Camptothecin Radiation Sensitization

  • Tyvin A. Rich
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The camptothecin analog CPT-11 has recently been approved for the treatment of 5-fluorouracil (5-FU)-resistant colorectal cancer (1), thus opening a new chapter in chemotherapeutic radiation sensitization. The camptothecins (CPT) are potent radiation sensitizers and are in their infancy in clinical studies. The combination of CPT with irradiation builds onto successful radiation-sensitization trials with 5-FU (2), because both classes of agents are cytotoxic for S-phase cells. They each have a defined role in the treatment of colorectal cancer, a site where radiation sensitization has improved local-regional control and overall survival (Table 1). Radiation sensitization with these agents is dose and schedule dependent and additional knowledge about this combination treatment, based on new laboratory data, may help optimize the use of the CPTs as radiosensitizers.


Maximum Tolerate Dose Radiat Oncol Biol Phys Replication Fork Radiation Sensitization Lung Squamous Cell Carcinoma 
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  1. 1.
    Rich TA, Kirichenko AV. Camptothecin radiation sensitization: mechanisms, schedules, and timing. Oncology (Huntingt) 1998; 12 (8 Suppl 6): 114–120.Google Scholar
  2. 2.
    Rich TA. Irradiation Plus 5-Fluorouracil: Cellular Mechanisms of Action and Treatment Schedules. Semin Radiat Oncol 1997; 7 (4): 267–273.PubMedCrossRefGoogle Scholar
  3. 3.
    Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG. Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 1972; 56 (1): 95–101.PubMedGoogle Scholar
  4. 4.
    Muggia FM, Creaven PJ, Hansen HH, Cohen MH, Selawry OS. Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother Rep 1972; 56 (4): 515–521.PubMedGoogle Scholar
  5. 5.
    Kunimoto T, Nitta K, Tanaka T, et al. Antitumor activity of 7-ethyl-l0-[4-(1-piperidino)-1piperidinolcarbonyloxy-camptothec in, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 1987; 47 (22): 5944–5947.PubMedGoogle Scholar
  6. 6.
    Kawato Y, Furuta T, Aonurna M, Yasuoka M, Yokokura T, Matsumoto K. Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. Cancer Chemother Pharmacol 1991; 28 (3): 192–198.PubMedCrossRefGoogle Scholar
  7. 7.
    Rothenberg ML. Topoisomerase I inhibitors: review and update. Ann Oncol 1997; 8 (9): 837–855.PubMedCrossRefGoogle Scholar
  8. 8.
    Liu LF, Desai SD, Li TK, Mao Y, Sun M, Sim SP. Mechanism of action of camptothecin. Ann NYAcad Sci 2000; 922: 1–10.CrossRefGoogle Scholar
  9. 9.
    Desai SD, Mao Y, Sun M, Li TK, Wu J, Liu LF. Ubiquitin, SUMO-1, and UCRP in camptothecin sensitivity and resistance. Ann NYAcad Sci 2000; 922: 306–308.CrossRefGoogle Scholar
  10. 10.
    Kohn KW, Pommier Y. Molecular and biological determinants of the cytotoxic actions of camptothecins. Perspective for the development of new topoisomerase I inhibitors. Ann NYAcad Sci 2000; 922: 11–26.CrossRefGoogle Scholar
  11. 11.
    Giovanella BC, Harris N, Mendoza J, Cao Z, Liehr J, Stehlin JS. Dependence of anticancer activity of camptothecins on maintaining their lactone function. Ann NYAcad Sci 2000; 922: 27–35.CrossRefGoogle Scholar
  12. 12.
    Takimoto CH. Why drugs fail: of mice and men revisited. Clin Cancer Res 2001; 7 (2): 229–230.PubMedGoogle Scholar
  13. 13.
    Rothenberg ML, Cox JV, DeVore RF, et al. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 1999; 85 (4): 786–795.PubMedCrossRefGoogle Scholar
  14. 14.
    Rothenberg ML. The current status of irinotecan (CPT-11) in the United States. Ann N YAcad Sci 1996; 803: 272–281.CrossRefGoogle Scholar
  15. 15.
    Hsiang YH, Hertzberg R, Hecht S, Liu LF. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985; 260 (27): 14873–14878.PubMedGoogle Scholar
  16. 16.
    Drengler RL, Kuhn JG, Schaaf LJ, et al. Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors. J Clin Oncol 1999; 17 (2): 685–696.PubMedGoogle Scholar
  17. 17.
    Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 1994; 54 (14): 3723–3725.PubMedGoogle Scholar
  18. 18.
    Rivory LP, Riou JF, Haaz MC, et al. Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res 1996; 56 (16): 3689–3694.PubMedGoogle Scholar
  19. 19.
    Chastagner P, Merlin JL, Marchal C, et al. In vivo potentiation of radiation response by topotecan in human rhabdomyosarcoma xenografted into nude mice. Clin Cancer Res 2000; 6 (8): 3327–3333.PubMedGoogle Scholar
  20. 20.
    Hennequin C, Giocanti N, Balosso J, Favaudon V. Interaction of ionizing radiation with the topoisomerase I poison camptothecin in growing V-79 and HeLa cells. Cancer Res 1994; 54(7):1720–1728.PubMedGoogle Scholar
  21. 21.
    Kirichenko AV, Travis EL, Rich TA. Radiation enhancement by 9-aminocamptothecin. Evidence for improved therapeutic ratio with a multiple dose schedule. Ann NYAcad Sci 1996; 803: 312–314.CrossRefGoogle Scholar
  22. 22.
    Kirichenko AV, Rich TA, Newman RA, Travis EL. Potentiation of murine MCa-4 carcinoma radioresponse by 9-amino-20(S)-camptothecin. Cancer Res 1997; 57 (10): 1929–1933.PubMedGoogle Scholar
  23. 23.
    Mattem MR, Hofmann GA, McCabe FL, Johnson RK. Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SKF 104864). Cancer Res 1991; 51 (21): 5813–5816.Google Scholar
  24. 24.
    Zanier R, De Salvia R, Fiore M, Degrassi F. Topoisomerase I activity and cellular response to radiation in Chinese hamster cells. Int J Radiat Biol 1996; 70 (3): 251–259.PubMedCrossRefGoogle Scholar
  25. 25.
    Huang TT, Wuerzberger-Davis SM, Seufzer BJ, et al. NF-kappaB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events. J Biol Chem 2000; 275 (13): 9501–9509.PubMedCrossRefGoogle Scholar
  26. 26.
    Kirichenko AV, Rich TA. Radiation enhancement by 9-aminocamptothecin: the effect of fractionation and timing of administration. Int J Radiat Oncol Biol Phys 1999; 44 (3): 659–664.PubMedCrossRefGoogle Scholar
  27. 27.
    Furman WL, Stewart CF, Poquette CA, et al. Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 1999; 17 (6): 1815–1824.PubMedGoogle Scholar
  28. 28.
    Rodriguez-Galindo C, Radomski K, Stewart CF, Furman W, Santana VM, Houghton Pi. Clinical use of topoisomerase I inhibitors in anticancer treatment. Med Pediatr Oncol 2000; 35 (4): 385–402.PubMedCrossRefGoogle Scholar
  29. 29.
    Ohdo S, Makinosumi T, Ishizaki T, et al. Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice. J Pharmacol Exp Ther 1997; 283 (3): 1383–1388.PubMedGoogle Scholar
  30. 30.
    Kirichenko AV, Mason K, Straume M, Teates CD, Rich TA. Nuclear scintigraphic assessment of intestinal dysfunction after combined treatment with 9-amino-20(S)-camptothecin (9-AC) and irradiation. Int J Radiat Oncol Biol Phys 2000; 47 (4): 1043–1049.PubMedCrossRefGoogle Scholar
  31. 31.
    Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 1993; 85 (4): 271–291.PubMedCrossRefGoogle Scholar
  32. 32.
    O’Dwyer PJ, LaCreta FP, Haas NB, et al. Clinical, pharmacokinetic and biological studies of topotecan. Cancer Chemother Pharmacol 1994; 34 Suppl:S46–S52.PubMedCrossRefGoogle Scholar
  33. 33.
    Perez-Soler R, Glisson BS, Lee JS, et al. Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 1996; 14 (10): 2785–2790.PubMedGoogle Scholar
  34. 34.
    Perez-Soler R, Fossella FV, Glisson BS, et al. Phase II study of topotecan in patients with advanced nonsmall-cell lung cancer previously untreated with chemotherapy. J Clin Oncol 1996; 14 (2): 503–513.PubMedGoogle Scholar
  35. 35.
    Robert F, Soong SJ, Wheeler RH. A phase II study of topotecan in patients with recurrent head and neck cancer. Identification of an active new agent. Am J Clin Oncol 1997; 20 (3): 298–302.PubMedCrossRefGoogle Scholar
  36. 36.
    Lamond JP, Wang M, Kinsella TJ, Boothman DA. Concentration and timing dependence of lethality enhancement between topotecan, a topoisomerase I inhibitor, and ionizing radiation. Int JRadiat Oncol Biol Phys 1996; 36 (2): 361–368.CrossRefGoogle Scholar
  37. 37.
    Kim JH, Kim SH, Kolozsvary A, Khil MS. Potentiation of radiation response in human carcinoma cells in vitro and murine fibrosarcoma in vivo by topotecan, an inhibitor of DNA topoisomerase I. Int J Radiat Oncol Biol Phys 1992; 22 (3): 515–518.PubMedCrossRefGoogle Scholar
  38. 38.
    Boscia RE, Korbut T, Holden SA, Ara G, Teicher BA. Interaction of topoisomerase I inhibitors with radiation in cis-diamminedichloroplatinum(II)-sensitive and -resistant cells in vitro and in the FSAIIC fibrosarcoma in vivo. Int J Cancer 1993; 53 (1): 118–123.PubMedCrossRefGoogle Scholar
  39. 39.
    Graham MV, Jahanzeb M, Dresler CM, Cooper JD, Emami B, Mortimer JE. Results of a trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall-cell lung cancer. Int J Radiat Oncol Biol Phys 1996; 36 (5): 1215–1220.PubMedCrossRefGoogle Scholar
  40. 40.
    Rothenberg ML, Blanke CD. Topoisomerase I inhibitors in the treatment of colorectal cancer. Semin Oncol 1999; 26 (6): 632–639.PubMedGoogle Scholar
  41. 41.
    Takeda K, Negoro S, Kudoh S, et al. Phase UII study of weekly irinotecan and concurrent radiation therapy for locally advanced non-small cell lung cancer. Br J Cancer 1999; 79 (9–10): 1462–1467.PubMedCrossRefGoogle Scholar
  42. 42.
    Tamura K, Takada M, Kawase I, et al. Enhancement of tumor radio-response by irinotecan in human lung tumor xenografts. Jpn J Cancer Res 1997; 88 (2): 218–223.PubMedCrossRefGoogle Scholar
  43. 43.
    Omura M, Torigoe S, Kubota N. SN-38, a metabolite of the camptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation in human colon adenocarcinoma cells grown as spheroids. Radiother Oncol 1997; 43 (2): 197–201.PubMedCrossRefGoogle Scholar
  44. 44.
    Pantazis P, Harris N, Mendoza J, Giovanella B. Conversion of 9-nitro-camptothecin to 9-aminocamptothecin by human blood cells in vitro. Eur J Haematol 1994; 53 (4): 246–248.PubMedCrossRefGoogle Scholar
  45. 45.
    Bernacki RJ, Pera P, Gambacorta P, Brun Y, Greco WR. In vitro antitumor activity of 9-nitrocamptothecin as a single agent and in combination with other antitumor drugs. Ann N YAcad Sci 2000; 922: 293–297.CrossRefGoogle Scholar
  46. 46.
    Kobayashi K, Shinbara A, Kamimura M, et al. Irinotecan (CPT-11) in combination with weekly administration of cisplatin (CDDP) for non-small-cell lung cancer. Cancer Chemother Pharmacol 1998; 42 (1): 53–58.PubMedCrossRefGoogle Scholar
  47. 47.
    Fukuoka M, Masuda N, Kudoh S, Negoro S. Irinotecan in small-cell lung cancer-Japanese trials. Oncology (Huntingt) 2000; 14 (7 Suppl 5): 57–62.Google Scholar
  48. 48.
    Komaki R, Janjan NA, Ajani JA, et al. Phase I study of irinotecan and concurrent radiation therapy for upper GI tumors. Oncology (Huntingt) 2000; 14 (12 Suppl 14): 34–37.Google Scholar
  49. 49.
    Mitchell EP. Irinotecan in preoperative combined-modality therapy for locally advanced rectal cancer. Oncology (Huntingt) 2000; 14 (12 Suppl 14): 56–59.Google Scholar
  50. 50.
    Saltz LB. Clinical Use of Irinotecan: Current Status and Future Considerations. Oncologist 1997; 2 (6): 402–409.PubMedGoogle Scholar

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© Springer Science+Business Media New York 2003

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  • Tyvin A. Rich

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