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Topoisomerase I Inhibitors: Chemical Biology

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DNA Topoisomerases and Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Topoisomerase I (Top1), an essential enzyme, produces a DNA single-strand break allowing DNA relaxation for replication. The enzymatic mechanism involves sequential transesterifications and the reaction is freely reversible. The Top1 reaction intermediate consists of enzyme covalently linked to DNA, thus a “cleavable complex”. Covalently bound Top1-DNA complexes can be recovered. Camptothecin analogs, topotecan and irinotecan, are approved Top1-targeted drugs. Gimatecan is a seven-position modified lipophilic camptothecin developed to provide rapid uptake and accumulation in cells and a stable Top1-DNA-drug ternary complex. Homocamptothecin replaces the metabolically labile camptothecin lactone with a more stable seven-membered β-hydroxylactone. Five-membered keto-analogs contract the lactone ring by removal of the oxygen to stabilize that region of the camptothecin structure. Non-camptothecins include edotecarin, an indolocarbazole that results in DNA C/T-G cleavage compared with T-G/A for camptothecins. Indenoisoquinolines identified as Top1 inhibitors by the “NCI 60-cell line COMPARE” analysis are in clinical development. Dibenzonaphthyridinone Top1 inhibitors have undergone extensive structure-activity examination and have entered Phase I clinical trial. Biomarkers are under investigation to predict clinical efficacy, to allow determination of drug targeting in vivo and to aid selection of patients most likely to benefit from Top1 inhibitor therapy. The goal of these efforts is clinically effective second generation Top1 inhibitors.

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References

  • Adams DJ, Dewhirst MW, Flowers JL, Gamcsik MP, Colvin OM, Manikumar G, Wani MC, Wall ME (2000) Camptothecin analogs with enhanced antitumor activity at acidic pH. Cancer Chemother Pharmacol 46:263–271

    CAS  PubMed  Google Scholar 

  • Ahmed F, Vyas V, Cornfield A et al (1999) In vitro activation of irinotecan to SN-38 by human liver and intestine. Anticancer Res 19:2067–2071

    CAS  PubMed  Google Scholar 

  • Anguiano A, Nevins JR, Potti A (2008) Towards the individualization of lung cancer therapy. Cancer 113:1760–1767

    PubMed  Google Scholar 

  • 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) (NSC727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity. Mol Pharmacol 70:1109–1120

    CAS  PubMed  Google Scholar 

  • Bates SE, Medina-Perez WY, Kohlhagen G, Antony S, Nadjem T, Robey RW, Pommier Y (2004) ABCG2 mediates differential resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and homocamptothecins. J Pharmacol Exp Therap 310:836–842

    CAS  Google Scholar 

  • Beidler DR, Cheng YC (1995) Camptothecin induction of a time- and concentration-dependent decrease of topoisomerase I and its implication in camptothecin activity. Mol Pharmacol 47:907–914

    CAS  PubMed  Google Scholar 

  • Beretta GL, Perego P, Zunino F (2006) Mechanisms of cellular resistance to camptothecins. Curr Med Chem 13:3291–3305

    CAS  PubMed  Google Scholar 

  • Boni C, Gamucci T, Bonetti A, Bisagni G, Dallo E, Zanna C, Marsoni S, Sessa C, Ospedaliera A, Maria Nuova S, Emilia R (2004) A phase II study of the novel oral camptothecin SR1481 in pretreated metastatic colorectal cancer (CRC). J Clin Oncol 22 suppl:abstr 3684

    Google Scholar 

  • Brill SJ, DiNardo S, Voelkel-Meiman K, Sternglanz R (1987) Need for DNA topoisomerase activity as a swivel for DNA replication for transcription of ribosomal RNA. Nature 326:414–416

    Google Scholar 

  • Bullock P, Champoux JJ, Botchan M (1985) Association of crossover points with topoisomerase I cleavage sites: A model for non-homologous recombination. Science 230:954–958

    CAS  PubMed  Google Scholar 

  • Cavazos CM, Keir ST, Yoshinari T, Bigner DD, Friedman HS (2001) Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyla-2-hydroxy)ethylamino-12,13-dihydro-13-(b-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole-5,7(6H)-dione] against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 48:250–254

    CAS  PubMed  Google Scholar 

  • Champoux JJ (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70:369–413

    CAS  PubMed  Google Scholar 

  • Chu X, Kato Y, Sugiyama Y (1997) Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rates. Cancer Res 57:1934–1938

    CAS  PubMed  Google Scholar 

  • Ciomei M, Croci V, Ciavolella A, Ballinari D, Pesenti E (2006) Antitumor efficacy of edotecarin as a single agent and in combination with chemotherapy agents in a xenograft model. Clin Cancer Res 12:2856–2861

    CAS  PubMed  Google Scholar 

  • Ciomei M, Croci V, Stellari F, Amboldi N, Giavarini R, Pesenti E (2007) Antitumor activity of edotecarin in breast carcinoma models. Cancer Chemother Pharmacol 60:229–235

    CAS  PubMed  Google Scholar 

  • Ciotti M, Basu N, Brangi M, Owens IS (1999) Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38) by human UDP-glucuronosyltransferases encoded at the UGT1 locus. Biochem Biophys Res Commun 260:199–202

    CAS  PubMed  Google Scholar 

  • Coleman LW, Rohr LR, Bronstein IB, Holden JA (2002) Human DNA topoisomerase I: an anticancer drug target present in human sarcomas. Hum Pathol 33:599–607

    CAS  PubMed  Google Scholar 

  • Cummings J, Boyd G, Ethell BT et al (2002) Enhanced clearance of topoisomerase I inhibitors from human colon cancer cells by glucuronidation. Biochem Pharmacol 63:607–613

    CAS  PubMed  Google Scholar 

  • D’Arpa P, Beardmore C, Liu LF (1990) Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res 50:6919–6924

    PubMed  Google Scholar 

  • Dean FB, Bullock P, Murakami Y, Wobbe CR, Weissback L, Hurwitz J (1987) Simian virus 40 (SC40) DNA replication: SV40 large T antigen unwinds DNA containing the SV40 origin of replication. Proc Natl Acad Sci USA 84:16–20

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dean FB, Borowiec JA, Ishimi Y, Deb S, Tegtmyer P, Hurwitz J (1987) Simian virus 40 large tumor antigen requires three core replication origin domains for DNA unwinding and replication in vivo. Proc Natl Acad Sci USA 84:8267–8271

    PubMed Central  CAS  PubMed  Google Scholar 

  • De Cesare M, Pratesi G, Veneroni S, Bergottini R, Zunino F (2004) Efficacy of the novel camptothecin gimatecan against orthotopic and metastatic human tumor xenograft models. Clin Cancer Res 10:7357–7364

    PubMed  Google Scholar 

  • De Cesare M, Pratesi G, Perego P, Carnini N, TTinelli S, Merlini L, Penco S, Pisano C, Bucci F, Vesci L, Pace S, Capocasa F, Carminati P, Zunino F (2001) Potent antitumor activity and improved pharmacological profile of ST1481, a novel 7-substituted camptothecin. Cancer Res 61:7189–7195

    Google Scholar 

  • Di Francesco AM, Riccardi AS, Barone G, Rutella S, Meco D, Frapolli R, Zucchetti M, D’Incalci M, Pisano C, Carminati P, Riccardi R (2005) The novel lipophilic camptothecin analogue gimatecan is very active in vitro in human neuroblastoma: a comparative study with SN38 and topotecan. Biochem Pharm 70:1125–1136

    PubMed  Google Scholar 

  • Demarquay D, Huchet M, Coulomb H, Lesueur-Ginot L, Lavergne O, Kasprzyk PG, Bailly C, Camara J, Bigg DCH (2001) The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison. Anti-Cancer Drugs 12:9–19

    CAS  PubMed  Google Scholar 

  • Demarquay D, Huchet M, Coulomb H, Lesueur-Ginot L, Lavergne O, Camara J, Kasprzyk PG, Prevost G, Bigg DCH (2004) BN80927: a novel homocamptothecin that inhibits proliferation of human cells in vitro and in vivo. Cancer Res 64:4942–4949

    CAS  PubMed  Google Scholar 

  • Desai SD, Zhang H, Rodriguez-Bauman A, Yang JM, Wu X, Gounder MK, Rubin EH, Liu LF (2003) Transcription-dependent degradation of topoisomerase I-DNA covalent complexes. Mol Cell Biol 23:2341–2350

    PubMed Central  CAS  PubMed  Google Scholar 

  • Desai SD, Liu LF, Vazquez-Abad D, D’Arpa P (1997) Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem 272:24159–24164

    CAS  PubMed  Google Scholar 

  • Desai SD, Li TK, Rodriguez-Bauman A, Rubin EH, Liu LF (2001) Ubiquitin-26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. Cancer Res 61:5926–5932

    CAS  PubMed  Google Scholar 

  • Drlica K, Franco RJ (1988) Inhibitors of DNA topoisomerases. Biochem 27:2252–2259

    Google Scholar 

  • DeWys WD, Humphreys SR, Goldin A (1968) Studies on the therapeutic effectiveness of drugs with tumor weight and survival time indices of Walker 256 carcinosarcoma. Cancer Chemo Rep 52:229–242

    CAS  Google Scholar 

  • Dexheimer TS, Pommier Y (2008) DNA cleavage assay for the identification of topoisomerase I inhibitors. Nature Protocols 3: 1736–1750

    CAS  PubMed  Google Scholar 

  • Erickson-Miller C (1997) Differential toxicity of Camptothecin, Topotecan and 9-Aminocamptothecin to Human, Canine, and Murine Myeloid Progenitors (CFU-GM) In Vitro. Cancer Chemother Pharmacol 1997; 39:467–472

    CAS  PubMed  Google Scholar 

  • Feng W, Satyanarayana M, Tsai YC, Liu AA, Liu LF, LaVoie EJ (2008) Facile formation of hydrophilic derivatives of 5H-8,9-dimethoxy-5-[2-(N,N-dimethylamino)ethyl]-2,3-methylene-dioxydibenzo[c,h][1,6]naphthyridin-6-one (ARC-111) and its 12-aza analog via quaternary ammonium intermediates. Bioorg Med Chem Lett 18:3570–3572

    Google Scholar 

  • Feng W, Satyanarayana M, Tsai YC, Liu AA, Liu LF, LaVoie EJ (2008) 11-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine derivatives as novel topoisomerase I-targeting agents. Bioorg Med Chem 16:8598–8606

    PubMed Central  CAS  PubMed  Google Scholar 

  • Feng W, Satyanarayana M, Cheng L, Liu AA, Tsai YC, Liu LF, LaVoie EJ (2008) Synthesis of N-substituted 5-[2-(N-alkylamino)ethyl]dibenzo[c,h][1,6]-naphthyridines as novel topoisomerase I-targeting antitumor agents. Bioorg Med Chem 16:9295–9301

    Google Scholar 

  • Feng W, Satyanarayana M, Tsai YC, Liu AA, Liu LF, LaVoie EJ (2009) 12-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridines as novel topoisomerase I-targeting antitumor agents. Bioorg Med Chem 17:2877–2885

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gallo RC, Whang-Peng J, Adamson RH (1971) Studies on the antitumor activity, mechanism of action, and cell cycle effects of camptothecin. J Natl Cancer Inst 46:789–795

    CAS  PubMed  Google Scholar 

  • Garg LC, DiAngelo S, Jacob ST (1987) Role of DNA Topoisomerase I in the transcription of supercoiled rRNA gene. Proc Natl Acad Sci USA 84: 3185–3188

    PubMed Central  CAS  PubMed  Google Scholar 

  • Giles I, Sharma RP (2005) Topoisomerase enzymes as therapeutic targets for cancer chemotherapy. Med Chem 1:383–394

    CAS  PubMed  Google Scholar 

  • Giovanella BC, Stehlin JS, Wall ME, Wani MC, Nicholas AW, Liu LF et al (1989) DNA topoisomerase I-targeted chemotherapy of human colon cancer xenografts. Science 246:1046–1048

    CAS  PubMed  Google Scholar 

  • Glaze E, Harder JB, McCormick D, Johnson W, Detrisac C, Pommier Y, Tomaszewski J (2009) Five-day intravenous toxicity study of indenoisoquinoline analogues in dogs. Proc Am Assoc Cancer Res 50: Abstr 2933

    Google Scholar 

  • Goto T, Wang JC (1985) Cloning of yeast TOP1, the gene encoding DNA topoisomerase I, and construction of mutants defective in both DNA topoisomerase I and topoisomerase II. Proc Natl Acad Sci USA 82:7178–7182

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gottlieb JA, Guarino AM, Call JB, Oliverio VT, Block JB (1970) Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC 100880). Cancer Chemo Rep 54:461–470

    CAS  Google Scholar 

  • Guo W, Miao Z, Sheng C, Yao J, Feng H, Zhang W, Zhu L, Liu W, Cheng P, Zhang J, Che X, Wang W, Luo C, Xu Y (2010) Synthesis and evaluation of 9-benzylideneamino derivatives of homocamptothecin as potent inhibitors of DNA topoisomerase I. Europ J Med Chem 45: 2223–2228

    CAS  Google Scholar 

  • Halligan BD, Davis JL, Edwards KA, Liu LF(1982) Intra-and inter-molecular strand transfer by HeLa DNA topoisomerase I. J Biol Chem 257:3995–4000

    CAS  PubMed  Google Scholar 

  • Hanioka N, Ozawa S, Jinno H, Ando M, Saito Y, Sawada J (2001) Human liver UDP-glucuro-nosyltransferase isoforms involved in the glucuronidation of 7-ethyl-10-hydroxycamptothecin. Xenobiotica 31:687–699

    Google Scholar 

  • Hautefaye P, Cimetiere B, Pierre A, Leonce S, Hickman J, Laine W, Bailly C, Lavielle G (2003) Synthesis and pharmacological evaluation of novel non-lactone analogues of camptothecin. Bioorg Med Chem Lett 13: 2731– 2735

    CAS  PubMed  Google Scholar 

  • Hertzberg RP, Caranfa MJ, Holden KG, Jakas DR, Gallagher G, Mattern MR, Mong SM, Bartus JO, Johnson RK, Kingsbury WD (1989) Modification of the hydroxyl lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem 32:715–720

    CAS  PubMed  Google Scholar 

  • Horwitz SB, Chang CK, Grollman AP (1971) On the mechanism of topoisomerase I inhibition by camptothecin: evidence for binding to an enzyme-DNA complex. Biochemistry 7:632–644

    CAS  Google Scholar 

  • Hochberg FH, Supko J, Amato A, Salem N, Carminati P, Wen P (2006) Phase I trial and pharmacokinetic study or oral gimatecan in adults with malignant glioma. J Clin Oncol 24 suppl:abstr 1559

    Google Scholar 

  • Holm C, Covey JM, Kerrigan D, Pommier Y (1989) Differeential requirement of DNA replication for the cytotoxicity of DNA topoiosmerase I and II inhibitors in Chinese hamster DC3F cells. Cancer Res 49:6365–6368

    CAS  PubMed  Google Scholar 

  • Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerse I. J Biol Chem 260:14873–14878

    CAS  PubMed  Google Scholar 

  • Hsiang YH, Liu LF (1988) Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722–1726

    CAS  PubMed  Google Scholar 

  • Hsiang YH, Lihou MG, Liu LF (1989) Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49:5077–5082

    CAS  PubMed  Google Scholar 

  • Hu J, Wen LE, Abrey LE, Fadul C, Drappatz J, Salem N, Amato A, Carminati P, Supko J, Hochberg F (2009) Phase II trial of oral gimatecan in adults with recurrent glioblastoma. J Clin Oncol 27 suppl:abstr 2009.

    Google Scholar 

  • Hurwitz HI, Cohen RB, McGovren JP, Hirawat S, Petros WP, Natsumeda Y, Yoshinari T (2007) A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel toposiosmerase I inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol 59:139–147

    CAS  PubMed  Google Scholar 

  • Ishimi Y, Sugasawa K, Hanaoka F, Eki T, Hurwitz J (1992) Topoisomerase II plays an essential role as a swivelase in the late stage of SV40 chromosome replication in vitro. J Biol Chem 267:462–466

    CAS  PubMed  Google Scholar 

  • Janin YL, Croisy A, Rious JL, Bisagni E (1993) Synthesis and evaluation of new 6-amino-substituted benzo[c]phenanthridine derivatives. J Med Chem 36:3686–3692

    CAS  PubMed  Google Scholar 

  • Ji JJ, Putvatana R, Zhang Y, Redon C, Sedelnikova O, Yang S, Pommier Y, Bonner W, Kinders R, Parchment R, Hollings head M, Low J, Murgo A, Tomaszewski JE, Doroshow J (2007) A validated assay for gamma-H2AX as a pharmacodynamic biomarker of response to DNA damage. Proc Am Assoc Cancer Res abstr 4027

    Google Scholar 

  • Khanna R, Morton CL, danks MK, Potter PM (2000) Proficient metabolism of irinotecan by a human intestinal carboxylesterase. Cancer Res 60:4725–4738

    CAS  PubMed  Google Scholar 

  • Kreuzer KN, Cozzarelli NR (1979) Escherechia coli mutants thermosensitive for deoxyribonucleic acid gyrase subunit A: Effects on deoxyribonucleic acid replication, transcription, and bacterial growth. J Bacteriol 140:424–435

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kroep JR, Gelderblom H (2009) Diflomotecan, a promising homocamptothecin for cancer therapy. Exp Opin Invest Drugs 18:69–75

    CAS  Google Scholar 

  • Komatani H, Kotani H, Hara Y, Nakagawa R, Matsumoto M, Arakawa H, Nishimura S (2001) Identification of breast cancer resistant protein/mitoxantrone resistance/placenta-specific, ATP-binding cassette transporter as a transporter of NB-506 and J-107088, topoisomerase I inhibitors with an indolocarbazole structure. Cancer Res 61:2827–2832

    CAS  PubMed  Google Scholar 

  • Kiselev E, Dexheimer TS, Pommier Y, Cushman MC (2010) Design, synthesis and evaluation of dibenzo[c,h][1,6]naphthyridines as topoisomerase I inhibitors and potential anticancer agents. J Med Chem 53:8716–8726

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kummar S, Gutierrez M, Doroshow JH, Murgo AJ (2006) Drug development in oncology: classical cytotoxics and molecularly targeted agents. Brit J Clin Pharmacol 62:15–26

    CAS  Google Scholar 

  • Kummar S, Kinders R, Rubenstein L, Parchment RE, Murgo AJ, Collins J, Pickeral O, Low J, Steinberg SM, Gutierrez M, Yang S, Helman L, Wiltrout R, Tomaszewski JE, Doroshow JH (2007) Compressing drug development timelines in oncology using phase “0” trials. Nature Rev Cancer 7:131–139

    CAS  Google Scholar 

  • Kurtzberg L, Battle T, Rouleau C, Bagley RG, Agata N, Yao M, Schmid S, Roth, S, Crawford J, Krumbholtz R, Yu X-J, Wang F, LaVoie E, Teicher BA (2007) Bone marrow and tumor line cytotoxicity and human tumor xenograft efficacy of non-camptothecin and camptothecin topoisomerase I inhibitors. Proc Am Assoc Cancer Res abstr 771

    Google Scholar 

  • Kurtzberg L, Battle T, Rouleau C, Bagley RG, Agata N, Yao M, Schmid S, Roth, S, Crawford J, Krumbholtz R, Yu X-J, Wang F, LaVoie E, Teicher BA (2008) Bone marrow and tumor line cytotoxicity and human tumor xenograft efficacy of non-camptothecin and camptothecin topoisomerase I inhibitors. Molec Cancer Therap 7:3212–3222

    CAS  Google Scholar 

  • Lansiaux A, Facompre M, Wattez N, Hildebrand M-P, Bal C, Demarquay D, Lavergne O, Bigg DCH, Bailly C (2001) Apoptosis induced by the homocamptothecin anticancer drug BN80915 in HL-60 cells. Mol Pharmacol 60:450–461

    CAS  PubMed  Google Scholar 

  • Leonce S, Lansiaux A, Kraus-Berthier L, Giraudet S, David-Cordonnier MH, Hautefaye P, Lavielle G, Hickman J, Pierre A (2007) High stability of the cleavage complex induced by novel non-lactone camptothecin derivatives. Proc Amer Assoc Cancer Res 48: Abstr 787

    Google Scholar 

  • Leppard JB, Champoux JJ (2005) Human DNA topoiosmerase I: relaxation, roles and damage control. Chromosoma 114:75–85

    CAS  PubMed  Google Scholar 

  • Lesueur-Ginot L, Demarquay D, Kiss R, Kasprzyk PG, Dassonneville L, Bailly C, Camara J, Lavergne O, Bigg DCH (1999) Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Res 59:2939–2943

    CAS  PubMed  Google Scholar 

  • Li TK, Liu LF (2001) Tumor cell death induced by topoisomerase –targeting drugs. Ann Rev Pharmacol Toxicol 41:53–77

    Google Scholar 

  • Li TK, Houghton PJ, Desai SD, Daroui P, Liu AA, Hars ES, Ruchelman AL, LaVoie EJ, Liu LF (2003) Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug. Cancer Res 63:8400–8407

    CAS  PubMed  Google Scholar 

  • Liu LF (1989) DNA topoisomerase poisons as antitumor drugs. Ann Rev Biochem 58:351–375

    CAS  PubMed  Google Scholar 

  • Long BH, Balasubramanian BN (2000) Non-camptothecin topoisomerase I active compounds as potential anticancer agents. Exp Opin Ther Patents 10:655–686

    Google Scholar 

  • Long BH, Rose WC, Vyas DM, Matson JA, Forenza S (2002) Discovery of antitumor indolocarbazoles: Rebeccamycin, NSC655649 and fluoroindolocabazoles. Curr Med Chem-Anticancer Agents 2:255–266

    CAS  PubMed  Google Scholar 

  • Lynch BJ, Komaromy-Hiller G, Bronstein IB, Holden JA (1998) Expression of DNA topoisomerase I, DNA topoisomerase II-α and p53 in metastatic malignant melanoma. Hum Pathol 29:1240–1245

    CAS  PubMed  Google Scholar 

  • Maliepaard M, van Gastelen MA, Tohgo A, Hausheer FH, van Waardenburg RC, de Jong LA, Pluim D, Beijnen JH, Schellens JH (2001) Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res 7:935–941

    CAS  PubMed  Google Scholar 

  • Mao Y, Sun M, Desai SD, Liu LF(2000) SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci USA 97:4046–4051

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mariani P, Moliterni A, DaPrada G, Hess D, Gamucci T, Zaniboni A, Malossi A, barbieri P, Marsoni S, Gianni L (2006) A phase II trial of the novel oral camptothecin grimatecan (G) in women with anthracycline (A) and taxane (T) pre-treated advanced breast cancer. J Clin Oncol 24 suppl:abstr 662

    Google Scholar 

  • Marchand C, Antony S, Kohn KW, Cushman M, Ioanoviciu A, Staker BL, Burgin AB, Stewart L, Pommier Y (2006) A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex. Mol Cancer Ther 5:287–295

    PubMed Central  CAS  PubMed  Google Scholar 

  • Masubuchi N (2004) A predictive model of human myelotoxicity using five camptothecin derivatives and the in vitro colony-forming unit granulocyte/macrophage assay. Clin Cancer Res 10:6722–6731

    CAS  PubMed  Google Scholar 

  • Miao Z, Zhang J, You L, Wang J, Sheng C, Yao J, Zhang W, Feng H, Guo W, Zhou L, Liu W, Zhu L, Cheng P, Che X, Wang W, Luo C, Xu Y, Dong G (2010) Phosphate ester derivatives of homocamptothecin: synthesis, solution stabilities and antitumor activities. Bioorg Med Chem 18: 3140– 3146.

    CAS  PubMed  Google Scholar 

  • Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG (1972) Phase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemo Rep 56:95–101

    CAS  Google Scholar 

  • Morisaki K, Robey RW, Ozvegy-Laczka C, Honjo Y, Polgar O, Steadman K, Sarkadi B, Bates SE (2005) Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother Pharmacol 56:161–172

    CAS  PubMed  Google Scholar 

  • Morrell A, Antony S, Kohlhagen G, Pommier Y, Cushman M (2006) A systematic study of nityrated indenoisoquinolines reveals a potent topoiosmerase I inhibitor. J Med Chem 49:7740–7753

    PubMed Central  CAS  PubMed  Google Scholar 

  • Morrell A, Placzek MS, Steffen JD, Antony S, Agama K, Pommier Y, Cushman M (2007) Investigation of the lactam side chain length necessary for optimal indenoquinoline topoisomerase I inhibition and cytotoxicity in human cancer cell cultures. J Med Chem 50:2040–2048

    PubMed Central  CAS  PubMed  Google Scholar 

  • Morrell A, Placzek M, Parmley S, Grella B, Antony S, Pommier Y, Cushman M (2007) Optimization of the indenone ring of indenoisoquinoline topoisomerase I inhibitors. J Med Chem 50:4388–4404

    CAS  PubMed  Google Scholar 

  • Nahum K, Shiba D, Padavanija P, Garcia M, Hurwitz HI, Mackintosh F, Natsumeda Y, Yatsuzuka N, Locker P, Gruia G (2003) Phase II efficacy and tolerability study of edotecarin (J107088) in patients with irinotecan-naïve metastatic colorectal cancer (MCRC). Proc Am Soc Oncol 22: abstr 1099

    Google Scholar 

  • Nagarajan M, Morrell A, Antony S, Kohlhagen G, Agama K, Pommier Y, Ragazzon PA, Garbett NC, Chaires JB, Hollingshead M, Cushman M (2006) Synthesis and biological evaluation of bisindenoisoquinolines as topoisomerase I inhibitors. J Med Chem 49:5129–5140

    CAS  PubMed  Google Scholar 

  • Nagarajan M, Morrell A,Ioanoviciu A, Antony S, Kohlhagen G, Agama K, 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

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nitiss JL, Wang JC (1996) Mechanisms of cell killing by drugs that trap covalent complexes between DNA topoisomerases and DNA. Mol Pharmaol 50:1095–1102

    CAS  Google Scholar 

  • O’Connor PM, Nieves-Neira W, Kerrigan D et al (1991) S-Phase population analysis does not correlate with the cytotoxicity of camptothecin and 10,11-methylene-dooxycamptothecin in human colon carcinoma HT-29 cells. Cancer Commun 3:233–240

    PubMed  Google Scholar 

  • Pecorelli S, Ray-Coquard I, Colombo N, Katsaros D, Lhomme C, Lissoni A, Vermorken JB, DuBois A, Poveda A, Frigerio L (2006) A phase II study or oral gimatecan (ST1481) in women with progressing or recurring advanced epithelial ovarian, fallopian tube and peritoneal cancers. J Clin Oncol 24 suppl: abstr 5088

    Google Scholar 

  • Perego P, Ciusani E, Gatti L, Carenini N, Corna E, Zunino F (2006) Sensitization to gimatecan-induced apoptosis by tumor necrosis factor-related apoptosis inducing ligand in prostate carcinoma cells. Biochem Pharm 71:791–798

    CAS  PubMed  Google Scholar 

  • Perego P, De Cesare M, De Isabella P, Carenini N, Beggiolin G, Pezzoni G, Palumbo M, Tartaglia L, Pratesi G, Pisano C, Carminati P, Scheffer GL, Zunino F (2001) A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line. Cancer Res 61:6034–6037

    CAS  PubMed  Google Scholar 

  • Perez RP, Hurwitz HI, Nahum K, Lee J, Shiba D, Garcia M et al (2002) Phase II trials of J-107088, a non-camptothecin topoisomerase I inhibitor, in irinotecan naïve/refractory metastatic colorectal cancer. Proc Am Soc Clin Oncol 21:abstr 632

    Google Scholar 

  • Pessina A (2003) Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial tovalidate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics. Toxicological Sciences 75:355–367

    CAS  PubMed  Google Scholar 

  • Pommier Y, Tanizawa A, Kohn KW (1994) Mechanisms of topoisomerase I inhibition by anticancer drugs. In Advances in Pharmacology; Liu, L.F.; Academic Press: New York, 29B, 73–92

    Google Scholar 

  • Pommier Y, Barcelo JM, Rao VA, Sordet O, Jonson AG, Thibaut AG, Miao ZH, Séller JA, Zhang H, Marchand C, Agama K, Nitiss JL, Redon C (2006) Repair of topoisomerase I-mediated DNA damage. Prog Nuc Acid Res Molec Biol 81:179–229

    CAS  Google Scholar 

  • Pommier Y (2009) DNA topoisomerase I inhibitors: chemistry, biology and interfacial inhibition. Chem Rev 109:2894–2902

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pommier Y (2006) Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6:789–802

    CAS  PubMed  Google Scholar 

  • Pommier Y, Cushman M (2009) The indenoisoquinoline non-camptothecin topoisomerase I inhibitors: update and perspectives. Molec Cancer Therap 8: 1008–1014

    CAS  Google Scholar 

  • Pommier Y, Pourquier P, Fan Y, Strumberg D (1998) Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochem Biophys Acta 1400:83–105

    CAS  PubMed  Google Scholar 

  • Pommier Y, Pourquier P, Urasaki Y, Wu J, Laco G (1999) Topoisomerase I inhibitors: selectivity and cellular resistance. Drug Resistance Update 2:307–318

    CAS  Google Scholar 

  • Pommier Y, Leo E, Zhang HL, Marchand C (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 17:421–33

    CAS  PubMed  Google Scholar 

  • Potti A, Dressman HK, Bild A, Riedel RF, Chan G, Sayer R, Cragun J, Cottrill H, Kelley MJ, Petersen R, Harpole D, Marks J, Berchuck A, Ginsburg GS, Febbo P, Lancaster J, Nevins JR (2006) Genomic signatures to guide the use of chemotherapeutics. Nat Med 12:1294–1300

    CAS  PubMed  Google Scholar 

  • Potti A, Nevins JR (2008) Utilization of genomic signatures to direct use of primary chemotherapy. Curr Opin Genet Develop 18:62–67

    CAS  Google Scholar 

  • Porter SE, Champoux JJ (1989) The basis for camptothecin enhancement of DNA breakage by eukaryotic topoisomerase I. Nuc Acids Res 17:8521–8532

    CAS  Google Scholar 

  • Pruss GJ, Drlica K (1989) DNA supercoiling and prokaryotic transcription. Cell 56:521–523

    CAS  PubMed  Google Scholar 

  • Ratain MJ (2000) Insights into the pharmacokinetics and pharmacodynamics of irinotecan. Clin Cancer Res 6:3393–3394

    CAS  PubMed  Google Scholar 

  • Ratain MJ (2002) Irinotecan dosing: does the CPT in CPT-11 stand for “Can’t predict toxicity”? J Clin Oncol 20:7–8

    PubMed  Google Scholar 

  • Riedel RF, Porrello A, Pontzer E, Chenette EJ, Hsu DS, Balakumaran B, Potti A, Nevins J, Febbo PG (2008) A genomic approach to identify molecular pathways associated with chemotherapy resistance. Mol Cancer Ther 7:3141–3149

    CAS  PubMed  Google Scholar 

  • Ruchelman AL, Houghton PJ, Zhou N, Liu AA, Liu LF, LaVoie EJ (2005) 5-(2-aminothyl)dibenzo[c,h]naphthyridin-6-ones: variation of N-alkyl substituents modulates sensitivity to efflux transporters associated with multidrug resistance. J Med Chem 48:792–804

    Google Scholar 

  • Ruchelman AL, Singh SK, Wu XH, Ray A, Yang JM, Li TK, Liu AA, Liu LF, LaVoie EJ (2002) Diaza- and triazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft MDA-MB-435. Bioog Med Chem Lett 12:3333–3336

    CAS  Google Scholar 

  • Ruchelman AL, Singh SK, Wu X, Ray A, Yang JM, Li TK, Liu AA, Liu LF, LaVoie EJ (2003) 5H-dibenzo[c,h]naphthyridin-6-ones: novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity. Bioorg Med Chem 11:2061–2073

    Google Scholar 

  • Ruchelman AL, Zhu S, Zhou N, Liu AA, Liu LF, LaVoie EJ (2004) Dimethoxybenzo[i]phenanthridine-12-carboxylic acid derivatives and 6H-dibenzo[c,h][2,6]naphthyridin-5-ones with potent topoisomerase I-targeting activity and cytotoxicity. Biorg Med Chem Lett 14:5585–5589

    Google Scholar 

  • Satyanarayana M, Feng W, Cheng L, Liu AA, Tsai YC, Liu LF, LaVoie EJ (2008) Syntheses and biological evaluation of topoisomerase I-targeting agents related to 11-[2-(N,N-dimethylamino)ethyl]-2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-one (ARC31). Bioorg Med Chem 16:7824–7831

    Google Scholar 

  • Schellens JHM, Melirpaard M, Scheper RJ, Scheffer GL, Jonker JW, Smit JW, Beijnen JH, Schinkel AH (2000) Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Ann NY Acad Sci 922:188–194

    CAS  PubMed  Google Scholar 

  • Solier S, Lansiaux A, Logette E, Wu J, Soret J, Tazi J, Bailly C, Desoche L, Solary E, Corcos L (2004) Topoisomerase I and II inhibitors control caspase-2 pre-messenger RNA splicing in human cells. Molec Cancer Res 2:53–61

    CAS  Google Scholar 

  • Stermitz FR, Gillespie JP, Amoros LG, Romero R, Stermitz TA, Larson KA, Earl S, Ogg JE (1975) Synthesis and biological activity of some antitumor benzophenanthridinium salts. J Med Chem 18:708–713

    CAS  PubMed  Google Scholar 

  • Stracker TH, Morales M, Couto SS, Hussein H, Petrini JHJ (2007) The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex. Nature 447:218–221

    PubMed Central  CAS  PubMed  Google Scholar 

  • Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB, Stewart L (2002) The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci USA 99:15387–15392

    PubMed Central  CAS  PubMed  Google Scholar 

  • Stewart AF, Schutz G (1987) Camptothecin-induced in vivo induced topoisomerase cleavages in the transcriptionally active tyrosine aminotransferase gene. Cell 50:1109–1117

    CAS  PubMed  Google Scholar 

  • Stewart L, Redinbo MR, Qiu X, Hol WGJ, Champoux JJ (1998) A model for the mechanism of human topoisomerase I. Science 279:1534–1541

    CAS  PubMed  Google Scholar 

  • Sundin O, Varshavsky A (1980) Terminal stages of SV40 DNA replication proceed via multiply intertwined catenated dimers. Cell 21:103–114

    CAS  PubMed  Google Scholar 

  • Sundin O, Varshavsky A (1981) Arrest of segregation leads to accumulation of highly intertwined catenated dimers. Cell 25:659–669

    CAS  PubMed  Google Scholar 

  • Takagi K, Dexheimer TS, Redon C, Sordet O, Agama K, Lavielle G, Pierre A, Bates SE, Pommier Y (2007) Novel E-ring campotethecin keto analogues 9S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters. Mol Cancer Therap 6: 3229– 3238

    CAS  Google Scholar 

  • Takemura H, Rao VA, Sordet O, Furuta T, Miao Z-H, Meng LH, Zhang H, Pommier Y (2006) Defective Mre-1-dependent activation of Chk2 by ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication-dependent DNA double strand breaks. J Biol Chem 41:30814–30823

    Google Scholar 

  • Troconiz IF, Garrido MJ, Segura C, Cendros J-M, Principe P, Peraire C, Obach R (2006) Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumors. Cancer Chemother Pharmacol 57:727–735

    CAS  PubMed  Google Scholar 

  • Tsao YP, D’Arpa P, Liu LF (1992) The involvement of active DNA synthesis in camptothecin-induced G2 arrest: altered regulation of p34cdc2/cyclin B. Cancer Res 52:1823–1829

    CAS  PubMed  Google Scholar 

  • Tse-Dinh Y-C, Kirkegaard K, Wang JC (1980) Covalent bonds between protein and DNA: Formation of phosphotyrosine linkage between certain DNA topoisomerases and DNA. J Biol Chem 255:5560–5565

    Google Scholar 

  • Urasaki Y, Laco G, Takebayashi Y, Bailly C, Kohlhagen G, Pommier Y (2001) Use of campthecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site. Cancer Res 61:504–508

    CAS  PubMed  Google Scholar 

  • Urasaki Y, Takebayashi Y, Pommier Y (2000) Activity of a novel camptothecin analogue, homocamptothecin, in camptothecin-resistant cell lines with topoisomerase I alterations. Cancer Res 60:6577–6580

    CAS  PubMed  Google Scholar 

  • Vassal G, Hamelin N, Opolon P, Versace R, Geoerger B (2008) The topoisomerase I inhibitor gimatecan exhibits synergistic antitumor activity in combination with imatinib mesylate and everolimus against malignant glioma xenografts. J Clin Oncol 26 suppl:abstr 2073

    Google Scholar 

  • Wang JC (1994) DNA Topoisomerases as targets of therapeutics: An overview. In Advances in Pharmacology, vol 29A; Liu, L.F.; Academic Press: New York, pp 1–19

    Google Scholar 

  • Wang JC (2009) A journey in the world of DNA rings and beyond. Annu Rev Biochem 78:31–54

    CAS  PubMed  Google Scholar 

  • Wang JC (2009) Untangling the Double Helix. DNA Entanglement and the Action of the DNA Topoisomerases, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 245 pp

    Google Scholar 

  • Wang JC (1991) DNA topoisomerases: why so many? J Biol Chem 266:6659–6662

    CAS  PubMed  Google Scholar 

  • Wang JC (1985) DNA topoisomerases. Ann Rev Biochem 54:665–697

    CAS  PubMed  Google Scholar 

  • Wang JC, Caron PR, Kim RA (1990) The role of DNA topoisomerases in recombination and genome stability: A double-edged sword? Cell 62:403–406

    CAS  PubMed  Google Scholar 

  • Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GM (1966) Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Amer Chem Soc 88:3888–3890

    CAS  Google Scholar 

  • Wall ME, Wani MC (1995) Camptothecin and taxol: discovery to clinic – thirteenth Bruce F. Cain Memorial Award lecture. Cancer Res 55:753–760

    CAS  PubMed  Google Scholar 

  • Wani MC, Wall ME (1969) Plant antitumor agents. II. The structure of two new alkaloids from Camptotheca acuminata. J Org Chem 34:1364–1367

    CAS  Google Scholar 

  • Weinstein JN, Pommier Y (2006) Connecting genes, drugs and disease. Nature Biotech 24:1365–1366

    CAS  Google Scholar 

  • Woo MM, Rodriguez L, Gu H, Crenshaw-Williams K, Rocha F, Freestone S, Dickson J, Jodrell D, Mangold JB (2007) Absorption, metabolism and excretion of 14C gimatecan (LBQ707) after oral administration in patients with advanced cancer. J Clin Oncol 25 suppl:abstr 2564

    Google Scholar 

  • Woo MM, Zhang J, Rocha F, Fandi A, Schran HF (2008) Clinical pharmacokinetics (PK) of two oral dosing schedules of gimatecan in a phase I study: implications for safety and efficacy. J Clin Oncol 26 suppl:abstr 2512

    Google Scholar 

  • Yang CH, Schneider E, Kuo ML, Volk EL, Rocchi E, Chen YC (2000) BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells. Biochem Pharmacol 60:831–837

    CAS  PubMed  Google Scholar 

  • Yamada Y, Tamura T, Yamamoto N, Shimoyama T, Ueda Y, Murakami H, Kusaba H, Kamiya Y, Saka H, Tanigawara Y, McGovren JP, Natsumeda Y (2006) Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors. Cancer Chemother Pharmacol 58:173–182

    CAS  PubMed  Google Scholar 

  • Yin D, Toler S, Guo F, Duncan B, Sharma A (2005) Pharmacokinetics (PK) of edotecarin (J-107088), a topoismerase I inhibitor, in patients with metastatic breast cancer (mBC) or glioblastoma (GBM). J Clin Soc 23 suppl:abstr 2073

    Google Scholar 

  • Zee-Cheng KY, Cheng CC (1975) Preparation and antileukemic activity of some alkoxybenzo[c]phenanthridinium salts and corresponding dihydro derivatives. J Med Chem 18:66–71

    CAS  PubMed  Google Scholar 

  • Zhang H, Wang JC, Liu LF (1988) Involvement of DNA topoisomerase I in the transcription of human ribosomal RNA genes. Proc Natl Acad Sci USA 85:1060–1064

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhu S, Ruchelman AL, Zhou N, Liu AA, Liu LF, LaVoie EJ (2005) Esters and amides of 2,3-dim­ethoxy-8,9-methylenedioxy-benzo[i]phenanthridine-12-carboxylic acid: potent cytotoxic and topoisomerase I-targeting agents. Bioorg Med Chem 13:6782–6794

    Google Scholar 

  • Zhu S, Ruchelman AL, Zhou N, Liu AA, Liu LF, LaVoie EJ (2006) 6-Substituted 6H-dibenzo[c,h][2,6]naphthyridin-5-ones: Reversed lactam analogues of ARC-111 with potent topoisomerase I-targeting activity and cytotoxicity. Bioorg Med Chem 14:3131–3143

    Google Scholar 

  • Zhu L, Miao Z, Sheng C, Guo W, Yao J, Liu W, Che X, Wang W, Cheng P, Zhang W (2010) Trifluoromethyl-promoted homocamptothecins: synthesis and bioloigcal activity. Europ J Med Chem 45: 2726–2732

    CAS  Google Scholar 

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  1. Developmental Therapeutics Program, National Cancer Institute, 6130 Executive Blvd., Rockville, MD, 20852, USA

    Beverly A. Teicher

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    Yves Pommier

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Teicher, B.A. (2012). Topoisomerase I Inhibitors: Chemical Biology. In: Pommier, Y. (eds) DNA Topoisomerases and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0323-4_10

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