Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1997 Feb;88(2):218–223. doi: 10.1111/j.1349-7006.1997.tb00369.x

Enhancement of Tumor Radio‐response by Irinotecan in Human Lung Tumor Xenografts

Kenji Tamura 1,6,✉, Minoru Takada 1,2, Ichirou Kawase 1, Takuhito Tada 3, Shinzoh Kudoh 4, Kyouichi Okishio 4, Masahiro Fukuoka 5, Naoki Yamaoka 6, Yasuhiro Fujiwara 6, Michio Yamakido 6
PMCID: PMC5921360  PMID: 9119752

Abstract

We investigated the ability of 7‐ethyl‐10‐[4‐(l‐piperidino)‐l‐piperidmo]carbonyloxycamptothecin (CPT‐11) to increase tumor radio‐response in vivo using human lung tumor xenografts. The xenografts were treated with (1) CPT‐11 (10 mg/kg) intraperitoneally on days 1, 5 and 9, (2) single dose radiation (10 Gy/leg) on day 1, or (3) a combination regimen of both treatments in which radiation was given 1 h after the first dose of CPT‐11. DNA flow cytometry studies were performed to define the cell cycle changes following treatment for 1 to 12 h with 0, 0.5, 2.0 or 8.0 ng/ml SN‐38, the major active metabolite of CPT‐11. In both small cell lung cancer (MS‐1) and small cell/large cell carcinoma (LX‐1) xenografts, combination treatment resulted in significant tumor regression compared with the use of CPT‐11 (P=0.0005, 0.0053) or radiation treatment (P=0.00221, 0.0035) alone. Neither severe body weight loss nor enhanced skin reaction was observed following the combined treatment. In flow cytometry studies, the proportion of cells in G2/M‐phase, the most radio‐sensitive phase, increased after 1 h exposure to the lowest dose of SN‐38 (0.5 ng/ml). These findings suggest that CPT‐11 is a potent radiosensitizing agent, and that its activity is related to the cell cycle. This is the first report to indicate that CPT‐11 serves as a radiosensitizer in vivo.

Keywords: CPT‐11, Radiosensitization, Lung cancer, Xenograft

Full Text

The Full Text of this article is available as a PDF (343.2 KB).

REFERENCES

  • 1. ) Slichenmyer , W. J. , Rowinsky , E. K. , Donehower , R. C. and Kaufmann , S. H.The current status of camptothecin analogues as antitumor agents , J. Natl. Cancer Inst. , 85 , 271 – 291 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Potmesil , M.Camptothecins: from bench research to hospital wards . Cancer Res. , 54 , 1431 – 1439 ( 1994. ). [PubMed] [Google Scholar]
  • 3. ) Schaake‐Koning , C. , van den Bogaert , W. , Dalesio , O. , Festen , J. , Hoogenhout , J. and van Houtte , P.Effects of concomitant cisplatin and radiotherapy on inoperable non‐small‐cell lung cancer . N. Engl. J. Med. , 326 , 524 – 530 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Takada , M. , Fukuoka , M. , Furuse , K. , Ariyoshi , Y. , Ikegani , H. and Kurita , Y.Phase III study of concurrent versus sequential thoracic radiotherapy in combination with small cell lung cancer . 32nd Proc. Am. Soc. Clin. Oncol , 372 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Kudoh , S. , Takada , M. , Masuda , N. , Nakagawa , K. , Itoh , K. , Kusunoki , Y. , Negoro , S. , Matsui , K. , Takifuji , N. , Morino , H. and Fukuoka , M.Enhanced antitumor efficacy of a combination of CPT‐11, a new derivative of camptothecin, and cisplatin against human lung tumor xenografts . Jpn. J. Cancer Res. , 84 , 203 – 207 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Goldin , A. , Venditti , J. M. , Macdonald , J. S. , Muggia , F. M. , Henney , J. E , and Devita , V.Jr.Current results of the screening program at the Division of Cancer Treatment, National Cancer Institute . Eur, J. Cancer , 17 , 129 – 142 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Marie‐Christine , B. , Daniel , G. , Françoise , G.‐V. and Françious , L.Experimental antitumor activity of Taxotere (RP56976, NSC628503), a taxol analogue . Cancer Res. , 51 , 4845 – 4852 ( 1991. ). [PubMed] [Google Scholar]
  • 8. ) Thomas , H. C. , Wilbur , R. L. , Donald , J. D. , Billy , J. R. , Daniel , P. G.Jr. and Schabel , F. M. , Jr.Toxicity and anticancer activity of a new triazine antifolate (NSC 127755) . Cancer Res. , 42 , 1707 – 1715 ( 1982. ). [PubMed] [Google Scholar]
  • 9. ) Nissen , V. C.A detergent‐trypsin method for the preparation of nuclei for flow cytometric DNA analysis . Cytometry , 3 , 323 – 327 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Belli , J. A. and Piro , A. J.The interaction between radiation and adriamycin damage in mammalian cells . Cancer Res. , 37 , 1624 – 1630 ( 1977. ). [PubMed] [Google Scholar]
  • 11. ) Phillips , T. L. and Fu , K. K.The interaction of drug and radiation effects on normal tissues . Int. J. Radial. Oncol. Biol. Phys. , 4 , 59 – 64 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Vokes , E. E. and Weichselbaum , R. R.Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors . J. Clin. Oncol. , 8 , 911 – 934 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Choy , H. , Rodriguez , F. F. , Koester , S. , Hilsenbeck , S. and Vonhoff , D. D.Investigation of taxol as a potential radiation sensitizer . Cancer , 71 , 3774 – 3778 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Liebmann , J. , Cook , J. A. , Fisher , J. , Teague , D. and Mitchell , J. B.In vitro studies of taxol as a radiation sensitizer in human tumor cells . J. Natl. Cancer Inst. , 86 , 441 – 446 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Musk , S. R. and Steel , G. G.The inhibition of cellular recovery in human tumour cells by inhibitors of topoisomerase . Br. J. Cancer , 62 , 364 – 367 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Boothman , D. A. , Wang , M. , Schea , R. A. , Burrows , H. L. , Strickfaden , S. and Owens , J. K.Posttreatment exposure to camptothecin enhances the lethal effects of x‐rays on radioresistant human malignant melanoma cells . Int. J. Radiat. Oncol Biol. Phys. , 24 , 939 – 948 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Boscia , R. E. , Korbut , T. , Holden , S. A. , Ara , G. and Teicher , B. A.Interaction of topoisomerase I inhibitors with radiation in cis‐diammine dichloroplatinum (II)‐sensitive and ‐resistant cells in vitro and in the FSAIIC flbrosarcoma in vivo . Int. J. Cancer , 53 , 118 – 123 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Mattern , M. R. , Hofmann , G. A. , McCabe , F. L. and Johnson , R. K.Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864) . Cancer Res. 51 , 5813 – 5816 ( 1991. ). [PubMed] [Google Scholar]
  • 19. ) Kim , J. H. , Kim , S. H. , Kolozsvary , A. and Khil , M. S.Potentiation of radiation response in human carcinoma cells in vitro and murine flbrosarcoma in vivo by topotecan, an inhibitor of DNA topoisomerase I . Int. J. Radiat. Oncol Biol Phys. , 22 , 515 – 518 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Terashima , R. and Tolmach , L. J.X‐ray sensitivity and DNA synthesis in synchronous populations of Hela cells . Science , 140 , 490 – 492 ( 1963. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Sinclair , W. K. and Morton , R. A.X‐ray sensitivity during the cell generation cycle of cultured Chinese hamster cells . Radial. Res. , 29 , 450 – 474 ( 1966. ). [PubMed] [Google Scholar]
  • 22. ) Hall , E. J. “ Radiobiology for the Radiologist ”, Ed , 3 ( 1988. ). J. B. Lippincott; , Philadelphia . [Google Scholar]
  • 23. ) Falk , S. J. and Smith , P. J.DNA damaging and cell cycle effects of the topoisomerase I poison camptothecin in irradiated human cells . Int. J. Radiat. Biol. , 61 , 749 – 757 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Strome , G. , Distelmans , W. , De Neve , W.Interaction between microtuble inhibitors and ionizing radiation . In “ Antitumor Drug‐Radiation Interaction ”, ed. , Hill B. T. and Bellamy A. S. , pp. 107 – 124 ( 1990. ). CRC Press; , Boca Raton , Florida . [Google Scholar]
  • 25. ) Tishler , R. B. , Gerard , C. R. , Hall , E. J. and Schiff , P. B.Taxol sensitized human astrocytoma cells to radiation . Cancer Res. , 52 , 3495 – 3497 ( 1992. ). [PubMed] [Google Scholar]
  • 26. ) Li , L. H. , Fraser , T. J. , Olin , E. J. and Bhuyan , B. K.Action of camptothecin on mammalian cells in culture . Cancer Res. , 32 , 2643 – 2650 ( 1972. ). [PubMed] [Google Scholar]
  • 27. ) Horwitz , S. B. and Horwitz , M. S.Effects of camptothecin on the breakage and repair of DNA during the cell cycle . Cancer Res. , 33 , 2834 – 2836 ( 1973. ). [PubMed] [Google Scholar]
  • 28. ) Drewinko , B. , Freireich , E. and Gottlieb , J.Lethal activity of camptothecin sodium on human lymphoma cells . Cancer Res. , 34 , 747 – 750 ( 1974. ). [PubMed] [Google Scholar]
  • 29. ) D'Arpa , P. , Beardmore , C. and Liu , L. F.Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons . Cancer Res. , 50 , 6919 – 6924 ( 1990. ). [PubMed] [Google Scholar]
  • 30. ) Kastan , M. B. , Onyekwere , O. , Sidransky , D. , Vogelstein , B. and Craig , R. W.Participation of p53 protein in the cellular response to DNA damage . Cancer Res. , 51 , 6304 – 6311 ( 1991. ). [PubMed] [Google Scholar]
  • 31. ) Del Bino , G. , Bruno , S. , Yi , P. N. and Darzynkiewicz , Z.Apoptotic cell death triggered by camptothecin or teniposide. The cell cycle specificity and effects of ionizing radiation . Cell Prolif. , 25 , 537 – 548 ( 1992. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES