, Volume 62, Issue 14, pp 2039–2057 | Cite as


A Review of Their Chemotherapeutic Potential
Review Article


Camptothecin analogues and derivatives appear to exert their antitumour activity by binding to topoisomerase I and have shown significant activity against a broad range of tumours. In general, camptothecins are not substrates for either the multidrug-resistance P-glycoprotein or the multidrug-resistance-associated protein (MRP). Because of manageable toxicity and encouraging activity against solid tumours, camptothecins offer promise in the clinical management of human tumours. This review illustrates the proposed mechanism(s) of action of camptothecins and presents a concise overview of current camptothecin therapy, including irinotecan and topotecan, and novel analogues undergoing clinical trails, such as exatecan (DX-8951f), IDEC-132 (9-aminocamptothecin), rubitecan (9-nitrocamptothecin), lurtotecan (GI-147211C), and the recently developed homocamptothecins diflomotecan (BN-80915) and BN-80927.


  1. 1.
    Wall ME, Wani MC, Cook CE, et al. Plant antitumor agents. I: the isolation and structure of camptothecin, a novel alkoloidal leukemia and tumor inhibitor from Camptotheca accuminata. J Am Chem Soc 1966; 88: 3888–90Google Scholar
  2. 2.
    Horwitz SB, Chang CK, Grollman AP. Studies on camptothecin. I. effects of nucleic acid and protein synthesis. Mol Pharmacol 1971; 7: 632–44Google Scholar
  3. 3.
    Kessel D. Effects of camptothecin on RNA synthesis in leukemia L1210 cells. Biochim Biophys Acta 1971; 246: 225–32PubMedCrossRefGoogle Scholar
  4. 4.
    Abelson HT, Penman S. Selective interruption of high molecular weight RNA synthesis in HeLa cells by camptothecin. Nat New Biol 1972; 237: 144–6PubMedGoogle Scholar
  5. 5.
    Kessel D, Bosmann HB, Lohr K. Camptothecin effects on DNA synthesis in murine leukemia cells. Biochim Biophys Acta 1972; 269: 210–6PubMedCrossRefGoogle Scholar
  6. 6.
    Horwitz MS, Horwitz SB. Intracellular degradation of HeLa and adenovirus type 2 DNA induced by camptothecin. Biochem Biophys Res Commun 1971; 45: 723–7PubMedCrossRefGoogle Scholar
  7. 7.
    Gottlieb JA, Guarino AM, Call JB, et al. Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep 1970; 54: 461–70PubMedGoogle Scholar
  8. 8.
    Gottlieb JA, Luce JK. Treatment of malignant melanoma with camptothecin (NSC-100880). Cancer Chemother Rep 1972; 56: 103–5PubMedGoogle Scholar
  9. 9.
    Moertel CG, Schutt AJ, Reitemeier RJ, et al. Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 1972; 56: 95–101PubMedGoogle Scholar
  10. 10.
    Muggia FM, Creaven PJ, Hansen HH, et al. Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother Rep 1972; 56: 515–21PubMedGoogle Scholar
  11. 11.
    Hsiang YH, Hertzberg R, Hecht S, et al. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985; 260: 14873–8PubMedGoogle Scholar
  12. 12.
    Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988; 48: 1722–6PubMedGoogle Scholar
  13. 13.
    Wani MC, Nicholas AW, Wall ME. Plant antitumor agents. 23.Synthesis and antileukemic activity of camptothecin analogues. J Med Chem 1986; 29: 2358–63PubMedCrossRefGoogle Scholar
  14. 14.
    Wall ME, Wani MC, Natschke SM, et al. Plant antitumor agents. 22.Isolation of 11-hydroxycamptothecin from Camptotheca acuminata Decne: total synthesis and biological activity. J Med Chem 1986; 29: 1553–5PubMedCrossRefGoogle Scholar
  15. 15.
    Sawada S, Okajima S, Aiyama R, et al. Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin. Chem Pharm Bull (Tokyo) 1991; 39: 1446–50CrossRefGoogle Scholar
  16. 16.
    Kingsbury WD, Boehm JC, Jakas DR, et al. Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J Med Chem 1991; 34: 98–107PubMedCrossRefGoogle Scholar
  17. 17.
    Kunimoto T, Nitta K, Tanaka T, et al. Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 1987; 47: 5944–7PubMedGoogle Scholar
  18. 18.
    Wani MC, Nicholas AW, Manikumar G, et al. Plant antitumor agents. 25.Total synthesis and antileukemic activivty of ring A substituted camptothecin analogues: structure-activity correlations. J Med Chem 1987; 30: 1774–9PubMedCrossRefGoogle Scholar
  19. 19.
    Negoro S, Fukuoka M, Masuda N, et al. Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 1991;83: 1164–8PubMedCrossRefGoogle Scholar
  20. 20.
    Rowinsky EK, Grochow LB, Hendricks CB, et al. Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992; 10: 647–56PubMedGoogle Scholar
  21. 21.
    Giovanella BC, Stehlin JS, Wall ME, et al. DNA topoisomerase I-targeted chemotherapy of human colon cancer in xeno-grafts. Science 1989; 246: 1046–8PubMedCrossRefGoogle Scholar
  22. 22.
    Hsiang YH, Liu LF, Wall ME, et al. DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues. Cancer Res 1989; 49: 4385–9PubMedGoogle Scholar
  23. 23.
    Lesueur-Ginot L, Demarquay D, Kiss R, et al. Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Res 1999; 59: 2939–43PubMedGoogle Scholar
  24. 24.
    Brown PO, Cozzarelli NR. A sign inversion mechanism for enzymatic supercoiling of DNA. Science 1979; 206: 1081–3PubMedCrossRefGoogle Scholar
  25. 25.
    Liu LF, Liu CC, Alberts BM. Type II DNA topoisomerases: enzymes that can unknot a topologically knotted DNA molecule via a reversible double-strand break. Cell 1980; 19: 697–707PubMedCrossRefGoogle Scholar
  26. 26.
    Liu LF. DNA topoisomerases: enzymes that catalyse the breaking and rejoining of DNA. CRC Crit Rev Biochem 1983; 15: 1–24PubMedCrossRefGoogle Scholar
  27. 27.
    Geliert M. DNA topoisomerases. Annu Rev Biochem 1981; 50: 879–910CrossRefGoogle Scholar
  28. 28.
    Wang JC. DNA topoisomerases. Annu Rev Biochem 1985; 54: 665–97PubMedCrossRefGoogle Scholar
  29. 29.
    D’Arpa P, Machlin PS, Ratrie HD, et al. cDNA cloning of human DNA topoisomerase I: catalytic activity of a 67.7-kDa carboxyl-terminal fragment. Proc Natl Acad Sci U S A 1988; 85: 2543–7PubMedCrossRefGoogle Scholar
  30. 30.
    Tsai-Pflugfelder M, Liu LF, Liu AA, et al. Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21-22. Proc Natl Acad Sci U S A1988; 85: 7177–81PubMedCrossRefGoogle Scholar
  31. 31.
    Cozzarelli NR. DNA gyrase and the supercoiling of DNA. Science 1980; 207: 953–60PubMedCrossRefGoogle Scholar
  32. 32.
    Liu LF, Wang JC. Supercoiling of the DNA template during transcription. Proc Natl Acad Sci U S A 1987; 84: 7024–7PubMedCrossRefGoogle Scholar
  33. 33.
    Wu HY, Shyy SH, Wang JC, et al. Transcription generates positively and negatively supercoiled domains in the template. Cell 1988; 53: 433–40PubMedCrossRefGoogle Scholar
  34. 34.
    Wang JC, Caron PR, Kim RA. The role of DNA topoisomerases in recombination and genome stability: a double-edged sword? Cell 1990; 62: 403–6PubMedCrossRefGoogle Scholar
  35. 35.
    Subramanian D, Rosenstein BS, Muller MT. Ultraviolet-induced DNA damage stimulates topoisomerase I-DNA complex formation in vivo: possible relationship with DNA repair. Cancer Res 1998; 58: 976–84PubMedGoogle Scholar
  36. 36.
    Liu LF, Miller KG. Eukaryotic DNA topoisomerases: two forms of type I DNA topoisomerases from HeLa cell nuclei. Proc Natl Acad Sci U S A 1981; 78: 3487–91PubMedCrossRefGoogle Scholar
  37. 37.
    Schmitt B, Buhre U, Vosberg HP. Characterisation of size variants of type I DNA topoisomerase isolated from calf thymus. Eur J Biochem 1984; 144: 127–34PubMedCrossRefGoogle Scholar
  38. 38.
    Shero JH, Bordwell B, Rothfield NF, et al. High titers of auto-antibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. Science 1986; 231: 737–40PubMedCrossRefGoogle Scholar
  39. 39.
    Juan CC, Hwang JL, Liu AA, et al. Human DNA topoisomerase I is encoded by a single-copy gene that maps to chromosome region 20q12–13. 2. Proc Natl Acad Sci U S A 1988; 85: 8910–3CrossRefGoogle Scholar
  40. 40.
    Vosberg HP. DNA topoisomerases: enzymes that control DNA conformation. Curr Top Microbiol Immunol 1985; 114: 19–102PubMedCrossRefGoogle Scholar
  41. 41.
    D’Arpa P, Liu LF. Topoisomerase-targeting antitumor drugs. Biochim Biophys Acta 1989; 989: 163–77PubMedGoogle Scholar
  42. 42.
    Osheroff N. Biochemical basis for the interactions of type I and type II topoisomerases with DNA. Pharmacol Ther 1989; 41: 223–41PubMedCrossRefGoogle Scholar
  43. 43.
    Schneider E, Hsiang YH, Liu LF. DNA topoisomerases as anticancer drug targets. Adv Pharmacol 1990; 21: 149–83PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang H, Wang JC, Liu LF. Involvement of DNA topoisomerase I in transcription of human ribosomal RNA genes. Proc Natl Acad Sci U S A 1988; 85: 1060–4PubMedCrossRefGoogle Scholar
  45. 45.
    Yang L, Wold MS, Li JJ, et al. Roles of DNA topoisomerases in simian virus 40 DNA replication in vitro. Proc Natl Acad Sci U S A 1987; 84: 950–4PubMedCrossRefGoogle Scholar
  46. 46.
    Champoux JJ. Mechanism of the reaction catalyzed by the DNA untwisting enzyme: attachment of the enzyme to 3’-terminus of the nicked DNA. J Mol Biol 1978; 118: 441–6PubMedCrossRefGoogle Scholar
  47. 47.
    Champoux JJ. DNA is linked to the rat liver DNA nicking-closing enzyme by a phosphodiester bond to tyrosine. J Biol Chem 1981; 256: 4805–9PubMedGoogle Scholar
  48. 48.
    Eng WK, Pandit SD, Sternglanz R. Mapping of the active site tyrosine of eukaryotic DNA topoisomerase I. J Biol Chem 1989; 264: 13373–6PubMedGoogle Scholar
  49. 49.
    Lynn RM, Bjornsti MA, Caron PR, et al. Peptide sequencing and site-directed mutagenesis identify tyrosine-727 as the active site tyrosine of Saccharomyces cerevisiae DNA topoisomerase I. Proc Natl Acad Sci U S A 1989; 86: 3559–63PubMedCrossRefGoogle Scholar
  50. 50.
    Liu LF. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 1989; 58: 351–75PubMedCrossRefGoogle Scholar
  51. 51.
    Rothenberg ML. Topoisomerase I inhibitors: review and update. Ann Oncol 1997; 8: 837–55PubMedCrossRefGoogle Scholar
  52. 52.
    Lima CD, Wang JC, Mondragon A. Three-dimensional structure of the 67K N-terminal fragment of E. coli DNA topoisomerase I. Nature 1994; 367: 138–46Google Scholar
  53. 53.
    Stivers JT, Harris TK, Mildvan AS. Vaccinia DNA topoisomerase I: evidence supporting a free rotation mechanism for DNA supercoil relaxation. Biochemistry 1997; 36: 5212–22PubMedCrossRefGoogle Scholar
  54. 54.
    Stewart L, Redinbo MR, Qiu X, et al. A model for the mechanism of human topoisomerase I. Science 1998; 279: 1534–41PubMedCrossRefGoogle Scholar
  55. 55.
    Bates AD, Maxwell A. DNA Topology. Oxford: IRL Press, 1993,83Google Scholar
  56. 56.
    Merino A, Madden KR, Lane WS, et al. DNA topoisomerase I is involved in both repression and activation of transcription. Nature 1993; 365: 227–32PubMedCrossRefGoogle Scholar
  57. 57.
    Gilmour DS, Pflugfelder G, Wang JC, et al. Topoisomerase I interacts with transcribed regions in Drosophila cells. Cell 1986; 44: 401–7PubMedCrossRefGoogle Scholar
  58. 58.
    Camilloni G, Di Martino E, Caserta M, et al. Eukaryotic DNA topoisomerase I reaction is topology dependent. Nucleic Acids Res 1988; 16: 7071–85PubMedCrossRefGoogle Scholar
  59. 59.
    Drolet M, Wu HY, and Liu LF. Roles of DNA topoisomerases in transcription. Adv Pharmacol 1994; 29A: 135–46PubMedCrossRefGoogle Scholar
  60. 60.
    Shuman S. Vaccinia DNA topoisomerase I promotes illegitimate recombination in Escherichia coli. Proc Natl Acad Sci U S A 1989; 86: 3489–93PubMedCrossRefGoogle Scholar
  61. 61.
    Shuman S. Recombination mediated by vaccinia virus DNA topoisomerase I in Escherichia coli is sequence specific. Proc Natl Acad Sci U S A 1991; 88: 10104–8PubMedCrossRefGoogle Scholar
  62. 62.
    Wang HP, Rogler CE. Topoisomerase I-mediated integration of hepadnavirus DNA in vitro. J Virol 1991; 65: 2381–92PubMedGoogle Scholar
  63. 63.
    Covey JM, Jaxel C, Kohn KW, et al. Protein-linked DNA strand breaks induced in mammalian cells by camptothecin, an inhibitor of topoisomerase I. Cancer Res 1989; 49: 5016–22PubMedGoogle Scholar
  64. 64.
    Shuman S. DNA strand transfer reactions catalyzed by vaccinia topoisomerase I. J Biol Chem 1992; 267: 8620–7PubMedGoogle Scholar
  65. 65.
    Anderson RD, Berger NA. International Commission for Protection Against Environmental Mutagens and Carcinogens. Mutagenicity and carcinogenicity of topoisomerase-interactive agents. Mutat Res 1994; 309: 109–42Google Scholar
  66. 66.
    Hsiang YH, Lihou MG, Liu LF. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 1989; 49: 5077–82PubMedGoogle Scholar
  67. 67.
    Kjeldsen E, Svejstrup JQ, Gromova II, et al. Camptothecin inhibits both the cleavage and religation reactions of eukaryotic DNA topoisomerase I. J Mol Biol 1992; 228: 1025–30PubMedCrossRefGoogle Scholar
  68. 68.
    D’Arpa P, Beardmore C, Liu LF. Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res 1990; 50: 6919–24PubMedGoogle Scholar
  69. 69.
    Tsao YP, D’Arpa P, Liu LF. The involvement of active DNA synthesis in camptothecin-induced G2 arrest: altered regulation of p34cdc2/cyclin B. Cancer Res 1992; 52: 1823–9PubMedGoogle Scholar
  70. 70.
    Beidler DR, Cheng YC. Camptothecin induction of a time- and concentration-dependent decrease of topoisomerase I and its implication in camptothecin activity. Mol Pharmacol 1995; 47: 907–14PubMedGoogle Scholar
  71. 71.
    Desai SD, Liu LF, Vazquez-Abad D, et al. Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem 1997; 272: 24159–64PubMedCrossRefGoogle Scholar
  72. 72.
    Kharbanda S, Rubin E, Gunji H, et al. Camptothecin and its derivatives induce expression of the c-jun protooncogene in human myeloid leukemia cells. Cancer Res 1991; 51: 6636–42PubMedGoogle Scholar
  73. 73.
    Piret B, Piette J. Topoisomerase poisons activate the transcription factor NF-kappaB in ACH-2 and CEM cells. Nucleic Acids Res 1996; 24: 4242–8PubMedCrossRefGoogle Scholar
  74. 74.
    Wu J, Liu LF. Processing of topoisomerase I cleavable complexes into DNA damage by transcription. Nucleic Acids Res 1997; 25: 4181–6PubMedCrossRefGoogle Scholar
  75. 75.
    Mao Y, Okada S, Chang LS, et al. p53 dependence of topoisomerase I recruitment in vivo. Cancer Res 2000; 60: 4538–43PubMedGoogle Scholar
  76. 76.
    Wall ME, Wani MC. In: Potmesil M, Pinedo H, editors. Camptothecins: new anticancer agents. Boca Raton: CRC Press, 1995: 21–42Google Scholar
  77. 77.
    Crow RT, Crothers DM. Structural modifications of camptothecin and effects on topoisomerase I inhibition. J Med Chem 1992; 35: 4160–4PubMedCrossRefGoogle Scholar
  78. 78.
    Wani MC, Ronman PE, Lindley JT, et al. Plant antitumor agents. 18.Synthesis and biological activity of camptothecin analogues. J Med Chem 1980; 23: 554–60PubMedCrossRefGoogle Scholar
  79. 79.
    Hertzberg RP, Caranfa MJ, Holden KG, et al. Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem 1989; 32: 715–20PubMedCrossRefGoogle Scholar
  80. 80.
    Jaxel C, Kohn KW, Wani MC, et al. Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res 1989; 49: 1465–9PubMedGoogle Scholar
  81. 81.
    Wall ME, Wani MC. Antineoplastic agents from plants. Annu Rev Pharmacol Toxicol 1977; 17: 117–32PubMedCrossRefGoogle Scholar
  82. 82.
    Wani MC, Nicholas AW, Wall ME. Plant antitumor agents. 28.Resolution of a key tricyclic synthon, 5’(RS)-l,5-dioxo-5′-ethyl-5′-hydroxy-2′H,5′H,6′H-6′-oxopyrano[3′,4′-f]delta 6,8-tetrahydro-indolizine: total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecin. J Med Chem 1987; 30: 2317–9PubMedCrossRefGoogle Scholar
  83. 83.
    Nicholas AW, Wani MC, Manikumar G, et al. Plant antitumor agents. 29.Synthesis and biological activity of ring D and ring E modified analogues of camptothecin. Med Chem1990; 33: 972–8CrossRefGoogle Scholar
  84. 84.
    Wang HK, Morris-Natschke SL, Lee KH. Recent advances in the discovery and development of topoisomerase inhibitors as antitumor agents. Med Res Rev 1997; 17: 367–425PubMedCrossRefGoogle Scholar
  85. 85.
    Sawada S, Yokokura T, Miyasaka T. Synthesis of CPT-11 (irinotecan hydrochloride trihydrate). Ann N Y Acad Sci 1996; 803: 13–28PubMedCrossRefGoogle Scholar
  86. 86.
    Tsuruo T, Matsuzaki T, Matsushita M, et al. Antitumor effect of CPT-11, a new derivative of camptothecin, against pleiotropic drug-resistant tumors in vitro and in vivo. Cancer Chemother Pharmacol 1988; 21: 71–4PubMedCrossRefGoogle Scholar
  87. 87.
    Kawato Y, Furuta T, Aonuma M, et al. Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. Cancer Chemother Pharmacol 1991; 28: 192–8PubMedCrossRefGoogle Scholar
  88. 88.
    Tsuji T, Kaneda N, Kado K, et al. CPT-11 converting enzyme from rat serum: purification and some properties. J Pharmacobiodyn 1991; 14: 341–9PubMedCrossRefGoogle Scholar
  89. 89.
    Wall ME, Wani MC, Nicholas AW, et al. Plant antitumor agents. 30.Synthesis and structure activity of novel camptothecin analogs. Med Chem1993; 36: 2689–700CrossRefGoogle Scholar
  90. 90.
    Fan Y, Weinstein JN, Kohn KW, et al. Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin. J Med Chem 1998; 41: 2216–26PubMedCrossRefGoogle Scholar
  91. 91.
    Emerson DL, Besterman JM, Brown HR, et al. In vivo antitumor activity of two new seven-substituted water-soluble camptothecin analogues. Cancer Res 1995; 55: 603–9PubMedGoogle Scholar
  92. 92.
    Besterman JM. Topoisomerase I inhibition by the camptothecin analog G1147211C: from the laboratory to the clinic. Ann N Y Acad Sci 1996; 803: 202–9PubMedCrossRefGoogle Scholar
  93. 93.
    Jew S, Kim HJ, Kim MG, et al. Synthesis and in vitro cytotoxicity of hexacyclic camptothecin analogues. Bioorg Med Chem Lett 1999; 9: 3203–6PubMedCrossRefGoogle Scholar
  94. 94.
    Sugimori M, Ejima A, Ohsuki S, et al. Synthesis and antitumor activity of ring A- and F-modified hexacyclic camptothecin analogues. J Med Chem 1998; 41: 2308–18PubMedCrossRefGoogle Scholar
  95. 95.
    Sugimori M, Ejima A, Ohsuki S, et al. Antitumor agents: 7. synthesis and antitumor activity of novel hexacyclic camptothecin analogues. J Med Chem 1994; 37: 3033–9Google Scholar
  96. 96.
    De Jager R, Cheverton P, Tamanoi K, et al. DX-8951f: summary of phase I clinical trials. Ann N Y Acad Sci 2000; 922: 260–73PubMedCrossRefGoogle Scholar
  97. 97.
    Rowinsky EK, Johnson TR, Geyer Jr CE, et al. DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies. J Clin Oncol 2000; 18: 3151–63PubMedGoogle Scholar
  98. 98.
    Lavergne O, Lesueur-Ginot L, Pla Rodas F, et al. Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem 1998; 41: 5410–9PubMedCrossRefGoogle Scholar
  99. 99.
    Lavergne O, Lesueur-Ginot L, Pia Rodas F, et al. BN80245: an E-ring modified camptothecin with potent antiproliferative and topoisomerase I inhibitory activities. Bioorg Med Chem Lett 1997; 7: 2235–8CrossRefGoogle Scholar
  100. 100.
    Bailly C, Lansiaux A, Dassonneville L, et al. Homo-camptothecin, an E-ring-modified camptothecin analogue, generates new topoisomerase I-mediated DNA breaks. Biochemistry 1999; 38: 15556–63PubMedCrossRefGoogle Scholar
  101. 101.
    Urasaki Y, Takebayashi Y, Pommier Y. Activity of a novel camptothecin analogue, homocamptothecin, in camptothecin-resistant cell lines with topoisomerase I alterations. Cancer Res 2000; 60: 6577–80PubMedGoogle Scholar
  102. 102.
    Lavergne O, Demarquay D, Kasprzyk PG, et al. Homo-camptothecins: E-ring modified CPT analogues. Ann N Y Acad Sci 2000; 922: 100–11PubMedCrossRefGoogle Scholar
  103. 103.
    Demarquay D, Coulomb H, Huchet M, et al. The homocamptothecin, BN 80927, is a potent topoisomerase I poison and topoisomerase II catalytic inhibitor. Ann N Y Acad Sci 2000; 922: 301–2PubMedCrossRefGoogle Scholar
  104. 104.
    Demarquay D, Huchet M, Coulomb H, et al. The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison. Anticancer Drugs 2001; 12: 9–19PubMedCrossRefGoogle Scholar
  105. 105.
    Bom D, Curran DP, Kruszewski S, et al. The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem 2000; 43: 3970–80PubMedCrossRefGoogle Scholar
  106. 106.
    Curran DP, Josien H, Bom D, et al. The cascade radical annulation approach to new analogues of camptothecins: combinatorial synthesis of silatecans and homosilatecans. Ann N Y Acad Sci 2000; 922: 112–21PubMedCrossRefGoogle Scholar
  107. 107.
    Redinbo MR, Stewart L, Kuhn P, et al. Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science 1998; 279: 1504–13PubMedCrossRefGoogle Scholar
  108. 108.
    Fujimori A, Harker WG, Kohlhagen G, et al. Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell line resistant to camptothecin. Cancer Res 1995; 55: 1339–46PubMedGoogle Scholar
  109. 109.
    Kaufmann SH. Cell death induced by topoisomerase-targeted drugs: more questions than answers. Biochim Biophys Acta 1998; 1400: 195–211PubMedCrossRefGoogle Scholar
  110. 110.
    Pommier Y, Kohlhagen G, Kohn KW, et al. Interaction of an alkylating camptothecin derivative with a DNA base at topoisomerase I-DNA cleavage sites. Proc Natl Acad Sci U S A 1995; 92: 8861–5PubMedCrossRefGoogle Scholar
  111. 111.
    Kerrigan JE, Pilch DS. A structural model for the ternary cleavable complex formed between human topoisomerase I, DNA, and camptothecin. Biochemistry 2001; 40: 9792–8PubMedCrossRefGoogle Scholar
  112. 112.
    de Forai M, Bugat R, Chabot GG, et al. Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients. Cancer Res 1994; 54: 4347–54Google Scholar
  113. 113.
    Takeuchi S, Takamizawa H, Takeda Y, et al. An early phase II study of CPT-11 in gynecologic cancers: Research Group of CPT-11 in Gynecologic Cancers. Gan To Kagaku Ryoho 1991; 18: 579–84PubMedGoogle Scholar
  114. 114.
    Tsuda H, Takatsuki K, Ohno R, et al. Treatment of adult T-cell leukaemia-lymphoma with irinotecan hydrochloride (CPT-11): CPT-11 Study Group on Hematological Malignancy. Br J Cancer 1994; 70: 771–4PubMedCrossRefGoogle Scholar
  115. 115.
    Ohno R, Okada K, Masaoka T, et al. An early phase II study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma. J Clin Oncol 1990; 8: 1907–12PubMedGoogle Scholar
  116. 116.
    Shimada Y, Yoshino M, Wakui A, et al. Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer: CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol 1993; 11: 909–13PubMedGoogle Scholar
  117. 117.
    Takimoto CH, Arbuck SG. Clinical status and optimal use of topotecan. Oncology (Huntingt) 1997; 11: 1635–1646; discussion 1649–1651, 1655–37Google Scholar
  118. 118.
    FDA approves irinotecan as first-line therapy for colorectal cancer. Oncology (Huntingt) 2000; 14: 652, 654Google Scholar
  119. 119.
    Taguchi T, Wakui A, Hasegawa K, et al. Phase I clinical study of CPT-11. Research group of CPT-11. Gan To Kagaku Ryoho 1990; 17: 115–20Google Scholar
  120. 120.
    Rothenberg ML, Kuhn JG, Burris HAd, et al. Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 1993; 11: 2194–204PubMedGoogle Scholar
  121. 121.
    Ohe Y, Sasaki Y, Shinkai T, et al. Phase I study and pharmaco-kinetics of CPT-11 with 5-day continuous infusion. J Natl Cancer Inst 1992; 84: 972–4PubMedCrossRefGoogle Scholar
  122. 122.
    Costin D, Potmesil M. Preclinical and clinical development of camptothecins. Adv Pharmacol 1994; 29B: 51–72PubMedCrossRefGoogle Scholar
  123. 123.
    Wall JG, Burris HAd, VonHoff DD, et al. A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days. Anticancer Drugs 1992; 3: 337–45PubMedCrossRefGoogle Scholar
  124. 124.
    Abigerges D, Armand JP, Chabot GG, et al. Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 1994; 86: 446–9PubMedCrossRefGoogle Scholar
  125. 125.
    Masuda N, Fukuoka M, Kudoh S, et al. Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer. J Clin Oncol 1994; 12: 1833–41PubMedGoogle Scholar
  126. 126.
    Klumpp TR, Goldberg SL, Mangan KF. Effect of granulocyte colony-stimulating factor on the rate of neutrophil engraft-ment following peripheral-blood stem-cell transplantation [letter]. J Clin Oncol 1995; 13: 2144PubMedGoogle Scholar
  127. 127.
    Takasuna K, Hagiwara T, Hirohashi M, et al. Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res 1996; 56: 3752–7PubMedGoogle Scholar
  128. 128.
    Potmesil M. Camptothecins: from bench research to hospital wards. Cancer Res 1994; 54: 1431–9PubMedGoogle Scholar
  129. 129.
    Rothenberg ML. The current status of irinotecan (CPT-11) in the United States. Ann N Y Acad Sci 1996; 803: 272–81PubMedCrossRefGoogle Scholar
  130. 130.
    Saijo N. Clinical trials of irinotecan hydrochloride (CPT, campto injection, topotecin injection) in Japan. Ann N Y Acad Sci 1996; 803: 292–305PubMedCrossRefGoogle Scholar
  131. 131.
    Miller AA, Hargis JB, Lilenbaum RC, et al. Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study. J Clin Oncol 1994; 12: 2743–50PubMedGoogle Scholar
  132. 132.
    Lilenbaum RC, Ratain MJ, Miller AA, et al. Phase I study of paclitaxel and topotecan in patients with advanced tumors: a cancer and leukemia group B study. J Clin Oncol 1995; 13: 2230–7PubMedGoogle Scholar
  133. 133.
    Crump M, Lipton J, Hedley D, et al. Phase I trial of sequential topotecan followed by etoposide in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study. Leukemia 1999; 13: 343–7PubMedCrossRefGoogle Scholar
  134. 134.
    Vey N, Kantarjian H, Beran M, et al. Combination of topotecan with cytarabine or etoposide in patients with refractory or relapsed acute myeloid leukemia: results of a randomized phase I/II study. Invest New Drugs 1999; 17: 89–95PubMedCrossRefGoogle Scholar
  135. 135.
    Murren JR, Anderson S, Fedele J, et al. Dose-escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer. J Clin Oncol 1997; 15: 148–57PubMedGoogle Scholar
  136. 136.
    Saltz L. Irinotecan-based combinations for the adjuvant treatment of stage III colon cancer. Oncology (Huntingt) 2000; 14: 47–50Google Scholar
  137. 137.
    Royce ME, Medgyesy D, Zukowski TH, et al. Colorectal cancer: chemotherapy treatment overview. Oncology (Huntingt) 2000; 14: 40–6Google Scholar
  138. 138.
    Douillard JY. Irinotecan and high-dose fluorouracil/leucovorin for metastatic colorectal cancer. Oncology (Huntingt) 2000; 14: 51–5Google Scholar
  139. 139.
    Fukuoka M, Masuda N, Kudoh S, et al. Irinotecan in small-cell lung cancer: Japanese trials. Oncology (Huntingt) 2000; 14: 57–62Google Scholar
  140. 140.
    Ajani JA, Fairweather J, Pisters PW, et al. Irinotecan and cisplatin in advanced gastric or gastroesophageal junction carcinoma. Oncology (Huntingt) 2000; 14: 19–21Google Scholar
  141. 141.
    Hammond LA, Eckardt JR, Ganapathi R, et al. A phase I and translational study of sequential administration of the topoisomerase I and II inhibitors topotecan and etoposide. Clin Cancer Res 1998; 4: 1459–67PubMedGoogle Scholar
  142. 142.
    Frasci G, Panza N, Cornelia P, et al. Cisplatin-topotecan-paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: a dose-finding study. Ann Oncol 1999; 10: 355–8PubMedCrossRefGoogle Scholar
  143. 143.
    Mitsui I, Kumazawa E, Hirota Y, et al. A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res 1995; 86: 776–82PubMedCrossRefGoogle Scholar
  144. 144.
    Takiguchi S, Kumazawa E, Shimazoe T, et al. Antitumor effect of DX-8951, a novel camptothecin analog, on human pancreatic tumor cells and their CPT-11-resistant variants cultured in vitro and xenografted into nude mice. Jpn J Cancer Res 1997; 88: 760–9PubMedCrossRefGoogle Scholar
  145. 145.
    Kumazawa E, Jimbo T, Ochi Y, et al. Potent and broad antitumor effects of DX-895 If, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice. Cancer Chemother Pharmacol 1998; 42: 210–20PubMedCrossRefGoogle Scholar
  146. 146.
    Pantazis P, Hinz HR, Mendoza JT, et al. Complete inhibition of growth followed by death of human malignant melanoma cells in vitro and regression of human melanoma xenografts in immunodeficient mice induced by camptothecins. Cancer Res 1992; 52: 3980–7PubMedGoogle Scholar
  147. 147.
    Jeha S, Kantarjian H, O’Brien S, et al. Activity of oral and intravenous 9-aminocamptothecin in SCID mice engrafted with human leukemia. Leuk Lymphoma 1998; 32: 159–64PubMedGoogle Scholar
  148. 148.
    de Souza PL, Cooper MR, Imondi AR, et al. 9-Aminocamptothecin: a topoisomerase I inhibitor with preclinical activity in prostate cancer. Clin Cancer Res 1997; 3: 287–94PubMedGoogle Scholar
  149. 149.
    Pantazis P, Kozielski AJ, Vardeman DM, et al. Efficacy of camptothecin congeners in the treatment of human breast carcinoma xenografts. Oncol Res 1993; 5: 273–81PubMedGoogle Scholar
  150. 150.
    Pantazis P, Kozielski AJ, Mendoza JT, et al. Camptothecin derivatives induce regression of human ovarian carcinomas grown in nude mice and distinguish between non-tumorigenic and tumorigenic cells in vitro. Int J Cancer 1993; 53: 863–71PubMedCrossRefGoogle Scholar
  151. 151.
    Keane TE, El-Galley RE, Sun C, et al. Camptothecin analogues/cisplatin: an effective treatment of advanced bladder cancer in a preclinical in vivo model system. J Urol 1998; 160: 252–6PubMedCrossRefGoogle Scholar
  152. 152.
    Rubin E, Wood V, Bharti A, et al. A phase I and pharmacokinetic study of a new camptothecin derivative, 9-amino-camptothecin. Clin Cancer Res 1995; 1: 269–76PubMedGoogle Scholar
  153. 153.
    Lad T, Rosen F, Sciortino D, et al. Phase II trial of aminocamptothecin (9-AC/DMA) in patients with advanced squamous cell head and neck cancer. Invest New Drugs 2000; 18: 261–3PubMedCrossRefGoogle Scholar
  154. 154.
    Takimoto CH, Thomas R. The clinical development of 9-aminocamptothecin. Ann N Y Acad Sci 2000; 922: 224–36PubMedCrossRefGoogle Scholar
  155. 155.
    Wilson WH, Little R, Pearson D, et al. Phase II and dose-escalation with or without granulocyte colony-stimulating factor study of 9-aminocamptothecin in relapsed and refractory lymphomas. J Clin Oncol 1998; 16: 2345–51PubMedGoogle Scholar
  156. 156.
    Dahut W, Harold N, Takimoto C, et al. Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients. J Clin Oncol 1996; 14: 1236–44PubMedGoogle Scholar
  157. 157.
    EderJR JP, Supko JG, Lynch T, et al. Phase I trial of the colloidal dispersion formulation of 9-amino-20(S)-camptothecin administered as a 72-hour continuous intravenous infusion. Clin Cancer Res 1998; 4: 317–24PubMedGoogle Scholar
  158. 158.
    Takimoto CH, Dahut W, Harold N. A phase I trial of a prolonged infusion of 9-aminocamptothecin (9-AC) in adult patients with solid tumors [abstract]. Proc Am Soc Clin Oncol 1996; 14: 471Google Scholar
  159. 159.
    Pantazis P. The water-insoluble camptothecin analogues: promising drugs for the effective treatment of haematological malignancies. Leuk Res 1995; 19: 775–88PubMedCrossRefGoogle Scholar
  160. 160.
    Verschraegen CF, Gupta E, Loyer E, et al. A phase II clinical and pharmacological study of oral 9-nitrocamptothecin in patients with refractory epithelial ovarian, tubal or peritoneal cancer. Anticancer Drugs 1999; 10: 375–83PubMedCrossRefGoogle Scholar
  161. 161.
    Chow DS, Gong L, Wolfe MD, et al. Modified lactone/carboxylate salt equilibria in vivo by liposomal delivery of 9-nitrocamptothecin. Ann N Y Acad Sci 2000; 922: 164–74PubMedCrossRefGoogle Scholar
  162. 162.
    Knight V, Kleinerman ES, Waldrep JC, et al. 9-Nitro-camptothecin liposome aerosol treatment of human cancer subcutaneous xenografts and pulmonary cancer metastases in mice. Ann N Y Acad Sci 2000; 922: 151–63PubMedCrossRefGoogle Scholar
  163. 163.
    Verschraegen CF, Gilbert BE, Huaringa AJ, et al. Feasibility, phase I, and pharmacological study of aerosolized liposomal 9-nitro-20(S)-camptothecin in patients with advanced malignancies in the lungs. Ann N Y Acad Sci 2000; 922: 352–4PubMedCrossRefGoogle Scholar
  164. 164.
    Gerrits CJ, Creemers GJ, Schellens JH, et al. Phase I and pharmacological study of the new topoisomerase I inhibitor GI147211, using a daily x 5 intravenous administration. Br J Cancer 1996; 73: 744–50PubMedCrossRefGoogle Scholar
  165. 165.
    Eckhardt SG, Baker SD, Eckardt JR, et al. Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks. Clin Cancer Res 1998; 4: 595–604PubMedGoogle Scholar
  166. 166.
    Gamucci T, Paridaens R, Heinrich B, et al. Activity and toxicity of GI147211 in breast, colorectal and non-small-cell lung cancer patients: an EORTC-ECSG phase II clinical study. Ann Oncol 2000; 11: 793–7PubMedCrossRefGoogle Scholar
  167. 167.
    Loos WJ, Kehrer D, Brouwer E, et al. Liposomal lurtotecan (NX211): determination of total drug levels in human plasma and urine by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 2000; 738: 155–63PubMedCrossRefGoogle Scholar
  168. 168.
    Emerson DL, Bendele R, Brown E, et al. Antitumor efficacy, pharmacokinetics, and biodistribution of NX 211: a low-clearance liposomal formulation of lurtotecan. Clin Cancer Res 2000; 6: 2903–12PubMedGoogle Scholar
  169. 169.
    Bonneterre J, Cottu P, Adenis A, et al. Phase I trial of BN80915 administered intravenously in patients with advanced malignant tumours [abstract]. Proc Am Assoc Cancer Res 2000; 41: A234Google Scholar
  170. 170.
    Huchet M, Demarquay D, Coulomb H, et al. The dual topoisomerase inhibitor, BN 80927, is highly potent against cell proliferation and tumor growth. Ann N Y Acad Sci 2000; 922: 303–5PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Division of Pharmaceutics, College of PharmacyThe Ohio State UniversityColumbusUSA

Personalised recommendations