Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1995 Oct;86(10):978–984. doi: 10.1111/j.1349-7006.1995.tb03010.x

Protective Effects of Kampo Medicines and Baicalin against Intestinal Toxicity of a New Anticancer Camptothecin Derivative, Irinotecan Hydrochloride (CPT‐11), in Rats

Kiyoshi Takasuna 1,✉, Yoshio Kasai 1, Yutaka Kitano 1, Kazuhiko Mori 1, Reiko Kobayashi 1, Takehiro Hagiwara 1, Kohji Kakihata 1, Masaaki Hirohashi 1, Mamoru Nomura 1, Eiichi Nagai 2, Tetsuya Kamataki 3
PMCID: PMC5920598  PMID: 7493918

Abstract

In clinical use, irinotecan hydrochloride (CPT‐11; 7‐ethyl‐10‐[4‐(piperidmo)‐l‐piperidino]carbonyl‐oxycamptothecin), a novel antitumor agent, causes a relatively high incidence of severe forms of diarrhea. We investigated whether baicalin, an inhibitor of β‐glucuronidase, which deconjugates the glucuronide of the active metabolite of CPT‐11, SN‐38 (7‐ethyl‐10‐hydorxycamptothecin), and Japanese herbal medicines (Kampo medicines) which contain baicalin can ameliorate CPT‐11‐induced intestinal toxicity in rats. CPT‐11 (60 mg/kg i.v. once daily for 4 consecutive days) induced intestinal toxicity characterized by diarrhea, loss of body weight, anorexia and disruption of intestinal epithelium. Treatment with baicalin (25 mg/kg p.o. twice daily) or Kampo medicines (TJ‐14 and TJ‐114; 1 g/kg p.o. twice daily) from the day before to 4 or 10 days after the start of CPT‐11 administration resulted in significantly decreased weight loss, improved anorexia and a delayed onset of diarrheal symptoms. Histological examination revealed that Kampo medicine‐treated animals had less damage to the intestinal epithelium and that damage was repaired more rapidly than in control rats. These results suggest that the prophylactic use of Kampo medicines (TJ‐14 and TJ‐114) may be of value against CPT‐11‐induced intestinal toxicity.

Keywords: CPT‐11 —Diarrhea, Kampomedicine, Baicalin, β‐Glucuronidase

Full Text

The Full Text of this article is available as a PDF (481.5 KB).

REFERENCES

  • 1. ) Wall , M. E. , Wani , M. C. , Cook , C. E. , Palmar , K. H. , McPhail , A. T. and Sim , G.A. Plant antitumor agents. 1. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata . J. Am. Chem. Soc. , 88 , 3888 – 3890 ( 1966. ). [Google Scholar]
  • 2. ) 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]
  • 3. ) Moerter , C. G. , Schutt , A. J. , Reitemeier , R. J. and Hahn , R. G.Phase II study of camptothecin (NSC‐100880) in the treatment of advanced gastrointestinal cancer . Cancer Chemother. Rep. , 56 , 95 – 101 ( 1972. ). [PubMed] [Google Scholar]
  • 4. ) 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]
  • 5. ) 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]
  • 6. ) 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]
  • 7. ) Takeuchi , S. , Dobashi , K. , Fujimoto , S. , Tanaka , K. , Suzuki , M. , Terashima , Y. , Hasumi , K. , Akiya , K. , Negishi , Y. , Tamaya , T. , Tanizawa , O. , Sugawa , T. , Umesaki , N. , Sekiba , K. , Aono , T. , Nakano , H. , Noda , K. , Shiota , M. , Yakushiji , M. , Sugiyama , T. , Hashimoto , M. , Yajima , A. , Takamizawa , H. , Sonoda , T. , Takeda , Y. , Tomoda , Y. , Ohta , M. , Ozaki , M. , Hirabayashi , K. , Hiura , M. , Hatae , M. , Nishigaki , K. and Taguchi , T.A late Phase II study of CPT‐11 on uterine cervical cancer and ovarian cancer . Jpn. J. Cancer Chemother. , 18 , 1681 – 1689 ( 1991. ) ( in Japanese ). [PubMed] [Google Scholar]
  • 8. ) 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. Aphase 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]
  • 9. ) 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]
  • 10. ) Masuda , N. , Fukuoka , M. , Kudoh , S. , Kusunoki , Y. , Matsui , K. , Nakazawa , K. , Hirashima , T. , Tamanoi , M. , Nitta , T. , Yana , T. , Negoro , S. , Takifuji , N. and Takada , M.Phase I study of irinotecan and cisplatin with granulo‐cyte colony‐stimulating factor support for advanced non‐small‐cell lung cancer . J. Clin. Oncol , 12 , 90 – 96 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Takasuna , K. , Yamashita , N. , Kasai , Y. , Kitano , Y. , Mori , K. , Takahashi , M. , Usui , C. and Hirohashi , M.Study on emetic response of CPT‐11, a new anti‐cancer drug, in dogs, ferrets and suncus . Jpn. J. Pharmacot , 55 ( Suppl. I ), 202 ( 1991. ). [Google Scholar]
  • 12. ) Ohe , Y. , Sakai , 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 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Abigerges , D. , Armand , J.‐P. , Chabot , G. G. , DaCosta , L. , Fadel , E. , Cote , C. , Herait , P. and Gandia , D.Irinotecan (CPT‐11) high‐dose escalation using intensive high‐dose loperamide to control diarrhea . J. Natl. Cancer Inst. , 86 , 446 – 449 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Kawato , Y. , Tsutomi , T. , Akahane , K. , Sekiguchi , M. and Sato , K.Inhibitory effect of CPT‐11, a derivative of camptothecin, on acetylcholinesterase, and its binding ability to acetylcholine receptors . Clin. Rep. , 24 , 7407 – 7412 ( 1990. ) ( in Japanese ). [Google Scholar]
  • 15. ) Takasuna , K. , Kasai , Y. , Kitano , Y. , Mori , K. , Kakihata , K. , Hirohashi , M. and Nomura , M.Study on the mechanisms of diarrhea induced by a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT‐11), in rats . Folia Pharmacol. Jpn. , 105 , 447 – 460 ( 1995. ) ( in Japanese ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Kaneda , N. , Nagata , H. , Furuta , T. and Yokokura , T.Metabolism and pharmacokinetics of the camptothecin analogue CPT‐11 in the mouse . Cancer Res. , 50 , 1715 – 1720 ( 1990. ). [PubMed] [Google Scholar]
  • 17. ) 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]
  • 18. ) Kaneda , N. and Yokokura , T.Nonlinear pharmacokinetics of CPT‐11 in rats . Cancer Res. , 50 , 1721 – 1725 ( 1990. ). [PubMed] [Google Scholar]
  • 19. ) Atsumi , R. , Suzuki , W. and Hakusui , H.Identification of the metabolites of irinotecan, a new derivative of camptothecin, in rat bile and its biliary excretion . Xenobiotica , 21 , 1159 – 1169 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Narita , M. , Nagai , E. , Hagiwara , H. , Aburada , M. , Yokoi , T. and Kamataki , T.Inhibition of β‐glucuronidase by natural glucuronides of Kampo medicines using glucu‐ronide of SN‐38 (7‐ethyl‐10‐hydroxycamptothecin) as a substrate . Xenobiotica , 23 , 5 – 10 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Funk , M. A. and Baker , D. H.Effect of fiber, protein source and time of feeding on methotrexate toxicity in rats . J. Nutr. , 121 , 1673 – 1683 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Houghton , P. J. , Cheshire , P. J. , Hallman , J. C. , Bissery , M. C. , Mathieru‐Boué , A. and Houghton , J. A.Therapeutic efficacy of the topoisomerase I inhibitor 7‐ethyl‐10‐(4‐ [1 ‐piperidino] ‐1 ‐piperidino)carbonyloxycamptothecin against human tumor xenografts: lack of cross‐resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9‐dimethylaminomethyl‐10‐hydroxy‐camptothecin . Cancer Res. , 53 , 2823 – 2829 ( 1993. ). [PubMed] [Google Scholar]
  • 23. ) Masuda , N. , Fukuoka , M. , Kudoh , S. , Kusunoki , Y. , Matsui , K. , Takifuji , N. , Nakagawa , K. , Tamanoi , M. , Nitta , T. , Hirashima , T. , Negoro , S. and Takada , M.Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer . Br. J. Cancer , 68 , 777 – 782 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Ooms , L. A. A. , Degryse , A. D. and Jansen , P. A. J.Mechanisms of action of loperamide . Scand. J. Gastro-enterol. , 19 , 145 – 155 ( 1984. ). [PubMed] [Google Scholar]

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

RESOURCES