Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Feb;82(4):913–923. doi: 10.1054/bjoc.1999.1019

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

R A Bras-Gonçalves 1, C Rosty 2, P Laurent-Puig 2, P Soulié 1, B Dutrillaux 1, M-F Poupon 1
PMCID: PMC2374412  PMID: 10732766

Abstract

Biological parameters influencing the response of human colorectal cancers (CRCs) to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability phenotype (MSI+when altered). Five CRC xenografts were established from clinical samples. All five had a functional p53, two were MSI+and three were MSI–. Tumour-bearing nude mice were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg–1of CPT-11, four injections at 4-day intervals, four of the five xenografts responded to CPT-11 (growth delay of up to 10 days); the non-responder tumour was MSI−. At 40 mg kg−1of CPT-11, six injections at 4-day intervals, the five CRCs displayed variable but marked responses with complete regressions. In order to assess the role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line was MSI−/ Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI+/ wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transfection. LoVo tumours (MSI+/ mutp53) were more sensitive than X17LoVo (MSI+/ mutp53. HT 29 tumours (MSI−Imutp53), were refractory to CPT-11 while HT29A3 tumours (MSI−/ wtp53) were sensitive, showing that wtp53 improves the drug-response in these MSI−tumours. Levels of mRNA expression of top1, fasR, TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken together, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI phenotype moderately influences the CPT-11 sensitivity, MSI+being more sensitive than MSI−CRC freshly obtained from patients, mutp53 status being associated with a poor response to CPT-11. © 2000 Cancer Research Campaign

Keywords: CPT-11, MSI, p53, top1, human colorectal cancer, nude mice

Full Text

The Full Text of this article is available as a PDF (220.9 KB).

Selected References

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

  1. Armand J. P., Ducreux M., Mahjoubi M., Abigerges D., Bugat R., Chabot G., Herait P., de Forni M., Rougier P. CPT-11 (irinotecan) in the treatment of colorectal cancer. Eur J Cancer. 1995 Jul-Aug;31A(7-8):1283–1287. doi: 10.1016/0959-8049(95)00212-2. [DOI] [PubMed] [Google Scholar]
  2. Armand J. P., Extra Y. M., Catimel G., Abigerges D., Marty M., Clavel M. Rationale for the dosage and schedule of CPT-11 (irinotecan) selected for phase II studies, as determined by European phase I studies. Ann Oncol. 1996 Oct;7(8):837–842. doi: 10.1093/oxfordjournals.annonc.a010763. [DOI] [PubMed] [Google Scholar]
  3. Arnheim N., Shibata D. DNA mismatch repair in mammals: role in disease and meiosis. Curr Opin Genet Dev. 1997 Jun;7(3):364–370. doi: 10.1016/s0959-437x(97)80150-5. [DOI] [PubMed] [Google Scholar]
  4. Attalla H., Mäkelä T. P., Wähälä K., Rasku S., Andersson L. C., Adlercreutz H. 2,6-Bis((3,4-dihydroxyphenyl)-methylene)cyclohexanone (BDHPC)-induced apoptosis and p53-independent growth inhibition: synergism with genistein. Biochem Biophys Res Commun. 1997 Oct 20;239(2):467–472. doi: 10.1006/bbrc.1997.7495. [DOI] [PubMed] [Google Scholar]
  5. Bubb V. J., Curtis L. J., Cunningham C., Dunlop M. G., Carothers A. D., Morris R. G., White S., Bird C. C., Wyllie A. H. Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. Oncogene. 1996 Jun 20;12(12):2641–2649. [PubMed] [Google Scholar]
  6. Casares S., Ionov Y., Ge H. Y., Stanbridge E., Perucho M. The microsatellite mutator phenotype of colon cancer cells is often recessive. Oncogene. 1995 Dec 7;11(11):2303–2310. [PubMed] [Google Scholar]
  7. Conti J. A., Kemeny N. E., Saltz L. B., Huang Y., Tong W. P., Chou T. C., Sun M., Pulliam S., Gonzalez C. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol. 1996 Mar;14(3):709–715. doi: 10.1200/JCO.1996.14.3.709. [DOI] [PubMed] [Google Scholar]
  8. Cottu P. H., Muzeau F., Estreicher A., Fléjou J. F., Iggo R., Thomas G., Hamelin R. Inverse correlation between RER+ status and p53 mutation in colorectal cancer cell lines. Oncogene. 1996 Dec 19;13(12):2727–2730. [PubMed] [Google Scholar]
  9. Céraline J., Deplanque G., Duclos B., Limacher J. M., Hajri A., Noel F., Orvain C., Frébourg T., Klein-Soyer C., Bergerat J. P. Inactivation of p53 in normal human cells increases G2/M arrest and sensitivity to DNA-damaging agents. Int J Cancer. 1998 Jan 30;75(3):432–438. doi: 10.1002/(sici)1097-0215(19980130)75:3<432::aid-ijc17>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  10. Fan S., el-Deiry W. S., Bae I., Freeman J., Jondle D., Bhatia K., Fornace A. J., Jr, Magrath I., Kohn K. W., O'Connor P. M. p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res. 1994 Nov 15;54(22):5824–5830. [PubMed] [Google Scholar]
  11. Fujiwara T., Grimm E. A., Mukhopadhyay T., Zhang W. W., Owen-Schaub L. B., Roth J. A. Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res. 1994 May 1;54(9):2287–2291. [PubMed] [Google Scholar]
  12. Goh H. S., Yao J., Smith D. R. p53 point mutation and survival in colorectal cancer patients. Cancer Res. 1995 Nov 15;55(22):5217–5221. [PubMed] [Google Scholar]
  13. Goldberg R. M., Hatfield A. K., Kahn M., Sargent D. J., Knost J. A., O'Connell M. J., Krook J. E., Maillard J. A., Wiesenfeld M., Schaefer P. L. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997 Nov;15(11):3320–3329. doi: 10.1200/JCO.1997.15.11.3320. [DOI] [PubMed] [Google Scholar]
  14. Goldwasser F., Bae I., Valenti M., Torres K., Pommier Y. Topoisomerase I-related parameters and camptothecin activity in the colon carcinoma cell lines from the National Cancer Institute anticancer screen. Cancer Res. 1995 May 15;55(10):2116–2121. [PubMed] [Google Scholar]
  15. Gottesman M. M., Pastan I., Ambudkar S. V. P-glycoprotein and multidrug resistance. Curr Opin Genet Dev. 1996 Oct;6(5):610–617. doi: 10.1016/s0959-437x(96)80091-8. [DOI] [PubMed] [Google Scholar]
  16. Gualberto A., Aldape K., Kozakiewicz K., Tlsty T. D. An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5166–5171. doi: 10.1073/pnas.95.9.5166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hamelin R., Jego N., Laurent-Puig P., Vidaud M., Thomas G. Efficient screening of p53 mutations by denaturing gradient gel electrophoresis in colorectal tumors. Oncogene. 1993 Aug;8(8):2213–2220. [PubMed] [Google Scholar]
  18. Hamelin R., Laurent-Puig P., Olschwang S., Jego N., Asselain B., Remvikos Y., Girodet J., Salmon R. J., Thomas G. Association of p53 mutations with short survival in colorectal cancer. Gastroenterology. 1994 Jan;106(1):42–48. doi: 10.1016/s0016-5085(94)94217-x. [DOI] [PubMed] [Google Scholar]
  19. Hoang J. M., Cottu P. H., Thuille B., Salmon R. J., Thomas G., Hamelin R. BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Res. 1997 Jan 15;57(2):300–303. [PubMed] [Google Scholar]
  20. Houghton P. J., Cheshire P. J., Hallman J. D., 2nd, Lutz L., Friedman H. S., Danks M. K., Houghton J. A. Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol. 1995;36(5):393–403. doi: 10.1007/BF00686188. [DOI] [PubMed] [Google Scholar]
  21. Ishimaru G., Adachi J., Shiseki M., Yamaguchi N., Muto T., Yokota J. Microsatellite instability in primary and metastatic colorectal cancers. Int J Cancer. 1995 Jun 22;64(3):153–157. doi: 10.1002/ijc.2910640302. [DOI] [PubMed] [Google Scholar]
  22. Jansen W. J., Hulscher T. M., van Ark-Otte J., Giaccone G., Pinedo H. M., Boven E. CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein. Br J Cancer. 1998;77(3):359–365. doi: 10.1038/bjc.1998.58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kaneda N., Nagata H., Furuta T., Yokokura T. Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res. 1990 Mar 15;50(6):1715–1720. [PubMed] [Google Scholar]
  24. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991 Dec 1;51(23 Pt 1):6304–6311. [PubMed] [Google Scholar]
  25. Kjeldsen E., Svejstrup J. Q., Gromova I. I., Alsner J., Westergaard O. Camptothecin inhibits both the cleavage and religation reactions of eukaryotic DNA topoisomerase I. J Mol Biol. 1992 Dec 20;228(4):1025–1030. doi: 10.1016/0022-2836(92)90310-g. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Laurence J., Mitra D., Steiner M., Lynch D. H., Siegal F. P., Staiano-Coico L. Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia. J Clin Invest. 1996 Feb 1;97(3):672–680. doi: 10.1172/JCI118464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Leteurtre F., Fesen M., Kohlhagen G., Kohn K. W., Pommier Y. Specific interaction of camptothecin, a topoisomerase I inhibitor, with guanine residues of DNA detected by photoactivation at 365 nm. Biochemistry. 1993 Aug 31;32(34):8955–8962. doi: 10.1021/bi00085a029. [DOI] [PubMed] [Google Scholar]
  29. Lowe S. W., Bodis S., McClatchey A., Remington L., Ruley H. E., Fisher D. E., Housman D. E., Jacks T. p53 status and the efficacy of cancer therapy in vivo. Science. 1994 Nov 4;266(5186):807–810. doi: 10.1126/science.7973635. [DOI] [PubMed] [Google Scholar]
  30. Lowe S. W., Ruley H. E., Jacks T., Housman D. E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993 Sep 24;74(6):957–967. doi: 10.1016/0092-8674(93)90719-7. [DOI] [PubMed] [Google Scholar]
  31. Lukish J. R., Muro K., DeNobile J., Katz R., Williams J., Cruess D. F., Drucker W., Kirsch I., Hamilton S. R. Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg. 1998 Jan;227(1):51–56. doi: 10.1097/00000658-199801000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Malkhosyan S., McCarty A., Sawai H., Perucho M. Differences in the spectrum of spontaneous mutations in the hprt gene between tumor cells of the microsatellite mutator phenotype. Mutat Res. 1996 May;316(5-6):249–259. doi: 10.1016/s0921-8734(96)90007-7. [DOI] [PubMed] [Google Scholar]
  33. McDonald A. C., Brown R. Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors. Br J Cancer. 1998 Sep;78(6):745–751. doi: 10.1038/bjc.1998.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Meterissian S. H., Kontogiannea M., Po J., Jensen G., Ferdinand B. Apoptosis induced in human colorectal carcinoma by anti-Fas antibody. Ann Surg Oncol. 1997 Mar;4(2):169–175. doi: 10.1007/BF02303801. [DOI] [PubMed] [Google Scholar]
  35. Micheau O., Solary E., Hammann A., Martin F., Dimanche-Boitrel M. T. Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. J Natl Cancer Inst. 1997 Jun 4;89(11):783–789. doi: 10.1093/jnci/89.11.783. [DOI] [PubMed] [Google Scholar]
  36. Moertel C. G., Fleming T. R., Macdonald J. S., Haller D. G., Laurie J. A., Goodman P. J., Ungerleider J. S., Emerson W. A., Tormey D. C., Glick J. H. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352–358. doi: 10.1056/NEJM199002083220602. [DOI] [PubMed] [Google Scholar]
  37. Murphy L. D., Herzog C. E., Rudick J. B., Fojo A. T., Bates S. E. Use of the polymerase chain reaction in the quantitation of mdr-1 gene expression. Biochemistry. 1990 Nov 13;29(45):10351–10356. doi: 10.1021/bi00497a009. [DOI] [PubMed] [Google Scholar]
  38. Olschwang S., Hamelin R., Laurent-Puig P., Thuille B., De Rycke Y., Li Y. J., Muzeau F., Girodet J., Salmon R. J., Thomas G. Alternative genetic pathways in colorectal carcinogenesis. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12122–12127. doi: 10.1073/pnas.94.22.12122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pazdur R., Diaz-Canton E., Ballard W. P., Bradof J. E., Graham S., Arbuck S. G., Abbruzzese J. L., Winn R. Phase II trial of 9-aminocamptothecin administered as a 72-hour continuous infusion in metastatic colorectal carcinoma. J Clin Oncol. 1997 Aug;15(8):2905–2909. doi: 10.1200/JCO.1997.15.8.2905. [DOI] [PubMed] [Google Scholar]
  40. Pocard M., Chevillard S., Villaudy J., Poupon M. F., Dutrillaux B., Remvikos Y. Different p53 mutations produce distinct effects on the ability of colon carcinoma cells to become blocked at the G1/S boundary after irradiation. Oncogene. 1996 Feb 15;12(4):875–882. [PubMed] [Google Scholar]
  41. Pommier Y. Eukaryotic DNA topoisomerase I: genome gatekeeper and its intruders, camptothecins. Semin Oncol. 1996 Feb;23(1 Suppl 3):3–10. [PubMed] [Google Scholar]
  42. Rivory L. P., Riou J. F., Haaz M. C., Sable S., Vuilhorgne M., Commerçon A., Pond S. M., Robert J. Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res. 1996 Aug 15;56(16):3689–3694. [PubMed] [Google Scholar]
  43. Rothenberg M. L. Topoisomerase I inhibitors: review and update. Ann Oncol. 1997 Sep;8(9):837–855. doi: 10.1023/a:1008270717294. [DOI] [PubMed] [Google Scholar]
  44. Rougier P., Bugat R. CPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile. Semin Oncol. 1996 Feb;23(1 Suppl 3):34–41. [PubMed] [Google Scholar]
  45. 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]
  46. Soulie P., Poupon M. F., Remvikos Y., Dutrillaux B., Muleris M. Distinct chromosomal alterations associated with TP53 status of LoVo cells under PALA selective pressure: a parallel with cytogenetic pathways of colorectal cancers. Oncogene. 1999 Jan 21;18(3):775–781. doi: 10.1038/sj.onc.1202336. [DOI] [PubMed] [Google Scholar]
  47. Sträter J., Wellisch I., Riedl S., Walczak H., Koretz K., Tandara A., Krammer P. H., Möller P. CD95 (APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis. Gastroenterology. 1997 Jul;113(1):160–167. doi: 10.1016/s0016-5085(97)70091-x. [DOI] [PubMed] [Google Scholar]
  48. 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]
  49. Takasuna K., Kasai Y., Kitano Y., Mori K., Kobayashi R., Hagiwara T., Kakihata K., Hirohashi M., Nomura M., Nagai E. Protective effects of kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats. Jpn J Cancer Res. 1995 Oct;86(10):978–984. doi: 10.1111/j.1349-7006.1995.tb03010.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. 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]
  51. Tanizawa A., Kohn K. W., Kohlhagen G., Leteurtre F., Pommier Y. Differential stabilization of eukaryotic DNA topoisomerase I cleavable complexes by camptothecin derivatives. Biochemistry. 1995 May 30;34(21):7200–7206. doi: 10.1021/bi00021a035. [DOI] [PubMed] [Google Scholar]
  52. Tillman D. M., Harwood F. G., Gibson A. A., Houghton J. A. Expression of genes that regulate Fas signalling and Fas-mediated apoptosis in colon carcinoma cells. Cell Death Differ. 1998 May;5(5):450–457. doi: 10.1038/sj.cdd.4400369. [DOI] [PubMed] [Google Scholar]
  53. Vamvakas S., Vock E. H., Lutz W. K. On the role of DNA double-strand breaks in toxicity and carcinogenesis. Crit Rev Toxicol. 1997 Mar;27(2):155–174. doi: 10.3109/10408449709021617. [DOI] [PubMed] [Google Scholar]
  54. Vaurs C., Bignon Y. J. Quoi de neuf sur la signification des instabilités microsatellitaires dans les pathologies tumorales humaines? Bull Cancer. 1997 Nov;84(11):1061–1071. [PubMed] [Google Scholar]
  55. Zhou X. P., Hoang J. M., Li Y. J., Seruca R., Carneiro F., Sobrinho-Simoes M., Lothe R. A., Gleeson C. M., Russell S. E., Muzeau F. Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites. Genes Chromosomes Cancer. 1998 Feb;21(2):101–107. doi: 10.1002/(sici)1098-2264(199802)21:2<101::aid-gcc4>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  56. de Gramont A., Bosset J. F., Milan C., Rougier P., Bouché O., Etienne P. L., Morvan F., Louvet C., Guillot T., François E. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808–815. doi: 10.1200/JCO.1997.15.2.808. [DOI] [PubMed] [Google Scholar]
  57. dos Santos N. R., Seruca R., Constância M., Seixas M., Sobrinho-Simões M. Microsatellite instability at multiple loci in gastric carcinoma: clinicopathologic implications and prognosis. Gastroenterology. 1996 Jan;110(1):38–44. doi: 10.1053/gast.1996.v110.pm8536886. [DOI] [PubMed] [Google Scholar]
  58. el-Mahdani N., Vaillant J. C., Guiguet M., Prévot S., Bertrand V., Bernard C., Parc R., Béréziat G., Hermelin B. Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation. Br J Cancer. 1997;75(4):528–536. doi: 10.1038/bjc.1997.92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. 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]

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

RESOURCES