Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May 1;80(3-4):364–370. doi: 10.1038/sj.bjc.6690364

CPT-11 converting carboxylesterase and topoisomerase I activities in tumour and normal colon and liver tissues

S Guichard 1, C Terret 1, I Hennebelle 1, I Lochon 1, P Chevreau 2, E Frétigny 3, J Selves 4, E Chatelut 1,5, R Bugat 1,5, R Canal 1
PMCID: PMC2362335  PMID: 10408839

Abstract

CPT-11 is a prodrug activated by carboxylesterases to the active metabolite SN-38 which is a potent inhibitor of topoisomerase I. CPT-11 is of clinical interest in the treatment of colorectal cancer. We evaluated the activities of CPT-11 converting carboxylesterase (CPT-CE) and topoisomerase I (topo I) in 53 colorectal tumours, in eight liver metastases and in normal tissue adjacent to the tumours. Both CPT-CE and topo I activities were widely variable in the malignant and the normal tissue of patients with colorectal carcinomas. CPT-CE was only two to threefold lower in primary tumours compared to normal liver, suggesting that a local conversion to SN-38 might occur in tumour cells. CPT-CE was similar in liver and in normal colon tissues. Levels of topo I in tumour ranged from 580 to 84 900 U mg protein−1 and was above 40 000 U mg protein−1 in 11 of 53 patients. Similarly, a very high ratio (> 5) between tumour and normal tissues were observed in 12 of 53 patients. An inverse correlation was observed between the topo I activity and the clinical stage of disease. Clinical studies are in progress in our institution to explore a possible relationship between CPT-CE and topo I activities in tumour cells and the response to CPT-11-based chemotherapy in patients with colorectal cancer. © 1999 Cancer Research Campaign

Full Text

The Full Text of this article is available as a PDF (162.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Benedetti P., Fiorani P., Capuani L., Wang J. C. Camptothecin resistance from a single mutation changing glycine 363 of human DNA topoisomerase I to cysteine. Cancer Res. 1993 Sep 15;53(18):4343–4348. [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Bronstein I. B., Vorobyev S., Timofeev A., Jolles C. J., Alder S. L., Holden J. A. Elevations of DNA topoisomerase I catalytic activity and immunoprotein in human malignancies. Oncol Res. 1996;8(1):17–25. [PubMed] [Google Scholar]
  4. Codegoni A. M., Castagna S., Mangioni C., Scovassi A. I., Broggini M., D'Incalci M. DNA-topoisomerase I activity and content in epithelial ovarian cancer. Ann Oncol. 1998 Mar;9(3):313–319. doi: 10.1023/a:1008207125986. [DOI] [PubMed] [Google Scholar]
  5. Cornarotti M., Capranico G., Bohm S., Oriana S., Spatti G. B., Mariani L., Ballabio G., Zunino F. Gene expression of DNA topoisomerases I, II alpha and II beta and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. Int J Cancer. 1996 Aug 7;67(4):479–484. doi: 10.1002/(SICI)1097-0215(19960807)67:4<479::AID-IJC3>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  6. Creemers G. J., Lund B., Verweij J. Topoisomerase I inhibitors: topotecan and irenotecan. Cancer Treat Rev. 1994 Jan;20(1):73–96. doi: 10.1016/0305-7372(94)90011-6. [DOI] [PubMed] [Google Scholar]
  7. Danks M. K., Morton C. L., Pawlik C. A., Potter P. M. Overexpression of a rabbit liver carboxylesterase sensitizes human tumor cells to CPT-11. Cancer Res. 1998 Jan 1;58(1):20–22. [PubMed] [Google Scholar]
  8. Deffie A. M., Batra J. K., Goldenberg G. J. Direct correlation between DNA topoisomerase II activity and cytotoxicity in adriamycin-sensitive and -resistant P388 leukemia cell lines. Cancer Res. 1989 Jan 1;49(1):58–62. [PubMed] [Google Scholar]
  9. Giovanella B. C., Stehlin J. S., Wall M. E., Wani M. C., Nicholas A. W., Liu L. F., Silber R., Potmesil M. DNA topoisomerase I--targeted chemotherapy of human colon cancer in xenografts. Science. 1989 Nov 24;246(4933):1046–1048. doi: 10.1126/science.2555920. [DOI] [PubMed] [Google Scholar]
  10. Gupta E., Lestingi T. M., Mick R., Ramirez J., Vokes E. E., Ratain M. J. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res. 1994 Jul 15;54(14):3723–3725. [PubMed] [Google Scholar]
  11. Haaz M. C., Rivory L., Riché C., Vernillet L., Robert J. Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. Cancer Res. 1998 Feb 1;58(3):468–472. [PubMed] [Google Scholar]
  12. Hosokawa M., Maki T., Satoh T. Characterization of molecular species of liver microsomal carboxylesterases of several animal species and humans. Arch Biochem Biophys. 1990 Mar;277(2):219–227. doi: 10.1016/0003-9861(90)90572-g. [DOI] [PubMed] [Google Scholar]
  13. Husain I., Mohler J. L., Seigler H. F., Besterman J. M. Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. Cancer Res. 1994 Jan 15;54(2):539–546. [PubMed] [Google Scholar]
  14. Jansen W. J., Zwart B., Hulscher S. T., Giaccone G., Pinedo H. M., Boven E. CPT-11 in human colon-cancer cell lines and xenografts: characterization of cellular sensitivity determinants. Int J Cancer. 1997 Jan 27;70(3):335–340. doi: 10.1002/(sici)1097-0215(19970127)70:3<335::aid-ijc15>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  15. Jaxel C., Kohn K. W., Wani M. C., Wall M. E., Pommier Y. Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res. 1989 Mar 15;49(6):1465–1469. [PubMed] [Google Scholar]
  16. Kawato Y., Furuta T., Aonuma 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. doi: 10.1007/BF00685508. [DOI] [PubMed] [Google Scholar]
  17. Knab A. M., Fertala J., Bjornsti M. A. Mechanisms of camptothecin resistance in yeast DNA topoisomerase I mutants. J Biol Chem. 1993 Oct 25;268(30):22322–22330. [PubMed] [Google Scholar]
  18. Kojima A., Hackett N. R., Ohwada A., Crystal R. G. In vivo human carboxylesterase cDNA gene transfer to activate the prodrug CPT-11 for local treatment of solid tumors. J Clin Invest. 1998 Apr 15;101(8):1789–1796. doi: 10.1172/JCI119888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kunimoto T., Nitta K., Tanaka T., Uehara N., Baba H., Takeuchi M., Yokokura T., Sawada S., Miyasaka T., Mutai M. Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothec in, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res. 1987 Nov 15;47(22):5944–5947. [PubMed] [Google Scholar]
  20. Lund-Pero M., Jeppson B., Pero R. W. Reduced nonspecific steroidal esterase activity in human malignant tumor tissue from liver, colon and breast when compared to peritumoral and normal tissue levels. Anticancer Res. 1994 Nov-Dec;14(6B):2747–2753. [PubMed] [Google Scholar]
  21. Massaad L., de Waziers I., Ribrag V., Janot F., Beaune P. H., Morizet J., Gouyette A., Chabot G. G. Comparison of mouse and human colon tumors with regard to phase I and phase II drug-metabolizing enzyme systems. Cancer Res. 1992 Dec 1;52(23):6567–6575. [PubMed] [Google Scholar]
  22. McKay J. A., Murray G. I., Weaver R. J., Ewen S. W., Melvin W. T., Burke M. D. Xenobiotic metabolising enzyme expression in colonic neoplasia. Gut. 1993 Sep;34(9):1234–1239. doi: 10.1136/gut.34.9.1234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McLeod H. L., Douglas F., Oates M., Symonds R. P., Prakash D., van der Zee A. G., Kaye S. B., Brown R., Keith W. N. Topoisomerase I and II activity in human breast, cervix, lung and colon cancer. Int J Cancer. 1994 Dec 1;59(5):607–611. doi: 10.1002/ijc.2910590506. [DOI] [PubMed] [Google Scholar]
  24. Miller S. K., Main A. R., Rush R. S. Purification and physical properties of oligomeric and monomeric carboxylesterases from rabbit liver. J Biol Chem. 1980 Aug 10;255(15):7161–7167. [PubMed] [Google Scholar]
  25. Niimi S., Nakagawa K., Sugimoto Y., Nishio K., Fujiwara Y., Yokoyama S., Terashima Y., Saijo N. Mechanism of cross-resistance to a camptothecin analogue (CPT-11) in a human ovarian cancer cell line selected by cisplatin. Cancer Res. 1992 Jan 15;52(2):328–333. [PubMed] [Google Scholar]
  26. Ogasawara H., Nishio K., Kanzawa F., Lee Y. S., Funayama Y., Ohira T., Kuraishi Y., Isogai Y., Saijo N. Intracellular carboxyl esterase activity is a determinant of cellular sensitivity to the antineoplastic agent KW-2189 in cell lines resistant to cisplatin and CPT-11. Jpn J Cancer Res. 1995 Jan;86(1):124–129. doi: 10.1111/j.1349-7006.1995.tb02997.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Potmesil M., Hsiang Y. H., Liu L. F., Bank B., Grossberg H., Kirschenbaum S., Forlenza T. J., Penziner A., Kanganis D., Forlenzar T. J. Resistance of human leukemic and normal lymphocytes to drug-induced DNA cleavage and low levels of DNA topoisomerase II. Cancer Res. 1988 Jun 15;48(12):3537–3543. [PubMed] [Google Scholar]
  28. Rivory L. P., Bowles M. R., Robert J., Pond S. M. Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by human liver carboxylesterase. Biochem Pharmacol. 1996 Oct 11;52(7):1103–1111. doi: 10.1016/0006-2952(96)00457-1. [DOI] [PubMed] [Google Scholar]
  29. Rivory L. P., Robert J. Identification and kinetics of a beta-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan. Cancer Chemother Pharmacol. 1995;36(2):176–179. doi: 10.1007/BF00689205. [DOI] [PubMed] [Google Scholar]
  30. Rivory L. P., Robert J. Reversed-phase high-performance liquid chromatographic method for the simultaneous quantitation of the carboxylate and lactone forms of the camptothecin derivative irinotecan, CPT-11, and its metabolite SN-38 in plasma. J Chromatogr B Biomed Appl. 1994 Nov 4;661(1):133–141. doi: 10.1016/0378-4347(94)00340-8. [DOI] [PubMed] [Google Scholar]
  31. Rothenberg M. L., Eckardt J. R., Kuhn J. G., Burris H. A., 3rd, Nelson J., Hilsenbeck S. G., Rodriguez G. I., Thurman A. M., Smith L. S., Eckhardt S. G. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996 Apr;14(4):1128–1135. doi: 10.1200/JCO.1996.14.4.1128. [DOI] [PubMed] [Google Scholar]
  32. Rougier P., Bugat R., Douillard J. Y., Culine S., Suc E., Brunet P., Becouarn Y., Ychou M., Marty M., Extra J. M. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol. 1997 Jan;15(1):251–260. doi: 10.1200/JCO.1997.15.1.251. [DOI] [PubMed] [Google Scholar]
  33. Satoh T., Hosokawa M., Atsumi R., Suzuki W., Hakusui H., Nagai E. Metabolic activation of CPT-11, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin, a novel antitumor agent, by carboxylesterase. Biol Pharm Bull. 1994 May;17(5):662–664. doi: 10.1248/bpb.17.662. [DOI] [PubMed] [Google Scholar]
  34. Satoh T., Hosokawa M. Molecular aspects of carboxylesterase isoforms in comparison with other esterases. Toxicol Lett. 1995 Dec;82-83:439–445. doi: 10.1016/0378-4274(95)03493-5. [DOI] [PubMed] [Google Scholar]
  35. Slatter J. G., Su P., Sams J. P., Schaaf L. J., Wienkers L. C. Bioactivation of the anticancer agent CPT-11 to SN-38 by human hepatic microsomal carboxylesterases and the in vitro assessment of potential drug interactions. Drug Metab Dispos. 1997 Oct;25(10):1157–1164. [PubMed] [Google Scholar]
  36. Slichenmyer W. J., Rowinsky E. K., Donehower R. C., Kaufmann S. H. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst. 1993 Feb 17;85(4):271–291. doi: 10.1093/jnci/85.4.271. [DOI] [PubMed] [Google Scholar]
  37. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. doi: 10.1016/0003-2697(85)90442-7. [DOI] [PubMed] [Google Scholar]
  38. Takano H., Kohno K., Matsuo K., Matsuda T., Kuwano M. DNA topoisomerase-targeting antitumor agents and drug resistance. Anticancer Drugs. 1992 Aug;3(4):323–330. doi: 10.1097/00001813-199208000-00002. [DOI] [PubMed] [Google Scholar]
  39. Takasuna K., Hagiwara T., Hirohashi M., Kato M., Nomura M., Nagai E., Yokoi T., Kamataki T. Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res. 1996 Aug 15;56(16):3752–3757. [PubMed] [Google Scholar]
  40. Tanizawa A., Fujimori A., Fujimori Y., Pommier Y. Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst. 1994 Jun 1;86(11):836–842. doi: 10.1093/jnci/86.11.836. [DOI] [PubMed] [Google Scholar]
  41. Tsuji T., Kaneda N., Kado K., Yokokura T., Yoshimoto T., Tsuru D. CPT-11 converting enzyme from rat serum: purification and some properties. J Pharmacobiodyn. 1991 Jun;14(6):341–349. doi: 10.1248/bpb1978.14.341. [DOI] [PubMed] [Google Scholar]
  42. van Ark-Otte J., Kedde M. A., van der Vijgh W. J., Dingemans A. M., Jansen W. J., Pinedo H. M., Boven E., Giaccone G. Determinants of CPT-11 and SN-38 activities in human lung cancer cells. Br J Cancer. 1998 Jun;77(12):2171–2176. doi: 10.1038/bjc.1998.362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. van der Zee A. G., de Jong S., Keith W. N., Hollema H., Boonstra H., de Vries E. G. Quantitative and qualitative aspects of topoisomerase I and II alpha and beta in untreated and platinum/cyclophosphamide treated malignant ovarian tumors. Cancer Res. 1994 Feb 1;54(3):749–755. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES