II. MECHANISM OF ACTION
A. POISONING OF TOPOISOMERASE I
In 1985, it was reported that CPT stabilized the DNA–topoisomerase I covalent binary complex.3 It had previously been shown that CPT is capable of inhibiting DNA synthesis, thereby causing cell death during the S-phase of the cell cycle.4 The S-phase specific cytotoxicity is directly correlated to the occurrence of irreversible DNA cleavage when the replication fork encounters the covalent DNA–enzyme binary complex (Figure 2.2).5 It has been demonstrated that deletion of the gene for topo I from Saccharomyces cerevisiae results in viable cells that are fully resistant to CPT.6 Further, a number of CPT-resistant cell lines have been identified, each containing mutations within topo I.7 These studies clearly support a mechanism of action for CPT involving topo I–mediated DNA cleavage.
The topoisomerases (type I and type II) are a class of enzymes that mediate the relaxation of chromosomal DNA prior to DNA replication and transcription.8 Mechanistically, topo II effects this relaxation via transient double-strand cleavage, DNA strand passage, and religation of the phosphodiester backbone. This process requires ATP and alters the DNA linking number by multiples of two. The topo I mechanism involves energy-independent single-strand DNA cleavage, followed by strand passage and religation.9 The mechanism of topo I–mediated DNA relaxation is known to involve an active site tyrosine that cleaves DNA by nucleophilic attack of the active site tyrosine phenolic OH group on the phosphodiester backbone (Figure 2.3). The resulting DNA–topo I intermediate is a covalent binary complex. The cleaved DNA strand can be passaged around the unbroken DNA strand; the intact duplex is reformed on religation of the phosphodiester bond, with the concomitant release of topo I.
Although topo I may be capable of DNA cleavage at a number of sites, it exhibits a strong preference for the nucleoside thymidine as the nucleobase directly upstream (the -I position) (cf. Figure 2.3). Stabilization of the covalent binary complex by CPT has been noted to involve an additional preference for guanosine at the +1 position.
Most of the agents that poison type I and type II topoisomerases are characterized by their ability to inhibit the religation step during DNA relaxation (Figure 2.3). Topo II poisons include a number of well-characterized clinical agents such as amsacrine and etopside.10 Several inhibitors of topo I have also been identified; however, CPT remains the most widely studied of this class of medicinal agents.
The development of a precise understanding of the way in which CPT stabilizes the DNA–topo I covalent binary complex, and thereby inhibits the religation of duplex DNA, is an important current goal. CPT has no binding affinity for topo I, and only the positively charged CPT analog topotecan (3) has shown any DNA binding.11,12 However, the ability of CPT to bind to the covalent binary complex formed between topo I and DNA is sufficient to inhibit religation. There is compelling evidence that CPT is capable of interacting with the covalent binary complex at or near the interface between DNA and topo I. Hertzberg and coworkers have established that a CPT analog containing a bromoacetamide at carbon 10 was, on prolonged exposure, capable of forming a drug–enzyme crosslink.13 Pommier and coworkers later showed that a 7-chloromethylated CPT analog alkylated N3 of the guanine at the +1 cleavage site of DNA.14
A number of computational models have been formulated depicting the interaction between CPT and the covalent binary complex.15–17 These models posit different energy-minimized inter- actions between CPT, the DNA 5-TpG-3 base pair, and selected topo I amino acid residues known to be important based on biochemical studies or their proximity to the putative CPT binding site.18–21 The analysis of several CPT-resistant cell lines has provided important information regarding the amino acid residues that play a role in CPT binding.7 For example, mutational analysis of Asp 533, Arg364, Asn722, and Lys532 has revealed that each of these amino acid residues likely play a role in CPT binding.19–21
Staker et al. have recently reported the X-ray crystal structure of a ternary complex formed between DNA, topo I, and topotecan (3).22 The reported complex used a DNA oligonucleotide containing a 5-bridging phosphothioate to facilitate crystal formation and indicated that topotecan bound the covalent binary complex in an intercalative fashion (Figure 2.4). The only direct drug–enzyme hydrogen bond interaction was between Asp533 and the 20-hydroxyl group of topotecan. In addition, one hydrogen bond was observed with a water molecule. Carbons 7, 9, and 10 of CPT were positioned in a manner that situated them in the vicinity of the major groove.
B. OTHER BIOCHEMICAL EFFECTS OF CPT
It is generally accepted that the basis for CPT-induced cytotoxicity is contingent on CPT acting as a topo I poison (as opposed to an inhibitor of enzyme activity, per se).3–7 However, the antitumor selectivity of CPT is somewhat surprising given that topo I is an enzyme found in all cell types. Elevated levels of topo I are present in tumors of the colon, ovary, and prostate, which may explain the therapeutic index of CPT.23 Deficiencies in DNA repair capabilities in some cancer cells may provide another possible basis for cancer cell selectivity. The selective inhibition of all dividing cell populations represents another possible source of antitumor selectivity. Further, other effects of CPT exposure have been noted and merit discussion.
Kauh and Bjornsti, using a genetic screen, have identified six dominant suppressors of camp- tothecin toxicity at a single genetic locus (SCT1).24 Mutant SCT1 cells were shown to express wild- type topo I, indicating additional factors in the overall cellular response to CPT. One report indicated that irinotecan, but not topotecan, inhibits acetylcholinesterase activity.25 Additional reports indicate that CPT activates the transcription factor NFκB, which has been implicated in numerous activities in vivo.26 Importantly, activation of NFκB has been implicated in the overproduction of interferons, triggering several cellular responses.26–29
In addition to its role in relaxation of supercoiled DNA, topo I is able to regulate transcription,30 recognize and cleave mismatched nucleotides at intrinsic cleavage sites,31 and associate with numerous proteins in vivo. Tazi and coworkers have reported that topo I is capable of influencing gene splicing by acting as a phosphorylating enzyme for SR proteins.32 This kinase activity is inhibited by CPT despite the fact that it has been shown to be unconnected to its DNA relaxation activity through mutational studies.33 Analysis of a family of topoisomerase I related function proteins (TRFp) demonstrate that one member of this family, TRF4p, plays a critical role in mitotic chromosome condensation during the S phase of the cell cycle.34 TRF4p is associated with the DNA binding protein Smc1p during chromosomal condensation, and reports detailing mutations to TRF4p have produced cell lines with unexpected hypersensitivity to CPT.35
REFERENCES
1. Wall, M.E. et al., Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, J. Am. Chem. Soc., 88, 3888, 1966.
2. Moertel, C.G. et al., Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer, Cancer Chemother. Rep., 56, 95, 1972.
3. Hsiang, Y.-H. et al., Camptothecin induces protein-linked DNA breaks via mammalian DNA topoi- somerase I, J. Biol. Chem., 260, 14873, 1985.
4. Gallo, R.C., Whang-Peng, J., and Adamson, R.H., Studies on the antitumor activity, mechanism of action, and cell cycle effects of camptothecin, J. Natl. Cancer Inst., 46, 789, 1971.
5. Hsiang, Y.-H., Lihou, M.G., and Liu, L.F., Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complex as a mechanism of cell killing by camptothecin, Cancer Res., 49, 5077, 1989.
6. Nitiss, J. and Wang, J.C., DNA topoisomerase-targeting antitumor drugs can be studied in yeast, Proc. Natl. Acad. Sci. USA, 85, 7501, 1988.
7. Pommier, Y. et al., Topoisomerase I inhibitors: selectivity and cellular resistance, Drug Resistance Updates, 2, 307, 1999.
8. Champoux, J.J., DNA topoisomerases: structure, function, and mechanism, Annu. Rev. Biochem., 70, 369, 2002.
9. Pommier, Y. et al., Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme, Biochim. Biophys. Acta, 1400, 83, 1998.
10. Sengupta, S.K., Topoisomerase II inhibitors, in Cancer Chemotherapeutic Agents, Foye, W.O., Ed., American Chemical Society, Washington D.C., 1995, pp. 205–292.
11. Hertzberg, R.P., Caranfa, M.J., and Hecht, S.M., On the mechanism of topoisomerase I inhibition by camptothecin: evidence for binding to an enzyme-DNA complex, Biochemistry, 28, 4629, 1989.
12. Yang, D. et al., DNA interactions of two clinical camptothecin drugs stabilize their active lactone forms, J. Am. Chem. Soc., 120, 2979, 1998.
13. Hertzberg, R.P. et al., Irreversible trapping of the DNA-topoisomerase I covalent complex, J. Biol. Chem., 265, 19287, 1990.
14. Pommier, Y. et al., Interaction of an alkylating camptothecin derivative with a DNA base at topoi- somerase I-DNA cleavage sites, Proc. Natl. Acad. Sci. USA, 92, 8861, 1995.
15. Fan, Y. et al., Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin, J. Med. Chem., 41, 2216, 1998.
16. Kerrigan, J.E. and Pilch, D.S., A structural model for the ternary cleavable complex formed between human topoisomerase I, DNA, and camptothecin, Biochemistry, 40, 9792, 2001.
17. Laco, G.S. et al., Human topoisomerase I inhibition: docking camptothecin and derivatives into a structure-based active site model, Biochemistry, 41, 1428, 2002.
18. Redinbo, M.R. et al., Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA, Science, 279, 1504, 1998.
19. Yoshimasa, U. et al., Characterization of a novel topoisomerase I mutation from a camptothecin- resistant human prostate cancer cell line, Cancer Res., 61, 1964, 2001.
20. Fujimori, A. et al., Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell line resistant to camptothecin, Cancer Res., 55, 1339, 1995.
21. Jensen, A.D., and Svejstrup, J.Q., Purification and characterization of human topoisomerase I mutants, Eur. J. Biochem., 236, 389, 1996.
22. Staker, B.L. et al., The mechanism of topoisomerase I poisoning by a camptothecin analog, Proc. Natl. Acad. Sci. USA, 99, 15387, 2002.
23. Husain, I. et al., Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy, Cancer Res., 54, 539, 1994.
24. Kauh, E.A. and Bjornsti, M.-A., SCT1 mutants suppress the camptothecin sensitivity of yeast cells expressing wild-type DNA topoisomerase I, Proc. Natl. Acad. Sci. USA, 92, 6299, 1995.
25. Kawato, Y. et al., Inhibitory activity of camptothecin derivatives against acetylcholinesterase in dogs and their binding activity to acetylcholine receptors in rats, J. Pharm. Pharmacol., 45, 444, 1993.
26. Siddoo-Atwal, C., Haas, A.L., and Rosin, M.P., Elevation of interferon beta-inducible proteins in ataxia telangiectasia cells, Cancer Res., 56, 443, 1996.
27. DeSai, S.D. et al., Ubiquitin, SUMO-1, and UCRP in camptothecin sensitivity and resistance, Ann. N. Y. Acad. Sci., 922, 306, 2000.
28. Ohwada, S. et al., Interferon potentiates antiproliferative activity of CPT-11 against human colon cancer xenografts, Cancer Lett., 110, 149, 1996.
29. Ibuki, Y., Mizuno, S., and Goto, R., γ-Irradiation-induced DNA damage enhances NO production via NF-κB activation in RAW264.7 cells, Biochim. Biophys. Acta, 1593, 159, 2003.
30. Kretzschmar, M., Meisterernst, M., and Roeder, R.G., Identification of human DNA topoisomerase I as a cofactor for activator-dependent transcription by RNA polymerase II, Proc. Natl. Acad. Sci. USA, 90, 11508, 1993.
31. Yeh, Y.C. et al., Mammalian topoisomerase I has base mismatch nicking activity, J. Biol. Chem., 269, 15498, 1994.
32. Rossi, F. et al., Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I, Nature, 381, 80, 1996.
33. Rossi, F. et al., The C-terminal domain but not the tyrosine 723 of human DNA topoisomerase I active site contributes to kinase activity, Nucleic Acids Res., 26, 2963, 1998.
34. Castano, I.B. et al., Mitotic chromosome condensation in the rDNA requires TRF4 and DNA topoi- somerase I in Saccharomyces cerevisiae, Genes Dev., 10, 2564, 1996.
35. Walowsky, C. et al., The topoisomerase-related function gene TRF4 affects cellular sensitivity to the antitumor agent camptothecin, J. Biol. Chem., 274, 7302, 1999.
36. Stork, G. and Schultz, A.G., The total synthesis of dl-camptothecin, J. Am. Chem. Soc., 93, 4074, 1971.
37. Jew, S.-S. et al., Synthesis and antitumor activity of camptothotecin analogues, Korean J. Med. Chem., 6, 263, 1996.
38. Thomas, C.J., Rahier, N.J., and Hecht, S.M., Camptothecin: current perspectives, Bioorg. Med. Chem., 12, 1585, 2004.
39. Corey, E.J., Crouse, D.N., and Anderson, J.E., A total synthesis of natural 20(S)-camptothecin, J. Org. Chem., 40, 2140, 1975.
40. Wani, M.C., Nicholas, A.W., and Wall, M.E., Plant antitumor agents 28. Resolution of a key tricyclic synthon, 5′(RS)-1,5-dioxo-5′-ethyl-5′-hydroxy-2′H,5′H,6′H-6′-oxopyrano[3′,4′-f]∆6,8-tetrahydro- indolizine: total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecin, J. Med. Chem., 30, 2317, 1987.
41. Terasawa, H. et al., Antitumor agents III. A novel procedure for inversion of the configuration of a tertiary alcohol related to camptothecin, Chem. Pharm. Bull., 37, 3382, 1989.
42. Ejima, A. et al., Antitumour agents. Part 2. Asymmetric synthesis of (S)-camptothecin, J. Chem. Soc., Perkin Trans. 1, 27, 1990.
43. Comins, D.L., Hong, H., and Jianhua, G., Asymmetric synthesis of camptothecin alkaloids: A nine- step synthesis of (S)-camptothecin, Tetrahedron Lett., 35, 5331, 1994.
44. Comins, D.L. and Nolan, J.M., A practical six-step synthesis of (S)-camptothecin, Org. Lett., 3, 4255, 2001.
45. Tagami, K. et al., Asymmetric synthesis of (+)-camptothecin and (+)-7-ethyl-10-methoxycamptothe- cin, Heterocycles, 53, 771, 2000.
46. Bennasar, M.-L. et al., Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: total synthesis of (±)-20-deoxycamptothecin and (+)-camptothecin, J. Org. Chem., 67, 7465, 2002.
47. Ciufolini, M.A. and Roschangar, F., Practical synthesis of (20 S)-(+)-camptothecin: the progenitor of a promising group of anticancer agents, Targets Heterocyclic Syst., 4, 25, 2000.
48. Imura, A., Itoh, M., and Miyadera, A., Enantioselective synthesis of 20(S)-camptothecin using an enzyme-catalyzed resolution, Tetrahedron: Asymmetry, 9, 2285, 1998.
49. Fang, F.G., Xie, S., and Lowery, M.W., Catalytic enantioselective synthesis of 20(S)-camptothecin: a practical application of the Sharpless asymmetric dihydroxylation reaction, J. Org. Chem., 59, 6142, 1994.
50. Jew. S.-S. et al., Enantioselective synthesis of 20(S)-camptothecin using Sharpless catalytic asymmet- ric dihydroxylation, Tetrahedron: Asymmetry, 6, 1245, 1995.
51. Blagg, B.S.J. and Boger, D.L., Total synthesis of (+)-camptothecin, Tetrahedron, 58, 6343, 2002.
52. Curran, D.P. et al., The cascade radical annulation approach to new analogues of camptothecins. Combinatorial synthesis of silatecans and homosilatecans, Ann. N. Y. Acad. Sci., 922, 112, 2000.
53. Yabu, K. et al., Studies toward practical synthesis of (20S)-camptothecin family through catalytic enantioselective cyanosilylation of ketones: improved catalyst efficiency by ligand-tuning, Tetrahedron Lett., 43, 2923, 2002.
54. Sawada, S. et al., Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin, Chem. Pharm. Bull., 39, 1446, 1991.
55. Kingsbury, W.D. et al., Synthesis of water-soluble (aminoalkyl) camptothecin analogs: inhibition of topoisomerase I and antitumor activity, J. Med. Chem., 34, 98, 1991.
56. Lackey, K. et al., Rigid analogues of camptothecin as DNA topoisomerase I inhibitors, J. Med. Chem., 38, 906, 1995.
57. Ihara, M. et al., Studies on the synthesis of heterocyclic compounds and natural products. 999. Double
enamine annelation of 3,4-dihydro-1-methyl-β-carboline and isoquinoline derivatives with 6-methyl- 2-pyrone-3,5-dicarboxylates and its application for the synthesis of (+/-)-camptothecin, J. Org. Chem., 48, 3150, 1983.
58. Kurihara, T. et al., Synthesis of C-nor-4,6-secocamptothecin and related compounds, J. Heterocycl. Chem., 30, 643, 1993.
59. Subrahmanyam, D. et al., Novel C-ring analogues of 20(S)-camptothecin Part 2. Synthesis and in vitro cytotoxicity of 5-C-substituted 20(S)-camptothecin analogues, Bioorg. Med. Chem. Lett., 9, 1633, 1999.
60. Sugimori, M. et al., Antitumor agents. VI. Synthesis and antitumor activity of ring A-, ring B-, ring C-modified derivatives of camptothecin, Heterocycles, 38, 81, 1993.
61. Camptothecins: New Anticancer Agents, Potmesil, M. and Pinedo, H., Eds., CRC Press, Boca Raton, 1995.
62. Kawato, Y. and Terasawa, H., Recent advances in the medicinal chemistry and pharmacology of camptothecin, in Progress in Medicinal Chemistry, Ellis, G.P., and Luscombe, D.K., Eds., Elsevier, London, 1997, Vol 34, pp. 70–100.
63. Wall, M.E. and Wani, M.C., Recent advances in the medicinal chemistry and pharmacology of camptothecin, in Cancer Chemotherapeutic Agents, Foye, W.O., Ed., American Chemical Society, Washington D.C., 1995, pp. 293–310.
64. Wani, M.C. et al., Plant antitumor agents 18. Synthesis and biological activity of camptothecin analogues, J. Med. Chem., 23, 554, 1980.
65. Wani, M.C., Nicholas, A.W., and Wall, M.E., Plant antitumor agents 23. Synthesis and antileukemic activity of camptothecin analogs, J. Med. Chem., 29, 2358, 1986.
66. Wani, M.C. et al., Plant Antitumor Agents 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations, J. Med Chem., 30, 1774, 1987.
67. Wall, M.E. et al., Plant antitumor agents 30. Synthesis and structure activity of novel camptothecin analogues, J. Med. Chem., 36, 2689, 1993.
68. Jaxel, C. 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., 49, 1465, 1989.
69. Wang, X., Zhou, X., and Hecht, S.M., Role of the 20-hydroxyl group in camptothecin binding by the topoisomerase I-DNA binary complex, Biochemistry, 38, 4374, 1999.
70. Hertzberg, R.P. et al., Modification of the hydroxy lactone ring of camptothecin: Inhibition of mam- malian topoisomerase I and biological activity, J. Med. Chem., 32, 715, 1989.
71. Burke, T.G. and Mi, Z., Ethyl substitution at the 7 position extends the half-life of 10-hydroxycamp- tothecin in the presence of human serum albumin, J. Med. Chem., 36, 2580, 1993.
72. Lavergne, O. et al., BN80245: An E-ring modified camptothecin with potent antiproliferative and topoisomerase I inhibitory activities, Bioorg. Med. Chem. Lett., 7, 2235, 1997.
73. Cagir, A. et al., Luotonin A. A naturally occurring DNA topoisomerase I poison, J. Am. Chem. Soc., 125, 13628, 2003.
74. Luzzio, M.J. et al., Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I, J. Med. Chem., 38, 395, 1995.
75. Van Hattum, A.H. et al., The activity profile of the hexacyclic camptothecin derivative DX-8951f in experimental human colon cancer and ovarian cancer, Biochem. Pharmacol., 64, 1267, 2002.
76. Josien, H. et al., 7-Silylcamptothecins (silatecans): a new family of camptothecin antitumor agents, Bioorg. Med. Chem. Lett., 7, 3189, 1997.
77. Dallavalle, S. et al., Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity, J. Med. Chem., 44, 3264, 2001.
78. Pollack, I.F. et al., Potent topoisomerase I inhibition by novel silatecans eliminates glioma proliferation in vitro and in vivo, Cancer Res., 59, 4898, 1999.
79. Bom, D. et al., Novel A, B, E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities, J. Med. Chem., 42, 3018, 1999.
80. Walker, M. A. et al., Synthesis of an immunoconjugate of camptothecin, Bioorg. Med. Chem. Lett., 12, 217, 2002.
81. Arimondo, P.B. et al., Design and optimization of camptothecin conjugates of triple helix-forming oligonucleotides for sequence-specific DNA cleavage by topoisomerase I, J. Biol. Chem., 277, 3132, 2002.
82. Wang, C.C.C. and Dervan, P.B., Sequence-specific trapping of topoisomerase I by DNA binding polyamide-camptothecin conjugates, J. Am. Chem. Soc., 123, 8657, 2001.
83. Conover, C.D. et al., Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker, Cancer Chemother. Pharmacol., 42, 407, 1998.
84. Greenwald, R.B., Zhao, H., and Xia, J., Tripartate poly(ethylene glycol) prodrugs of the open lactone form of camptothecin, Bioorg. Med. Chem., 11, 2635, 2003.
85. Garcia-Carbonero, R. and Supko, J.G., Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins, Clinical Cancer Res., 8, 641, 2002.
86. Ulukan, H. and Swaan, P.W., Camptothecins. A review of their chemotherapeutic potential, Drugs, 62, 2039, 2002.
87. Kim, D.-K. and Lee, N., Recent advances in topoisomerase I-targeting agents, camptothecin analogues, Mini Rev. Med. Chem., 2, 611, 2002.
88. Dallavalle, S. et al., Perspectives in camptothecin development, Expert Opin. Ther. Patents, 12, 837, 2002.
89. Bailly, C., Homocamptothecins: Potent topoisomerase I inhibitors and promising anticancer drugs, Critical Rev. Oncology/Hematology, 45, 91, 2003.
90. Hatefi, A. and Amsden, B., Camptothecin delivery methods, Pharm. Res., 19, 1389, 2002.
0 Comment:
Post a Comment