Skip to main content
SpringerLink
Log in

Organ distribution and antitumor activity of free and liposomal doxorubicin injected into the hepatic artery

  • Original Articles
  • Doxorubicin, Liposomes, Hepatic Artery
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

The plasma levels, organ distribution, and in vivo antitumor activity of free and liposomal doxorubicin injected into the hepatic artery of rats bearing W256 liver tumors were studied. The administration of liposomal doxorubicin resulted in liver-tumor and liver-parenchyma doxorubicin areas under the curve (AUCs) that were 4.7-and 3.8-fold, respectively, those obtained after the administration of free doxorubicin. Spleen and plasma AUCs were also increased by 2.8 and 2.5 times, respectively, following administration of the liposomal form. In contrast, liposomal doxorubicin did not affect heart AUCs; peak doxorubicin levels in heart tissue were three times lower in animals treated with liposomal doxorubicin. Following treatment with the liposomal form, the cumulative urinary excretion of doxorubicin at 8 h was 38 times lower. In good correlation with these findings, liposomal doxorubicin (2.35 mg/kg on day 7) was more effective than free doxorubicin against liver W256 tumors as measured by tumor-growth inhibition at 5 days after treatment (16% for liposomal doxorubicin versus −53.7% for free doxorubicin,P<0.05) and increased life span (ILS; 108% for liposomal doxorubicin versus 27% for free doxorubicin,P<0.05). These results demonstrate that as compared with free doxorubicin, the administration of liposomal doxorubicin into the hepatic artery results in higher drug levels in the liver tumor and enhanced antitumor activity while maintaining the cardioprotective effect of the liposome carrier as suggested by the decreased peak drug levels measured in the heart tissue.

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

Similar content being viewed by others

References

  1. Balazsovitz JAE, Mayer LD, Bally MB, Cullis PR, McDonell M, Ginsberg RS, Falk RE (1989) Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin. Cancer Chemother Pharmacol 23:81–86

    Google Scholar 

  2. Bartlett GR (1959) Phosphorus assay in column chromatography. J Biol Chem 234:466–470

    Google Scholar 

  3. Bern MM, McDermott W, Cady B, Oberfield RA, Trey C, Clouse ME, Tullis JL, Parker LM (1978) Intraarterial hepatic infusion and intravenous Adriamycin for treatment of hepatocellular carcinoma. Cancer 42:399–405

    Google Scholar 

  4. Breedis C, Young G (1954) The blood supply of neoplasma in the liver. Am J Pathol 30:227–232

    Google Scholar 

  5. Carlsson G, Gustavsson B, Hafstrom L (1989) Effect on liver tumor growth in rats of allopurinol and 5-fluorouracil in combination with hepatic artery ligation. Cancer Chemother Pharmacol 23:169–172

    Google Scholar 

  6. Doci R, Bignanmi P, Bozzetti F, Bonfanti, G, Audisio R, Colombo M, Gennari L (1988) Intrahepatic chemotherapy for unresectable hepatocellular carcinoma. Cancer 61:1983–1987

    Google Scholar 

  7. Eksborg S, Cedermark BJ, Strandler HS (1987) Intrahepatic and intravenous administration of Adriamycin. A comparative pharmacokinetic study in patients with malignant liver tumors. Med Oncol Tumor Pharmacother 2:47–54

    Google Scholar 

  8. Gabizon A, Goren D, Fuks Z, Meshorer A, Barenholz Y (1985) Superior therapeutic activity of liposome-associated Adriamycin in murine metastatic tumor model. Br J Cancer 51:681–687

    Google Scholar 

  9. Gabizon A, Meshorer A, Barenholz Y (1986) Comparative long-term study of the toxicities of free and liposome-associated doxorubicin in mice after intravenous administration. J Natl Cancer Inst 77: 459–469

    Google Scholar 

  10. Gregoriadis G, Neerunjun DE, Hunt R (1977) Fate of a liposome-associated agent injected into normal and tumor-bearing rodents; attempts to improve localization in tumor tissues. Life Sci 21: 357–369

    Google Scholar 

  11. Hag IAEL, Teder H, Roos G, Christensson PI, Stenram U (1990) Enhanced effect of Adriamycin on a rat liver adenocarcinoma after hepatic artery injection with degradable starch microspheres. Select Cancer Ther 6:23–34

    Google Scholar 

  12. Healy JE (1965) Vascular patterns in human metastatic liver tumor. Surg Gynecol Obstet 120:1187–1193

    Google Scholar 

  13. Herman EH, Rahman A, Ferrans V, Vick JA, Schein PS (1983) Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation. Cancer Res 43:5427–5432

    Google Scholar 

  14. Inoue H, Kobayashi H, Itoh Y, Shinohara S (1989) Treatment of liver metastases by arterial injection of Adriamycin/mitomycin C lipiodol suspension. Acta Radiol 30:603–608

    Google Scholar 

  15. Kemeny N, Schneider A (1989) Regional treatment of hepatic metastases and hepatocellular carcinoma. Curr Probl Cancer 13:197–283

    Google Scholar 

  16. Kemeny N, Daly J, Reichman B, Geller N, Botet J, Oderman P (1987) Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma, a randomized trial. Ann Intern Med 107:459–467

    Google Scholar 

  17. Khokhar AR, Wright K, Siddik ZH, Perez-Soler R (1988) Organ distribution and tumor uptake of liposome-entrappedcis-bis-neodecanoato-trans-R, R-1,2-diamino-cyclohexane platinum(II) administered intravenously and into the proper hepatic artery. Cancer Chemother Pharmacol 22:223–227

    Google Scholar 

  18. Kinami Y, Miyazaki I (1978) The superselective and the selective one shot methods for treating inoperable cancer of the liver. Cancer 41:1720–1727

    Google Scholar 

  19. Lien WM, Ackerman NB (1970) The blood supply of experimental liver metastases. A microcirculatory study of the normal and tumor vessels of the liver with the use of perfused silicone rubber. Surgery 68:334–340

    Google Scholar 

  20. Mayhew E, Papahandjopoulos D (1983) Therapeutic application of liposomes. In: Ostro MJ (ed) Liposomes. Marcel Dekker, New York, pp 289–341

    Google Scholar 

  21. Mayhew E, Rustum Y, Vail WJ (1983) Inhibition of liver metastases of M-5076 tumor by liposome-entrapped Adriamycin. Cancer Drug Deliv 1:43–49

    Google Scholar 

  22. Mayhew E, Goldrosen MH, Vaage J, Rustum YM (1987) Effects of liposome-entrapped doxorubicin on liver metastases of mouse colon carcinomas 26 and 38. J Natl Cancer Inst 78:707–713

    Google Scholar 

  23. Nakamura H, Hashimoto T, Oi H, Sawada S (1989) Transcatheter oily chemoembolization of hepatocellular carcinoma. Radiology 170:783–789

    Google Scholar 

  24. Patt YZ, Claghorn L, Charnsangavej C, Soski M, Cleary K, Mavligit G (1988) Hepatocellular carcinoma. A retrospective analysis of treatments to manage disease confined to the liver. Cancer 61: 1884–1888

    Google Scholar 

  25. Ridge JA, Collin C, Bading JR, Hancock C, Conti PS, Daly JM, Raaf JH (1988) Increased Adriamycin levels in hepatic implants of rabbit VX2 carcinoma from regional infusion. Cancer Res 48: 4584–4587

    Google Scholar 

  26. Sasaki Y, Imaoka S, Hasegawa Y, Nagano S, Ishikawa O, Ohigashi H, Taniguchi K, Koyama H, Iwanaga T, Terasawa T (1985) Distribution of arterial blood flow in human hepatic cancer during chemotherapy-examination by short-lived81mKr. Surgery 97: 409–413

    Google Scholar 

  27. Sterchi JM (1985) Hepatic artery infusion for metastatic neoplastic disease. Surg Gynecol Obstet 169:477–489

    Google Scholar 

  28. Szoka F Jr, Papahadjopoulos D (1978) Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci USA 75:4194–4199

    Google Scholar 

  29. Wondergem J, Stephen LC, Strebel FR, Baba H, Ohno S, Siddik ZH, Newman RA, Bull JMC (1991) Effect of Adriamycin combined with whole body hyperthermia on tumor and normal tissues. Cancer Res 51:3559–3567

    Google Scholar 

  30. Zou Y, Ueno M, Yamagishi M, Yamashita I, Horikoshi I, Tazawa K, Gu X (1990) Targeting behavior of hepatic artery-injected temperature-sensitive liposomal Adriamycin on tumor-bearing rats. Select Cancer Ther 6:119–127

    Google Scholar 

  31. Zou Y, Horikoshi I, Ueno M, Gu X (1992) The quantitative analysis of Adriamycin and liposomal Adriamycin injected into the hepatic artery in vivo. J SYC Pharm 9:6–9

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmaceutical Research Institute, Shenyang College of Pharmacy, 110015, Shenyang City, China

    Yiyu Zou & Xueqiu Gu

  2. Toyama Medical and Pharmaceutical University, 930-01, Toyama City, Japan

    Isamu Horikoshi & Tokuzou Kasagi

  3. Section of Head, Neck, and Thoracic Medical Oncology, Department of Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 60, 77030, Houston, TX, USA

    Roman Perez-Soler

Authors
  1. Yiyu Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isamu Horikoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tokuzou Kasagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xueqiu Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roman Perez-Soler
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zou, Y., Horikoshi, I., Kasagi, T. et al. Organ distribution and antitumor activity of free and liposomal doxorubicin injected into the hepatic artery. Cancer Chemother. Pharmacol. 31, 313–318 (1993). https://doi.org/10.1007/BF00685677

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00685677

Keywords

Search

Navigation