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*[[ICRF-193]].<ref name="pmid17495539">{{cite journal |pages=1265–7 |doi=10.4161/cc.6.10.4225 |title=Chk1 is required for G2/M Checkpoint Response Induced by the Catalytic Topoisomerase II Inhibitor ICRF-193 |year=2007 |last1=Robinson |first1=Helen |last2=Bratlie-Thoresen |first2=Sigrid |last3=Brown |first3=Robert |last4=Gillespie |first4=David A.F. |journal=Cell Cycle |volume=6 |issue=10 |pmid=17495539}}</ref> 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.<ref name="Baird">{{cite journal |pages=27893–8 |doi=10.1074/jbc.M102544200 |title=The ATPase Reaction Cycle of Yeast DNA Topoisomerase II. SLOW RATES OF ATP RESYNTHESIS AND Pi RELEASE |year=2001 |last1=Baird |first1=C. L. |journal=Journal of Biological Chemistry |volume=276 |issue=30 |pmid=11353771 |last2=Gordon |first2=MS |last3=Andrenyak |first3=DM |last4=Marecek |first4=JF |last5=Lindsley |first5=JE}}</ref>
*[[ICRF-193]].<ref name="pmid17495539">{{cite journal |pages=1265–7 |doi=10.4161/cc.6.10.4225 |title=Chk1 is required for G2/M Checkpoint Response Induced by the Catalytic Topoisomerase II Inhibitor ICRF-193 |year=2007 |last1=Robinson |first1=Helen |last2=Bratlie-Thoresen |first2=Sigrid |last3=Brown |first3=Robert |last4=Gillespie |first4=David A.F. |journal=Cell Cycle |volume=6 |issue=10 |pmid=17495539}}</ref> 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.<ref name="Baird">{{cite journal |pages=27893–8 |doi=10.1074/jbc.M102544200 |title=The ATPase Reaction Cycle of Yeast DNA Topoisomerase II. SLOW RATES OF ATP RESYNTHESIS AND Pi RELEASE |year=2001 |last1=Baird |first1=C. L. |journal=Journal of Biological Chemistry |volume=276 |issue=30 |pmid=11353771 |last2=Gordon |first2=MS |last3=Andrenyak |first3=DM |last4=Marecek |first4=JF |last5=Lindsley |first5=JE}}</ref>
* [[genistein]].
* [[genistein]].

==[[Synthetic lethality]] with deficient ''[[Werner syndrome ATP-dependent helicase|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 ''[[Werner syndrome ATP-dependent helicase|WRN]]''.

The analysis of 630 human primary tumors in 11 tissues shows that [[DNA methylation|hypermethylation]] of the ''[[Werner syndrome ATP-dependent helicase|WRN]]'' CpG island promoter (with loss of expression of WRN protein) is a common event in tumorigenesis.<ref name=Agrelo>{{cite journal |vauthors=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 |title=Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=23 |pages=8822–7 |year=2006 |pmid=16723399 |pmc=1466544 |doi=10.1073/pnas.0600645103 |url=}}</ref> ''[[Werner syndrome ATP-dependent helicase|WRN]]'' is repressed in about 38% of [[colorectal cancer]]s and [[non-small-cell lung carcinoma]]s and in about 20% or so of [[stomach cancer]]s, [[prostate cancer]]s, [[breast cancer]]s, [[non-Hodgkin lymphoma]]s and [[chondrosarcoma]]s, plus at significant levels in the other cancers evaluated. The [[Werner syndrome ATP-dependent helicase|WRN]] protein helicase is important in [[homologous recombination]]al DNA repair and also has roles in [[non-homologous end joining]] DNA repair and [[base excision repair|base excision DNA repair]].<ref name="pmid20934517">{{cite journal |vauthors=Monnat RJ |title=Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology |journal=Semin. Cancer Biol. |volume=20 |issue=5 |pages=329–39 |year=2010 |pmid=20934517 |pmc=3040982 |doi=10.1016/j.semcancer.2010.10.002 |url=}}</ref>

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.<ref name=Agrelo /> 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.<ref name="pmid24359226">{{cite journal |vauthors=Wang L, Xie L, Wang J, Shen J, Liu B |title=Correlation between the methylation of SULF2 and WRN promoter and the irinotecan chemosensitivity in gastric cancer |journal=BMC Gastroenterol |volume=13 |issue= |pages=173 |year=2013 |pmid=24359226 |pmc=3877991 |doi=10.1186/1471-230X-13-173 |url=}}</ref><ref name="pmid21786128">{{cite journal |vauthors=Bird JL, Jennert-Burston KC, Bachler MA, Mason PA, Lowe JE, Heo SJ, Campisi J, Faragher RG, Cox LS |title=Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease |journal=Biogerontology |volume=13 |issue=1 |pages=49–62 |year=2012 |pmid=21786128 |doi=10.1007/s10522-011-9341-8 |url=}}</ref><ref name="pmid22797812">{{cite journal |vauthors=Masuda K, Banno K, Yanokura M, Tsuji K, Kobayashi Y, Kisu I, Ueki A, Yamagami W, Nomura H, Tominaga E, Susumu N, Aoki D |title=Association of epigenetic inactivation of the WRN gene with anticancer drug sensitivity in cervical cancer cells |journal=Oncol. Rep. |volume=28 |issue=4 |pages=1146–52 |year=2012 |pmid=22797812 |pmc=3583574 |doi=10.3892/or.2012.1912 |url=}}</ref><ref name="pmid17917271">{{cite journal |vauthors=Futami K, Takagi M, Shimamoto A, Sugimoto M, Furuichi Y |title=Increased chemotherapeutic activity of camptothecin in cancer cells by siRNA-induced silencing of WRN helicase |journal=Biol. Pharm. Bull. |volume=30 |issue=10 |pages=1958–61 |year=2007 |pmid=17917271 |doi= |url=}}</ref><ref name="pmid18312465">{{cite journal |vauthors=Futami K, Ishikawa Y, Goto M, Furuichi Y, Sugimoto M |title=Role of Werner syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells |journal=Cancer Sci. |volume=99 |issue=5 |pages=843–8 |year=2008 |pmid=18312465 |doi=10.1111/j.1349-7006.2008.00778.x |url=}}</ref>


==References==
==References==

Revision as of 19:08, 14 October 2016

Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes[1] (topoisomerase I and II), which are enzymes that control 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.

Classification

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

Numerous plant derived natural phenols (ex. EGCG,[6][7][8][9][10] 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.[11][12][13] 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.[14][15]

Compounds that target Type I topoisomerase

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. http://clinicaltrials.gov/ct2/show/NCT01051635

Compounds that target Type II topoisomerase

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 such fluoroquinolones as ciprofloxacin.

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

Interestingly, 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. The mechanism for this specificity is unknown, but drug-resistant mutants cluster in regions around the active site.

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.[16] 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.[17]
  • 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.[18] 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.[19]

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.[18] 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.[20][21][22][23][24]

References

  1. ^ [http://www.cancer.gov/dictionary?CdrID=46665[dead link] "Definition of topoisomerase inhibitor - NCI Dictionary of Cancer Terms"]. {{cite web}}: Check |url= value (help)
  2. ^ [http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/nine/14181948.htm[dead link] "Dorlands Medical Dictionary:topoisomerase inhibitor"]. {{cite web}}: Check |url= value (help)
  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, vol. 142, pp. 11–23, doi:10.1007/978-1-59745-246-5_2, ISBN 978-1-58829-915-4
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ a b 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.
  19. ^ 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.
  20. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ 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.
  22. ^ 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.
  23. ^ 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. PMID 17917271.
  24. ^ 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.

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  • 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.
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  • 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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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