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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1995 Aug;86(8):776–782. doi: 10.1111/j.1349-7006.1995.tb02468.x

A New Water‐soluble Camptothecin Derivative, DX‐8951f, Exhibits Potent Antitumor Activity against Human Tumors in vitro and in vivo

Ikuo Mitsui 1,✉, Eiji Kumazawa 1, Yasuhide Hirota 1, Masashi Aonuma 1, Masamichi Sugimori 1, Satoru Ohsuki 1, Kouichi Uoto 1, Akio Ejima 1, Hirofumi Terasawa 1, Keiki Sato 1
PMCID: PMC5920901  PMID: 7559102

Abstract

CPT‐11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT‐11 is a pro‐drug that is converted to an active metabolite, SN‐38, in vivo by enzymes such as carboxylesterase. We synthesized a water‐soluble and non‐pro‐drug analog of camptothecin, DX‐8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti‐proliferative activity of DX‐8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN‐38 or SK&F 10486‐A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX‐8951f administered i.v. at 4‐day intervals against human gastric adenocarcinoma SC‐6 xenografts was greater than that of CPT‐11 or SK&F 10486‐A. Moreover, it overcame P‐glycoprotein‐mediated multi‐drug resistance. These data suggest that DX‐8951f has a high antitumor activity and is a potential therapeutic agent.

Keywords: Camptothecin, Topoisomerase I, P‐Glycoprotein, CPT‐11, Topotecan

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REFERENCES

  • 1. ) Wall , M. E. , Wani , M. C. , Cook , C. E. , Palmar , K. H. , McPhail , A. T. and Sim , G. A.Plant antitumor agents, I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptothecaacuminata . J. Am. Chem. Soc. , 88 , 3888 – 3890 ( 1966. ). [Google Scholar]
  • 2. ) Hsiang , Y.‐H. , Hertzberg , R. , Hecht , S. and Liu , L. F.Camptothecin induces protein‐linked DNA breaks via mammalian DNA topoisomerase I . J. Biol Chem. , 260 , 14873 – 14878 ( 1985. ). [PubMed] [Google Scholar]
  • 3. ) Hsiang , Y.‐H. and Liu , L. F.Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin . Cancer Res. , 48 , 1722 – 1726 ( 1988. ). [PubMed] [Google Scholar]
  • 4. ) 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 – 4638 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) 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 – 795 ( 1971. ). [PubMed] [Google Scholar]
  • 6. ) Gottlieb , J. A. , Guarino , A. M. , Call , J. B. , Oliverio , V. T. and Block , J. B.Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC‐100880) . Cancer Chemother. Rep. , 54 , 461 – 470 ( 1970. ). [PubMed] [Google Scholar]
  • 7. ) Muggia , F. M. , Creaven , P. J. , Hansen , H. H. , Cohen , M. H. and Selawry , O. S.Phase I clinical trial of weekly and daily treatment with camptothecin (NSC‐100880): correlation with preclinical studies . Cancer Chemother. Rep. , 56 , 515 – 521 ( 1972. ). [PubMed] [Google Scholar]
  • 8. ) Kunimoto , T. , Nitta , K. , Tanaka , T. , Uehara , N. , Baba , H. , Takeuchi , M. , Yokokura , T. , Sawada , S. , Miyasaka , T. and Mutai , M.Antitumor activity of 7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin, a novel water‐soluble derivative of camptothecin, against murine tumors . Cancer Res. , 47 , 5944 – 5947 ( 1987. ). [PubMed] [Google Scholar]
  • 9. ) Ohno , R. , Okada , K. , Masaoka , T. , Kuramoto , A. , Arima , T. , Yoshida , Y. , Ariyoshi , H. , Ichimaru , M. , Sakai , Y. , Oguro , M. , Ito , Y. , Morishima , Y. , Yokomaku , S. and Ota , K.An early phase II study of CPT‐11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma . J. Clin. Oncol. , 8 , 1907 – 1912 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Masuda , N. , Fukuoka , M. , Kusunoki , Y. , Matsui , K. , Takifuji , N. , Kudoh , S. , Negoro , S. , Nishioka , M. , Nakagawa , K. and Takada , M.CPT‐11: a new derivative of campthothecin for the treatment of refractory or relapsed small‐cell lung cancer . J. Clin. Oncol. , 10 , 1225 – 1229 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Fukuoka , M. , Niitani , H. , Suzuki , A. , Motomiya , M. , Hasegawa , K. , Nishiwaki , Y. , Kuriyama , T. , Ariyoshi , Y. , Negoro , S. , Masuda , N. , Nakajima , S. and Taguchi , T.A phase II study of CPT‐11, a new derivative of camptothecin, for previously untreated non‐small‐cell lung cancer . J, Clin. Oncol. , 10 , 16 – 20 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Shimada , Y. , Yoshino , M. , Wakui , A. , Nakao , I. , Futatsuki , K. , Sakata , Y. , Kambe , M. , Taguchi , T. and Ogawa , N.Phase II study of CPT‐11, a new camptothecin derivative, in metastatic colorectal cancer . J. Clin. Oncol. , 11 , 909 – 913 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Futatsuki , K. , Wakui , A. , Nakao , I. , Sakata , Y. , Kambe , M. , Shimada , Y. , Yoshino , M. , Taguchi , T. and Ogawa , N.Late phase II study of Irinotecan hydrochloride (CPT‐11) in advanced gastric cancer . Jpn. J. Cancer Chemother. , 21 , 1033 – 1038 ( 1994. ) ( in Japanese ). [PubMed] [Google Scholar]
  • 14. ) Takeuchi , S. , Takamizawa , H. , Takeda , Y. , Okawa , T. , Tamaya , T. , Noda , K. , Sugawa , T. , Sekiba , K. , Yakushiji , M. and Taguchi , T.Clinical study of CPT‐11, camptothecin derivative, on gynecological malignancy . Proc. Am. Soc. Clin. Oncol. , 10 , 189 ( 1991. ). [Google Scholar]
  • 15. ) Kanzawa , F. , Sugimoto , Y. , Minato , K. , Kasahara , K. , Bungo , M. , Nakagawa , K. , Fujiwara , Y. , Liu , L. F. and Saijo , N.Establishment of a camptothecin analogue (CPT‐11)‐resistant cell line of human non‐small cell lung cancer: characterization and mechanism of resistance . Cancer Res. , 50 , 5919 – 5924 ( 1990. ). [PubMed] [Google Scholar]
  • 16. ) Kawato , Y. , Furuta , T. , Aonuma , M. , Yasuoka , M. , Yokokura , T. and Matsumoto , K.Antitumor activity of a camptothecin derivative, CPT‐11, against human tumor xenografts in nude mice . Cancer Chemother. Pharmacol. , 28 , 192 – 198 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Ohe , Y. , Sasaki , Y. , Shinkai , T. , Eguchi , K. , Tamura , T. , Kojima , A. , Kunikane , H. , Okamoto , H. , Karato , A. , Ohmatsu , H. , Kanzawa , F. and Saijo , N.Phase I study and pharmacokinetics of CPT‐11 with 5‐day continuous infusion . J. Natl. Cancer Inst. , 84 , 972 – 974 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Tsuji , T. , Kaneda , N. , Kado , K. , Yokokura , T. , Yoshimoto , T. and Tsuru , D.CPT‐11 converting enzyme from rat serum: purification and some properties . J. Pharmacobio-Dyn. , 14 , 341 – 349 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Kawato , Y. , Sekiguchi , M. , Akahane , K. , Tsutomi , Y. , Hirota , Y. , Kuga , H. , Suzuki , W. , Hakusui , H. and Sato , K.Inhibitory activity of camptothecin derivatives against acetylcholinesterase in dogs and their binding activity to acetylcholme receptors in rats . J. Pharm. Pharmacol. , 45 , 444 – 448 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Kingsbury , W. D. , Boehm , J. C. , Jakas , D. R. , Holden , K. G. , Hecht , S. M. , Gallagher , G. , Caranfa , M. J. , McCabe , F. L. , Faucette , L. F. , Johnson , R. K. and Hertzberg , R. P.Synthesis of water‐soluble (aminoalkyl) camptothecin analogues: inhibition of topoisomerase I and antitumor activity . J. Med. Chem. , 34 , 98 – 107 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Terasawa , H. , Ohsuki , S. and Uoto , K.Hexa‐cyclic compound . European Patent 0495432A1 ( 1992. ).
  • 22. ) 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]
  • 23. ) Weinstein , J. N. , Kohn , K. W. , Grever , M. R. , Viswanadhan , V. N. , Rubinstein , L. V. , Monks , A. P. , Scudiero , D. A. , Welch , L. , Koutsoukos , A. D. , Chiausa , A. J. and Paull , K. D.Neural computing in cancer drug development: predicting mechanism of action . Science , 258 , 447 – 451 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Ishii , K. , Hasegawa , T. , Fujisawa , K. and Andoh , T.Rapid purification and characterization of DNA topoisomerase I from cultured mouse mammary carcinoma FM3A cells . J. Biol. Chem. , 258 , 12728 – 12732 ( 1983. ). [PubMed] [Google Scholar]
  • 25. ) Kawato , Y. , Aonuma , M. , Hirota , Y. , Kuga , H. and Sato , K.Intracellular roles of SN‐38, a metabolite of the camptothecin derivative CPT‐11, in the antitumor effect of CPT‐11 . Cancer Res. , 51 , 4187 – 4191 ( 1991. ). [PubMed] [Google Scholar]
  • 26. ) Chen , A. Y. , Yu , C. , Potmesil , M. , Wall , M. E. , Wani , M. C. and Liu , L. F.Camptothecin overcomes MDR1‐mediated resistance in human KB carcinoma cells . Cancer Res. , 51 , 6039 – 6044 ( 1991. ). [PubMed] [Google Scholar]
  • 27. ) Hendricks , C. B. , Rowinsky , E. K. , Grochow , L. B. , Donehower , R. C. and Kaufmann , S. H.Effect of P‐glycoprotein expression on the accumulation and cytotoxicity of Topotecan (SK&F 104864), a new camptothecin analogue . Cancer Res. , 52 , 2268 – 2278 ( 1992. ). [PubMed] [Google Scholar]
  • 28. ) Goldstein , L. J. , Galski , H. , Fojo , A. , Willingham , M. , Lai , S.‐L. , Gazdar , A. , Pirker , R. , Green , A. , Crist , W. , Brodeur , G. M. , Lieber , M. , Cossman , J. , Gottesman , M. M. and Pastan , I.Expression of a multidrug resistance gene in human cancers . J. Natl. Cancer Inst. , 81 , 116 – 124 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Rowinsky , E. K. , Grochow , L. B. , Hendricks , C. B. , Ettinger , D. S. , Forastiere , A. A. , Hurowitz , L. A. , McGuire , W. P. , Sartorius , S. E. , Lubejko , B. G. , Kaufmann , S. H. and Donehower , R. C.Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor . J. Clin. Oncol. , 10 , 647 – 656 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Hochster , H. , Liebes , L. , Speyer , J. , Sorich , J. , Taubes , B. , Oratz , R. , Wernz , J. , Chachoua , A. , Raphael , B. , Vinci , R. Z. and Blum , R. H.Phase I trial of low‐dose continuous topotecan infusion in patients with cancer: an active and well‐tolerated regimen . J. Clin. Oncol. , 12 , 553 – 559 ( 1994. ). [DOI] [PubMed] [Google Scholar]

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