Skip to main content
SpringerLink
Log in

Synergistic Effect of Interstitial Laser Coagulation and Doxorubicin in a Murine Tumor Recurrence Model of Solitary Colorectal Liver Metastasis

  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Interstitial laser coagulation (ILC) is gaining acceptance for treatment of unresectable colorectal liver metastases. However, local recurrence rates are still high. To overcome this problem, we investigated the potential of additional systemic therapy after ILC in a murine model.

Methods

Single C26 colon carcinoma nodules (∼1 mm3) expressing firefly luciferase were implanted in the left liver lobe of 32 BALB/c mice. Seven days after implantation, tumors were treated with either ILC alone (neodymium–yttrium aluminum garnet; 6 W/cm; 800 J/cm) or ILC followed by 1 mg/kg of doxorubicin intravenously. Controls received either doxorubicin alone or sham treatment. Tumor load was measured by in vivo bioluminescent imaging.

Results

Solitary colorectal liver metastases developed over 7 days after tumor implantation in the liver. Extrahepatic disease was not observed. The ILC dose was set to ablate the liver metastases with recurrent tumor growth in 9 of 16 mice after 7 days. After ILC plus doxorubicin, complete tumor destruction occurred without recurrence (0 of 14). Sham treatment or treatment with doxorubicin alone showed an exponential increase in tumor load.

Conclusions

A murine tumor recurrence model after local ablative treatment of solitary liver metastasis was developed. The combination of ILC and doxorubicin had a strong synergistic effect that led to complete tumor remission in all animals treated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 1986;150:195–203

    Article  CAS  PubMed  Google Scholar 

  2. Steele G Jr, Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 1989;210:127–38

    PubMed  Google Scholar 

  3. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet 1994;343:1405–10

    Article  CAS  PubMed  Google Scholar 

  4. Nakamura S, Suzuki S, Baba S. Resection of liver metastases of colorectal carcinoma. World J Surg 1997;21:741–7

    Article  CAS  PubMed  Google Scholar 

  5. Nanko M, Shimada H, Yamaoka H, et al. Micrometastatic colorectal cancer lesions in the liver. Surg Today 1998;28:707–13

    Article  CAS  PubMed  Google Scholar 

  6. Curley SA. Radiofrequency ablation of malignant liver tumors. Ann Surg Oncol 2003;10:338–47

    Article  PubMed  Google Scholar 

  7. Goldberg SN, Gazelle GS, Compton CC, Mueller PR, Tanabe KK. Treatment of intrahepatic malignancy with radiofrequency ablation: radiologic-pathologic correlation. Cancer 2000;88:2452–63

    Article  CAS  PubMed  Google Scholar 

  8. Gillams AR, Lees WR. Survival after percutaneous, image-guided, thermal ablation of hepatic metastases from colorectal cancer. Dis Colon Rectum 2000;43:656–61

    Article  CAS  PubMed  Google Scholar 

  9. Giorgio A, Tarantino L, de Stefano G, et al. Interstitial laser photocoagulation under ultrasound guidance of liver tumors: results in 104 treated patients. Eur J Ultrasound 2000;11:181–8

    Article  CAS  PubMed  Google Scholar 

  10. Vogl TJ, Straub R, Eichler K, Sollner O, Mack MG. Colorectal carcinoma metastases in liver: laser-induced interstitial thermotherapy local tumor control rate and survival data. Radiology 2004;230:450–8

    PubMed  Google Scholar 

  11. te Velde EA, Vogten JM, Gebbink MF, van Gorp JM, Voest EE, Borel Rinkes IHM. Enhanced antitumour efficacy by combining conventional chemotherapy with angiostatin or endostatin in a liver metastasis model. Br J Surg 2002;89:1302–9

    CAS  PubMed  Google Scholar 

  12. Smakman N, Martens A, Kranenburg O, Borel Rinkes I. Validation of bioluminescence imaging of colorectal liver metastases in the mouse. J Surg Res 2004;122:225–30

    Article  CAS  PubMed  Google Scholar 

  13. Honigman A, Zeira E, Ohana P, et al. Imaging transgene expression in live animals. Mol Ther 2001;4:239–49

    Article  CAS  PubMed  Google Scholar 

  14. Wilmanns C, Fan D, O’Brian CA, Bucana CD, Fidler IJ. Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxorubicin and 5-fluorouracil. Int J Cancer 1992;52:98–104

    CAS  PubMed  Google Scholar 

  15. Fang S, Thomas RM, Conklin JL, Oberley LW, Christensen J. Co-localization of manganese superoxide dismutase and NADH diaphorase. J Histochem Cytochem 1995;43:849–55

    CAS  PubMed  Google Scholar 

  16. Kuruppu D, Christophi C, Bertram JF, O’Brien PE. Characterization of an animal model of hepatic metastasis. J Gastroenterol Hepatol 1996;11:26–32

    CAS  PubMed  Google Scholar 

  17. Okuno K, Shirayama Y, Ohnishi H, et al. A successful liver metastasis model in mice with neuraminidase treated colon 26. Surg Today 1993;23:795–9

    Article  CAS  PubMed  Google Scholar 

  18. Stapfer M, Hu J, Wei D, Groshen S, Beart RW Jr. Establishment of a nude mouse model of hepatic metastasis for evaluation of targeted retroviral gene delivery. J Surg Oncol 2003;82:121–30

    Article  PubMed  Google Scholar 

  19. Grady ED, Nolan TR, Craumbley AJ, Cheek WV, Copelan N, Kunzler HC. Cryotherapy of implanted cancer in the rat liver. Oncology 1973;28:104–9

    CAS  PubMed  Google Scholar 

  20. Ernst M, Bauknecht KJ, Hartmann CA, Herter M, Haring R, Dressler S. Animal experiment studies of cryosurgical treatment of DS sarcomas and Morris hepatomas implanted in the liver. Zentralbl Chir 1988;113:1111–5

    CAS  PubMed  Google Scholar 

  21. van Hillegersberg R, Kort WJ, ten Kate FJW, Terpstra OT. Water-jet-cooled Nd:YAG laser coagulation: selective destruction of rat liver metastases. Lasers Surg Med 1991;11:445–54

    PubMed  Google Scholar 

  22. Yang R, Rescorla FJ, Reilly CR, et al. A reproducible rat liver cancer model for experimental therapy: introducing a technique of intrahepatic tumor implantation. J Surg Res 1992;52:193–8

    Article  CAS  PubMed  Google Scholar 

  23. Pestana C, Reitemeier RJ, Moertel CG, Judd ES, Dockerty MB. The natural history of carcinoma of the colon and rectum. Am J Surg 1964;108:826–9

    Article  CAS  PubMed  Google Scholar 

  24. Bengtsson G, Carlsson G, Hafstrom L, Jonsson PE. Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 1981;141:586–9

    Article  CAS  PubMed  Google Scholar 

  25. Goslin R, Steele G Jr, Zamcheck N, Mayer R, MacIntyre J. Factors influencing survival in patients with hepatic metastases from adenocarcinoma of the colon or rectum. Dis Colon Rectum 1982;25:749–54

    CAS  PubMed  Google Scholar 

  26. Sakakima Y, Inoue S, Takeda S, Kaneko T, Nakao A. Factors in successful radiofrequency ablation therapy for malignant liver tumors. Hepatogastroenterology 2004;51:1761–5

    PubMed  Google Scholar 

  27. Geoghegan JG, Scheele J. Treatment of colorectal liver metastases. Br J Surg 1999;86:158–69

    CAS  PubMed  Google Scholar 

  28. Wei AC, Tung-Ping PR, Fan ST, Wong J. Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma. Br J Surg 2003;90:33–41

    Article  CAS  PubMed  Google Scholar 

  29. Vogl TJ, Eichler K, Straub R, et al. Laser-induced thermotherapy of malignant liver tumors: general principals, equipment(s), procedure(s)—side effects, complications and results. Eur J Ultrasound 2001;13:117–27

    Article  CAS  PubMed  Google Scholar 

  30. van Hillegersberg R, van Staveren HJ, Kort WJ, Zondervan PE, Terpstra OT. Interstitial Nd:YAG laser coagulation with a cylindrical diffusing fiber tip in experimental liver metastases. Lasers Surg Med 1994;14:124–38

    PubMed  Google Scholar 

  31. Goldberg SN, Girnan GD, Lukyanov AN, et al. Percutaneous tumor ablation: increased necrosis with combined radio-frequency ablation and intravenous liposomal doxorubicin in a rat breast tumor model. Radiology 2002;222:797–804

    PubMed  Google Scholar 

  32. Goldberg SN, Kamel IR, Kruskal JB, et al. Radiofrequency ablation of hepatic tumors: increased tumor destruction with adjuvant liposomal doxorubicin therapy. Am J Roentgenol 2002;179:93–101

    Google Scholar 

  33. Ahmed M, Monsky WE, Girnun G, et al. Radiofrequency thermal ablation sharply increases intratumoral liposomal doxorubicin accumulation and tumor coagulation. Cancer Res 2003;63:6327–33

    CAS  PubMed  Google Scholar 

  34. Eddy HA. Alterations in tumor microvasculature during hyperthermia. Radiology 1980;137:515–21

    CAS  PubMed  Google Scholar 

  35. Lefor AT, Makohon S, Ackerman NB. The effects of hyperthermia on vascular permeability in experimental liver metastasis. J Surg Oncol 1985;28:297–300

    CAS  PubMed  Google Scholar 

  36. Toffoli G, Bevilacqua C, Franceschin A, Boiocchi M. Effect of hyperthermia on intracellular drug accumulation and chemosensitivity in drug-sensitive and drug-resistant P388 leukaemia cell lines. Int J Hyperthermia 1989;5:163–72

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Andre Verheem for his expert technical assistance.

Author information

Authors and Affiliations

  1. Department of Surgery, University Medical Center Utrecht, Utrecht, GA, P. O. Box 85500, 3508, The Netherlands

    Liesbeth M. Veenendaal MD, Richard van Hillegersberg MD, PhD, Niels Smakman MD, Jarmila D. W. van der Bilt MD, Onno Kranenburg PhD & Inne H. M. Borel Rinkes MD, PhD

  2. Department of Pathology, University Medical Center Utrecht, Utrecht, GA, P.O. Box 85500, 3508, The Netherlands

    Paul J. van Diest MD, PhD

Authors
  1. Liesbeth M. Veenendaal MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard van Hillegersberg MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Niels Smakman MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jarmila D. W. van der Bilt MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul J. van Diest MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Onno Kranenburg PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Inne H. M. Borel Rinkes MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Inne H. M. Borel Rinkes MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veenendaal, L.M., van Hillegersberg, R., Smakman, N. et al. Synergistic Effect of Interstitial Laser Coagulation and Doxorubicin in a Murine Tumor Recurrence Model of Solitary Colorectal Liver Metastasis. Ann Surg Oncol 13, 168–175 (2006). https://doi.org/10.1245/ASO.2006.03.076

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/ASO.2006.03.076

Keywords

Search

Navigation