Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1999 May;90(5):578–587. doi: 10.1111/j.1349-7006.1999.tb00786.x

In vitro Antitumor Activity of TAS‐103, a Novel Quinoline Derivative That Targets Topoisomerases I and II

Yoshimi Aoyagi 1, Takashi Kobunai 1, Teruhiro Utsugi 1, Tomoko Oh‐hara 2, Yuji Yamada 1,✉
PMCID: PMC5926096  PMID: 10391099

Abstract

TAS‐103 is a novel anticancer agent targeting both topoisomerase (Topo) I and Topo II, that stabilizes cleavable complexes of Topo‐DNA at the cellular level. In this study, the in vitro antitumor effects of TAS‐103 were compared with those of other known Topo I and Topo II inhibitors. TAS‐103 inhibited DNA synthesis more strongly than RNA and protein synthesis, and induced an increase of cell population in the S‐G2/M phase. The cytotoxicity of TAS‐103 was strongest against S‐phase cells, but its cell cycle phase specificity was not clear, and depended on drug concentration and exposure time. The cytotoxicity of TAS‐103 (IC50: 0.0030–0.23 μM) against various tumor cell lines was much stronger than that of VP‐16 and comparable to that of SN‐38. The cytotoxicity of TAS‐103 seemed to be more related to the amount of protein‐DNA complexes than to the accumulation of TAS‐103 in the cells. P‐Glycoprotein (P‐gp)‐mediated MDR, CDDP‐resistant and 5‐FU‐resistant cell lines did not show cross‐resistance to TAS‐103. Although PC‐7/CPT cells bearing a Topo I gene mutation showed cross‐resistance to TAS‐103, the sensitivity of P388/CPT, HT‐29/ CPT and St‐4/CPT cells, showing decreased Topo I expression, was not changed. KB/VM4 and HT‐29/Etp cells, showing decreased Topo II expression, were slightly cross‐resistant to TAS‐103. These results suggest that TAS‐103 may act as an inhibitor of both Topo I and Topo II at the cellular level. This property may be responsible for its strong antitumor effect and broad‐spectrum, growth‐inhibitory effect on drug‐resistant cell lines.

Keywords: TAS‐103, Quinoline derivative, Topoisomerase, Cytotoxicity, Drug resistance

Full Text

The Full Text of this article is available as a PDF (180.0 KB).

REFERENCES

  • 1).Sugimoto , Y. , Tsukahara , S. , Oh‐hara , T. , Isoe , T. and Tsuruo , T.Decreased expression of DNA topoisomerase I in camptothecin‐resistant tumor cell lines as determined by a monoclonal antibody . Cancer Res. , 50 , 6925 – 6930 ( 1990. ). [PubMed] [Google Scholar]
  • 2).Matsuo , K. , Kohno , K. , Takano , H. , Sato , S. , Kiue , A. and Kuwano , M.Reduction of drug accumulation and DNA topoisomerase II activity in acquired teniposide‐resistant human cancer KB cell lines . Cancer Res. , 50 , 5919 – 6824 ( 1990. ). [PubMed] [Google Scholar]
  • 3).Long , B. H. , Wang , L. , Lorico , A. , Wang , R. C. C. , Brattain , M. G. and Casazza , A. M.Mechanisms of resistance to etoposide and teniposide in acquired resistant human colon and lung carcinoma cell lines . Cancer Res. , 51 , 5275 – 5284 ( 1991. ). [PubMed] [Google Scholar]
  • 4).Kubota , N. , Nishio , K. , Takeda , Y. , Ohmori , T. , Funayama , Y. , Ogasawara , H. , Ohira , T. , Kunikake , H. , ter ashima , Y. and Saijo , N.Characterization of an etoposide‐resistant human ovarian cancer cell line . Cancer Chemother. Pharmacol. , 34 , 183 – 190 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 5).Tamura , H. , Kohchi , C. , Yamada , R. , Ikeda , T. , Koiwai , O. , Patterson , E. , Keene , D. J. , Okada , K. , Kjeidsen , E. , Nishikawa , K. and Andho , T.Molecular cloning of a cDNA of a camptothecin‐resistant human DNA topoisomerase I and identification of mutation sites . Nucleic Acids Res. , 19 , 69 – 75 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6).Kubota , N. , Kanzawa , F. , Nishio , K. , Takeda , Y. , Ohmori , T. , Fujiwara , Y. , ter ashima , Y. and Saijo , N.Detection of topoisomerase I gene point mutation in CPT‐11 resistant lung cancer cell line . Biochem. Biophys. Res. Commun. , 188 , 571 – 577 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 7).Bugg , B. Y. , Danks , M. K. , Beck , W. T. and Suttle , D. P.Expression of a mutant DNA topoisomerase II in CCRF‐CEM human leukemia cells selected for resistance to teniposide . Proc. Natl. Acad. Sci. USA , 88 , 7654 – 7658 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8).Minato , K. , Kanazawa , F. , Nishio , K. , Nakagawa , K. , Fujiwara , Y. and Saijo , N.Characterization of an etoposide‐resistant human small‐cell lung cancer cell line . Cancer Chemother. Pharmacol. , 26 , 313 – 317 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 9).Kawato , Y. , Aonuma , M. , Hirota , Y. , Kuga , H. and Sato , K.Intracellular roles of SN‐38, metabolite of the camp‐tothecin derivative CPT‐11, in the antitumor effect of CPT‐11 . Cancer Res. , 51 , 4187 – 4191 ( 1991. ). [PubMed] [Google Scholar]
  • 10).Sugimoto , Y. , Tsukahara , S. , Oh‐hara , T. , Liu , L. F. and Tsuruo , T.Elevated expression of DNA topoisomerase II in camptothecin‐resistant human tumor cell lines . Cancer Res. , 50 , 7962 – 7965 ( 1990. ). [PubMed] [Google Scholar]
  • 11).Kim , R. , Hirabayashi , N. , Nishiyama , M. , Jinushi , K. , Toge , T. and Okada , K.Experimental studies on biochemical modulation targeting topoisomerase I and II in human tumor xenografts in nude mice . Int. J. Cancer , 50 , 760 – 766 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 12).Whitacre , C. M. , Zborowska , E. , Gohdon , N. H. , Mackay , W. and Berger , N. A.Topotecan increases topoisomerase II α levels and sensitivity to treatment with etoposide in schedule‐dependent process . Cancer Res. , 57 , 1425 – 1428 ( 1997. ). [PubMed] [Google Scholar]
  • 13).Kano , Y. , Suzuki , K. , Akutsu , M. , Suda , K. , Inoue , Y. , Yoshida , M. , Sakamoto , S. and Miura , Y.Effects of CPT‐11 in combination with other anti‐cancer agent in culture . Int. J. Cancer , 50 , 604 – 610 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 14).Bertrand , R. , O'Connor , P. M. , Kerrigan , D. and Pommier , Y.Sequential administration of camptothecin and etoposide circumvents the antagonistic cytotoxicity of simultaneous drug administration in slowly growing human colon carcinoma HT‐29 cells . Eur. J. Cancer , 28A, 743 , 748 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 15).Bonner , J. A. and Kozelsky , T. F.The significance of the sequence of administration of topotecan and etoposide . Cancer Chemother. Pharmacol. , 39 , 109 – 112 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 16).Tolcher , A. W.A phase I study of topotecan (a topoisomerase I inhibitor) in combination with doxorubucin (a topoisomerase II inhibitor ). Proc. Am. Soc. Clin. Oncol. 13 , 422 ( 1994. ). [Google Scholar]
  • 17).Saijo , N.Clinical trials of irinotecan hydrochloride (CPT, campto injection, topotecan injection) in Japan . Ann. N.Y. Acad. Sci. , 803 , 292 – 305 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 18).Utsugi , T. , Aoyagi , K. , Asao , T. , Okazaki , S. , Aoyagi , Y. , Sano , M. , Wierzba , K. and Yamada , Y.Antitumor activity of a novel quinoline derivative, TAS‐103, with inhibitory effects on topoisomerase I and II . Jpn. J. Cancer Res. , 88 , 992 – 1002 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19).Skehan , P. , Storeng , R. , Scudiero , D. , Monks , A. , McMahon , J. , Vistica , D. , Warren , J. T. , Bokesch , H. , Kenney , S. and Boyd , M. R.New colorimetric cytotoxicity assay for anticancer‐drug screening . J. Natl. Cancer Inst. 82 , 1107 – 1112 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 20).Saotome , T. , Morita , H. and Umeda , M.Cytotoxicity test with simplified crystal violet staining method using microtitre plates and its application to injection drugs . Toxic. in Vitro , 3 , 317 – 321 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 21).Mosmann , T.Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays . J. Immunol. Methods , 65 , 55 – 63 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 22).Zwelling , L. A. , Hinds , M. , Chan , D. , Mayes , J. , Sie , K. L. , Parker , E. , Silberman , L. , Redcliffe , A. , Beran , M. and Blick , M.Characterization of an amsacrine‐resistant line of human leukemia cells . J. Biol. Chem. , 264 , 16411 – 16420 ( 1989. ). [PubMed] [Google Scholar]
  • 23).Ozawa , S. , Sugiyama , Y. , Mitsuhashi , J. and Inaba , M.Kinetic analysis of cell killing effect induced by cytosine arabinoside and cisplatin in relation to cell cycle phase specificity in human colon cancer and Chinese hamster cells . Cancer Res. , 49 , 3823 – 3828 ( 1989. ). [PubMed] [Google Scholar]
  • 24).Inaba , M. , Mitsuhashi , J. , Kawada , S. and Nakano , H.Different modes of cell‐killing action between DNA topoisomerase I and II inhibitors revealed by kinetic analysis . Jpn. J. Cancer Res. , 85 , 187 – 193 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25).Sone , S. , Ishii , K. and Tsuruo , T.Augmentation of 1‐β‐d‐Arabinofuranosylcytosine resistance in human KB epidermoid carcinoma cells upon induction of a second resistance to vincristine . Cancer Res. , 46 , 3099 – 3104 ( 1986. ). [PubMed] [Google Scholar]
  • 26).Fairchild , C. R. , Ivy , S. P. , Kao‐Shan , C. , Whang‐Peng , J. , Rosen , M. , Israel , M. A. , Melera , P. W. , Cowan , K. H. and Goldsmith , M. E.Isolation of amplified and overexpressed DNA sequences from adriamycin‐resistant human breast cancer cells . Cancer Res. , 47 , 5141 – 5148 ( 1987. ). [PubMed] [Google Scholar]
  • 27).Hong , W. S. , Saijo , S. , Sasaki , Y. , Minato , K. , Nakano , H. , Nakagawa , K. , Fujiwara , Y. , Nomura , K. and Twentyman , P. R.Establishment and characterization of cisplatin‐resistant sublines of human lung cancer cell lines . Int. J. Cancer , 41 , 462 – 67 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 28).Bungo , M. , Fujiwara , Y. , Kasahara , K. , Nakagawa , K. , Ohe , Y. , Sasaki , Y. , Irino , S. and Saijo , N.Decreased accumulation as a mechanism of resistance to cis‐diamminedichloroplatinum(II) in human non‐small cell lung cancer cell lines: relation to DNA damage and repair . Cancer Res. , 50 , 2549 – 2553 ( 1990. ). [PubMed] [Google Scholar]
  • 29).Ohmori , T. , Morikage , T. , Sugimoto , Y. , Fujiwara , Y. , Kasahara , K. , Nishio , K. , Ohta , S. , Sasaki , Y. , Takahashi , T. and Saijo , N.The mechanism of the difference in cellular uptake of platinum derivatives in non‐small cell lung cancer cell line (PC‐14) and its cisplatin‐resistant subline (PC‐14/CDDP) . Jpn. J. Cancer Res. , 84 , 83 – 92 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30).Johnston , P. G. , Drake , J. C. , Trepel , J. and Allegra , C. J.Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5‐fluorouracil‐sensitive and ‐resistant human cancer cell lines . Cancer Res. , 52 , 4306 – 312 ( 1992. ). [PubMed] [Google Scholar]
  • 31).D'Arpa , P. , Beadmore , C. and Liu , L. E.Involvement of nucleic acid synthesis in cell killing mechanism of topo‐isomerase poisons . Cancer Res. , 50 , 6919 – 6924 ( 1990. ). [PubMed] [Google Scholar]
  • 32).Hsiang , Y. , Lihou , M. G. and Liu , L. F.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 ( 1989. ). [PubMed] [Google Scholar]
  • 33).Roberge , M. , Th'ng , J. , Hamaguchi , J. and Bradbury , E. M.The topoisomerase II inhibitor VM‐26 induces marked changes in histone H1 kinase activity, histone Hi and H3 phosphorylation, and chromosome condensation in G2 phase and mitotic BHK cells . J. Cell Biol. , 111 , 1753 – 1762 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34).Taagepera , S. , Rao , P. N. , Drake , F. H. and Gorbsky , G. J.DNA topoisomerase IIα is the major chromosome protein recognized by the mitotic phosphoprotein antibody MPM‐2 . Proc. Natl. Acad. Sci. USA , 90 , 8407 – 8411 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35).Woessner , R. D. , Mattern , M. R. , Mirabelli , C. K. , Johnson , R. K. and Drake , F. H.Proliferation‐ and cell cycle‐dependent differences in expression of the 170 kDa and 180 kDa forms of topoisomerase II in NIH‐3T3 cells . Cell Growth Differ. , 2 , 209 – 214 ( 1991. ). [PubMed] [Google Scholar]
  • 36).Prosperi , E. , Marchese , G. and Astaldi‐Ricotti , G. C. B.Expression of the 170‐kDa and 180‐kDa isoforms of DNA topoisomerase II in resting and proliferating human lymphocytes . Cell Prolif. , 27 , 257 – 267 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 37).Poot , M. , Hiller , K. H. , Heimpel , S. and Hoehn , H.Distinct patterns of cell cycle distribution elicited by compounds interfering with DNA topoisomerase I and II activity . Exp. Cell Res. , 218 , 326 – 330 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 38).Bino , G. D. , Skierski , J. S. and Darzynkiewicz , Z.The concentration‐dependent diversity of effects of DNA topoisomerase I and II inhibitors on the cell cycle of HL‐60 cells . Exp. Cell Res. , 195 , 485 – 491 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 39).Kaufmann , S. H. , Karp , J. E. , Jones , R. J. , Miller , C. B. , Schneider , E. , Zwelling , L. A. , Cowan , K. , Wendel , K. and Burke , P. J.Topoisomerase II level and drug sensitivity in adult acute myelogenous leukemia . Blood , 83 , 517 – 530 ( 1994. ). [PubMed] [Google Scholar]
  • 40).Takatani , H. , Oka , M. , Fukuda , M. , Narasaki , F. , Nakano , R. , Ikeda , K. , ter ashi , K. , Kinoshita , A. , Soda , H. , Kanda , T. , Schneider , E. and Kohno , S.Gene mutation analysis and quantitation of DNA topoisomerase I in previously untreated non‐small cell lung carcinomas . Jpn. J. Cancer Res. , 88 , 160 – 165 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES