerase I inhibitor activity". Clin. Cancer Res. 16 (22): 5447–57. doi:10.1158/1078-0432.ccr-09-3076. 
  • Kiselev E, Dexheimer TS, Pommier Y, Cushman M (Dec 2010). "Design, synthesis, and evaluation of dibenzo[c,h][1,6]naphthyridines as topoisomerase I inhibitors and potential anticancer agents". J. Med. Chem. 53 (24): 8716–26. doi:10.1021/jm101048k. 
  • Marchand C, Antony S, Kohn KW, Cushman M, Ioanoviciu A, Staker BL, Burgin AB, Stewart L, Pommier Y (Feb 2006). "A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trappingof topoisomerase I-DNA covalent complexes". Mol. Cancer Ther. 5 (2): 287–95. doi:10.1158/1535-7163.mct-05-0456. 
  • Morrell A, Placzek M, Parmley S, Grella B, Antony S, Pommier Y, Cushman M (Sep 2007). "Optimization of the indenone ring of indenoisoquinoline topoisomerase I inhibitors". J. Med. Chem. 50 (18): 4388–404. doi:10.1021/jm070307+. 
  • Morrell A, Placzek M, Parmley S, Antony S, Dexheimer TS, Pommier Y, Cushman M (Sep 2007). "Nitrated indenoisoquinolines as topoisomerase I inhibitors: a systematic study and optimization". J. Med. Chem. 50 (18): 4419–30. doi:10.1021/jm070361q. 
  • Morrell A, Jayaraman M, Nagarajan M, Fox BM, Meckley MR, Ioanoviciu A, Pommier Y, Antony S, Hollingshead M, Cushman M (Aug 2006). "Evaluation of indenoisoquinoline topoisomerase I inhibitors usinga hollow fiber assay". Bioorg. Med. Chem. Lett. 16 (16): 4395–9. doi:10.1016/j.bmcl.2006.05.048. 
  • Nagarajan M, Morrell A, Antony S, Kohlhagen G, Agama K, Pommier Y, Ragazzon PA, Garbett NC, Chaires JB, Hollingshead M, Cushman M (Aug 2006). "Synthesis and biological evaluation of bisindenoisoquinolines as topoisomerase I inhibitors". J. Med. Chem. 49 (17): 5129–40. doi:10.1021/jm060046o. 
  • Nagarajan M, Xiao X, Antony S, Kohlhagen G, Pommier Y, Cushman M (2003). "Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen". J. Med. Chem. 46: 5712–24. doi:10.1021/jm030313f. 
  • Pfister TD, Reinhold WC, Agama K, Gupta S, Khin SA, Kinders RJ, Parchment RE, Tomaszewski JE, Doroshow JH, Pommier Y (Jul 2009). "Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity". Mol. Cancer Ther. 8 (7): 1878–84. doi:10.1158/1535-7163.mct-09-0016. 
  • Pommier Y, Cushman M (May 2009). "The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives". Mol. Cancer Ther. 8 (5): 1008–14. doi:10.1158/1535-7163.mct-08-0706. 
  • Pommier Y, Leo E, Zhang H, Marchand C (May 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chem. Biol. 17 (5): 421–33. doi:10.1016/j.chembiol.2010.04.012. PMID 20534341. 
  • Pommier Y (Jul 2009). "DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition". Chem. Rev. 109 (7): 2894–902. doi:10.1021/cr900097c. 
  • Pommier Y (2006). "Topoisomerase I inhibitors: camptothecins and beyond". Nat. Rev. Cancer. 6: 789–802. doi:10.1038/nrc1977. 
  • Pommier Y (2004). "Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair and cell cycle checkpoints". Curr. Med. Chem. Anticancer Agents. 4: 429–34. doi:10.2174/1568011043352777. 
  • Song Y, Shao Z, Dexheimer TS, Scher ES, Pommier Y, Cushman M (Mar 2010). "Structure-based design, synthesis, and biological studies of new anticancer norindenoisoquinoline topoisomerase I inhibitors". J. Med. Chem. 53 (5): 1979–89. doi:10.1021/jm901649x. 
  • Sordet O, Goldman A, Redon C, Solier S, Rao VA, Pommier Y (Aug 2008). "Topoisomerase I requirement for death receptor-induced apoptotic nuclear fission". J. Biol. Chem. 283 (34): 23200–8. doi:10.1074/jbc.m801146200. PMC 2516995. PMID 18556653. 
  • Staker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin AB (Apr 2005). "Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex". J. Med. Chem. 48 (7): 2336–45. doi:10.1021/jm049146p. 
  • Teicher BA (2008). "Next generation topoisomerase I inhibitors: rationale and biomarker strategies". Biochem. Pharmacol. 75: 1262–71. doi:10.1016/j.bcp.2007.10.016. 
  • Seng CH, Chen YL, Lu PJ, Yang CN, Tzeng CC (2008). "Synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives". Bioorg. Med. Chem. 16: 3153–62. doi:10.1016/j.bmc.2007.12.028. 
  • Tuduri S, Crabbé L, Conti C, Tourrière H, Holtgreve-Grez H, Jauch A, Pantesco V, DeVos J, Thomas A, Theillet C, Pommier Y, Tazi J, Coquelle A, Pasero P (Nov 2009). "Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription". Nat. Cell Biol. 11 (11): 1315–24. doi:10.1038/ncb1984. 
  • Van HT, Le QM, Lee KY, Lee ES, Kwon Y, Kim TS, Le TN, Lee SH, Cho WJ. Convenient synthesis of indeno[1,2-c]isoquinolines as constrained forms of 3-arylisoquinolines and docking study of a topoisomerase I inhibitor into DNA-topoisomerase I complex. Bioorg Med Chem Lett. 2007 Nov;17(21):5763-7.
  • Nagarajan M.; Morrell A.; Ioanoviciu A.; Antony S.; Kohlhagen G.; Hollingshead M.; Pommier Y.; Cushman M. (2006). "Synthesis and Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Substituted with Nitrogen Heterocycles". J. Med. Chem. 49: 6283–6289. doi:10.1021/jm060564z. 
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