Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-04-2004 | Original Paper

Chemoembolization of rat liver metastasis with irinotecan and quantification of tumor cell reduction

Authors: Jan Saenger, Maike Leible, Matthias H. Seelig, Martin R. Berger

Published in: Journal of Cancer Research and Clinical Oncology | Issue 4/2004

Abstract

Purpose

Hematogenic metastasis of patients with colorectal cancer most frequently effects the liver; the prognosis of affected patients is dramatically worsened by the presence of this lesion. The aim of this study was to evaluate the effect of hepatic arterial chemoembolization (HACE) with irinotecan versus 5-fluorouracil as a standard agent in a rat liver metastasis model.

Materials and methods

Diffuse liver metastasis was induced by injecting 4×10⁶ CC531-lac-Z rat colorectal carcinoma cells into the portal vein of male Wag/Rij rats. Irinotecan (10 mg/kg, 30 mg/kg, and 60 mg/kg) and 5-fluorouracil (40 mg/kg, 60 mg/kg, and 90 mg/kg) were administered concomitantly with degradable starch microspheres (30 mg/kg) for temporary embolization. The tumor cell load was determined quantitatively using a chemoluminescence assay.

Results

HACE with irinotecan induced a complete remission in 44% of the animals and the highest dose reduced the mean tumor cell load by 66% (P <0.001). In contrast, the highest dose of 5-FU caused a reduction of only 18% (P = 0.026) and altogether 23% complete remissions were observed in response to 5-FU. The sensitivity of CC531-lac-Z cells versus irinotecan (IC50 32 pM after 72 h) and 5-FU (IC50 80 µM) mirrored the effects observed in vivo on a qualitative basis.

Conclusion

In conclusion, the effect of HACE with irinotecan surpassed that of HACE with 5-FU and prompts further investigation in clinical trials.

Ambiru S, M Miyazaki, H Ito, K Nakagawa, H Shimizu, N Nakajima (1999) Adjuvant regional chemotherapy after hepatic resection for colorectal metastases. Br J Surg 86:1025–1031CrossRefPubMed

Archer S G, BN Gray (1988) A new reproducible model of hepatic and peritoneal metastases from colonic carcinoma. Eur J Cancer Clin Oncol 24:1623–1632PubMed

Bartkowski R, MR Berger, JL Aguiar, TH Henne, J Dorsam, GH Geelhaar, P Schlag, C Herfarth (1986) Experiments on the efficacy and toxicity of locoregional chemotherapy of liver tumors with 5-fluoro-2’-deoxyuridine (FUDR) and 5-fluorouracil (5-FU) in an animal model. J Cancer Res Clin Oncol 111:42–46

Benson AB III, RM Goldberg 2003) Optimal use of the combination of irinotecan and 5-fluorouracil. Semin Oncol 30:68–77

Biasco G, E Gallerani (2001) Treatment of liver metastases from colorectal cancer: what is the best approach today? Dig Liver Dis 33:438–444CrossRefPubMed

Boedeker H, EJ Kamphorst, PH Wünsch, U Linnemann, MR Berger (2003) Superiority of combined chemo-embolisation and portal infusion with 5-flurouracil over locoregional infusion concepts in Novikoff hepatoma bearing rats. J Cancer Res Clin Oncol 129:655–661CrossRefPubMed

Brand MI, S Casillas, DW Dietz, JW Milsom, A Vladisavljevic (1996) Development of a reliable colorectal cancer liver metastasis model. J Surg Res 63:425–432CrossRefPubMed

Chang AE, PD Schneider, PH Sugarbaker, C Simpson, M Culnane, SM Steinberg (1987) A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 206:685–693PubMed

Civalleri D, M Esposito, R A Fulco, M Vannozzi, N Balletto, F DeCian, P L Percivale, F Merlo (1991) Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases. Cancer 68:988–994PubMed

Conti JA, NE Kemeny, LB Saltz, Y Huang, W P Tong, TC Chou, M Sun, S Pulliam, C Gonzalez (1996) Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709–715PubMed

Cunningham D, S Pyrhonen, RD James, CJ Punt, TF Hickish, R Heikkila, TB Johannesen, H Starkhammar, C A Topham, L Awad, C Jacques, P Herait (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418PubMed

Douillard JY, A Sobrero, C Carnaghi, P Comella, E Diaz-Rubio, A Santoro, E Van Cutsem (2003) Metastatic colorectal cancer: integrating irinotecan into combination and sequential chemotherapy. Ann Oncol 14 [Suppl 2]:7–12

Dworkin MJ, D Burke, S Earlam, C Fordy, TG Allen-Mersh (1995) Measurement of response to treatment in colorectal liver metastases. Br J Cancer 71:873–876PubMed

Fuchs CS, MR Moore, G Harker, L Villa, D Rinaldi, JR Hecht (2003) Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21:807–814CrossRefPubMed

Geoghegan JG, J Scheele (1999) Treatment of colorectal liver metastases. Br J Surg 86:158–169CrossRefPubMed

Germer CT, C Isbert, D Albrecht, A Roggan, J Pelz, JP Ritz, G Muller, HJ Buhr (1999) Laser-induced thermotherapy combined with hepatic arterial embolization in the treatment of liver tumors in a rat tumor model. Ann Surg 230:55–62CrossRefPubMed

Hagenaars M, NG Ensink, R Koelemij, PH Basse, AM Eggermont, CJ van de Velde, GJ Fleuren, PJ Kuppen (1998) Regional administration of natural killer cells in a rat hepatic metastasis model results in better tumor infiltration and anti-tumor response than systemic administration. Int J Cancer 75:233–238CrossRefPubMed

Hagenaars M, R Koelemij, NG Ensink, JD van Eendenburg, R L van Vlierberghe, AM Eggermont, CJ van de Velde, GJ Fleuren, PJ Kuppen (2000) The development of novel mouse monoclonal antibodies against the CC531 rat colon adenocarcinoma. Clin Exp Metastasis 18:281–289CrossRefPubMed

Hohn DC, RJ Stagg, MA Friedman, JF Hannigan Jr, A Rayner, RJ Ignoffo, P Acord, BJ Lewis (1989) A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial. J Clin Oncol 7:1646–1654

Holland JF, E Frei (1981) Cancer medicine. Lea & Febiger, Philadelphia

Hsiang YH, R Hertzberg, S Hecht, LF Liu (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873–14878PubMed

Kamphorst EJ, H Bodeker, S Koroma, U Linnemann, MR Berger (1999) New technique for superselective arterial (chemo-) embolization of the rat liver. Lab Anim Sci 49:216–219

Kato T, R Nemoto, H Mori, M Takahashi, Y Tamakawa, M Harada (1981) Arterial chemoembolization with microencapsulated anticancer drug. An approach to selective cancer chemotherapy with sustained effects. JAMA 245:1123CrossRefPubMed

Kemeny MM, D Goldberg, JD Beatty, D Blayney, S Browning, J Doroshow, L Ganteaume, RL Hill, WA Kokal, DU Riihimaki (1986) Results of a prospective randomized trial of continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries. Cancer 57:492–498PubMed

Kemeny N, J Daly, B Reichman, N Geller, J Botet, P Oderman (1987) Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med 107:459–465PubMed

Kerr DJ, CS McArdle, J Ledermann, I Taylor, DJ Sherlock, P M Schlag, J Buckels, D Mayer, D Cain, RJ Stephens (2003) Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 361:368–373CrossRefPubMed

Kuan HY, DE Smith, WD Ensmiger, JA Knol, SJ DeRemer, Z Yang, PL Stetson (1996) Regional pharmacokinetics of 5-bromo-2’-deoxyuridine and 5-fluorouracil in dogs: hepatic arterial versus portal venous infusions. Cancer Res 56:4724–4727PubMed

Li X, CS Zheng, GS Feng, CK Zhuo, JG Zhao, X Liu (2002) An implantable rat liver tumor model for experimental transarterial chemoembolization therapy and its imaging features. World J Gastroenterol 8:1035–1039PubMed

Liu LX, WH Zhang, HC Jiang (2003) Current treatment for liver metastases from colorectal cancer. World J Gastroenterol 9:193–200PubMed

Llovet JM, MI Real, X Montana, R Planas, S Coll, J Aponte, C Ayuso, M Sala, J Muchart, R Sola, J Rodes, J Bruix (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739CrossRefPubMed

Marquet RL, DL Westbroek, J Jeekel (1984) Interferon treatment of a transplantable rat colon adenocarcinoma: importance of tumor site. Int J Cancer 33:689–692PubMed

Martin JK Jr, MJ O’Connell, HS Wieand, RJ Fitzgibbons Jr, JA Mailliard, J Rubin, DM Nagorney, LK Tschetter, JE Krook (1990) Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial. Arch Surg 125:1022–1027PubMed

Pitot HC, DB Wender, MJ O’Connell, G Schroeder, RM Goldberg, J Rubin, JA Mailliard, JA Knost, C Ghosh, RJ Kirschling, R Levitt, HE Windschitl (1997) Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910–2919PubMed

Rothenberg ML, JR Eckardt, JG Kuhn, HA Burris III, J Nelson, SG Hilsenbeck, GI Rodriguez, AM Thurman, LS Smith, SG Eckhardt, GR Weiss, GL Elfring, DA Rinaldi, LJ Schaaf, DD Von Hoff (1996) Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14:1128–1135PubMed

Rougier P, A Laplanche, M Huguier, JM Hay, JM Ollivier, J Escat, R Salmon, M Julien, JC Roullet Audy, D Gallot (1992) Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 10:1112–1118PubMed

Rougier P, E Mitry (2003) Epidemiology, treatment and chemoprevention in colorectal cancer. Ann Oncol 14 [Suppl 2]:3–5

Rudroff C, A Altendorf-Hoffmann, R Stangl, J Scheele (1999) Prospective randomised trial on adjuvant hepatic-artery infusion chemotherapy after R0 resection of colorectal liver metastases. Langenbecks Arch Surg 384:243–249CrossRefPubMed

Ruers T, RP Bleichrodt (2002) Treatment of liver metastases, an update on the possibilities and results. Eur J Cancer 38:1023–1033CrossRefPubMed

Sanz-Altamira PM, LD Spence, MS Huberman, MR Posner, G Steele Jr, L J Perry, KE Stuart (1997) Selective chemoembolization in the management of hepatic metastases in refractory colorectal carcinoma: a phase II trial. Dis Colon Rectum 40:770–775PubMed

Schimanski CC, U Linnemann, PR Galle, R Arbogast, MR Berger (2003) Hepatic disseminated tumor cells in colorectal cancer UICC stage 4 patients: prognostic implications. Int J Oncol 23:791–796PubMed

Starkhammar H, L Hakansson (1987) Effect of starch microspheres on the passage of labelled erythrocytes and a low molecular weight marker through the liver. Acta Oncol 26:361–365PubMed

Sundin A, W Graf, B Glimelius, H Ahlstrom, A Magnusson (1992) Contrast-enhanced CT scanning in vivo for the quantification of hepatic metastases from a human colonic cancer in the nude rat. Eur J Surg Oncol 18:615–623PubMed

Tellez C, AB Benson III, MT Lyster, M Talamonti, J Shaw, MA Braun, AA Nemcek Jr, RL Vogelzang (1998) Phase II trial of chemoembolization for the treatment of metastatic colorectal carcinoma to the liver and review of the literature. Cancer 82:1250–1259PubMed

Thomas C, AM Nijenhuis, W Timens, PJ Kuppen, T Daemen, GL Scherphof (1993) Liver metastasis model of colon cancer in the rat: immunohistochemical characterization. Invasion Metastasis 13:102–112PubMed

Wittmer A, K Khazaie, MR Berger (1999) Quantitative detection of lac-Z-transfected CC531 colon carcinoma cells in an orthotopic rat liver metastasis model. Clin Exp Metastasis 17:369–376CrossRefPubMed

Title: Chemoembolization of rat liver metastasis with irinotecan and quantification of tumor cell reduction
Authors: Jan Saenger
Maike Leible
Matthias H. Seelig
Martin R. Berger
Publication date: 01-04-2004
Publisher: Springer-Verlag
Published in: Journal of Cancer Research and Clinical Oncology / Issue 4/2004
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-003-0523-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Materials and methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 4/2004

A decade’s studies on metastasis of hepatocellular carcinoma

Tyrosine kinase receptor expression in thymomas

Professor Carl-Gottfried Schmidt

Prophylaxis of port system-associated thromboses in advanced oncology patients using heparin flushing

Detection of telomerase activity in prostate massage samples improves differentiating prostate cancer from benign prostatic hyperplasia

Poor prognostic factors of hepatectomy in patients with resectable small hepatocellular carcinoma and cirrhosis

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials