Summary
The antitumor activity of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes was evaluated in P388 ascitic leukemia, disseminated Gross leukemia, and advanced mammary carcinoma. In P388 leukemia, free drug and drug entrapped in liposomes demonstrated equivalent antitumor activity at doses of 2.2 and 4.4 mg/kg, demonstrating 52% and 69% ILS (increase in life-span), respectively. Free doxorubicin at a dose of 10 mg/kg was superior, producing a 185% ILS against 82% with liposomal doxorubicin. With an increase in administered dose the antitumor response with liposomal doxorubicin was much more pronounced; at doses of 20 and 25 mg/kg the ILS was in excess of 376%, with five of ten mice surviving tumor-free. In Gross leukemia, the optimum dose of free doxorubicin, 10 mg/kg, brought about 186% T/C (median survival in treated mice over that in controls, x100), whereas with liposomal doxorubicin the optimum dose was 16.9 mg/kg, which yielded 214% T/C. In advanced mammary carcinoma, the maximum tumor regression with free doxorubicin was at a dose of 7.5 mg/kg, with two of six mice dying of toxicity. Liposomal doxorubicin caused maximum tumor regression at 10.8 mg/kg dose with no toxic deaths. Doxorubicin entrapped in cardiolipin liposomes was much less toxic than free drug at high doses in normal mice.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bachur NR, Moore AL, Bernstein JC, Lio A (1970) A tissue distibution and disposition of daunomycin in mice: fluorometric and isotopic methods. Cancer Chemother Rep 54: 89–94
Bristow MR, Billingham MR, Mason JW, Daniels TR (1978) Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat Rep 62: 873–879
Conne A, Sculier JP, Fruhhing J, Stryekmans P, Brassinne C, Ghanem G, Ladpuron C, Atassi G, Ruysschaert JM, Hildebrand (1983) IV administration of a water-insoluble antimitotic compound entrapped in liposomes. Preliminary report on infusion of large volumes of liposomes to man. Cancer Treat Rep 67: 1031–1033
DiMarco A, Lenaz L, Casazza AM, Scarpinato BM (1972) Activity of adriamycin (NSC 123127) and Daunomycin (NSC 82151) against mouse mammary carcinoma. Cancer Chemother Rep 56: 153–161
Forssen EA, Tokes ZA (1981) Use of aniomic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity. Proc Natl Acad Sci USA 78: 1873–1877
Forssen EA, Tokes ZA (1983) Improved therapeutic benefits of doxorubicin by entrapment in anionic liposomes. Cancer Res 43: 546–550
Gabizon A, Dagan A, Goren D, Barenholz Y, Fuks Z (1982) Liposomes as in vivo carries of Adriamycin: reduced cardiac uptake and preserved antitumor activity in mice. Cancer Res 42: 4734–4739
Geran RI, Greenberg NH, MacDonald MM (1972) Protocols for screening chemical agents and natural products against animal tumors and other biological system, 3rd edn. Cancer Chemother Rep [3] 3: 1–103
Goormaghtigh E, Chatelain P, Caspers J, Ruysschaert JM (1980) Evidence of a specific complex between adriamycin and negatively charged phospholipids. Biochim Biophys Acta 597: 1–14
Herman EH, Rahman A, Ferrans VJ, Vick JA, Schein PS (1983) Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation. Cancer Res 43: 5427–5432
Juliano RL, Stamp D (1978) Pharmacokinetic of liposome-encapsulated antitumor drugs. Biochem Pharmacol 27:21–27
Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA (1973) A clinico-pathologic analysis of adriamycin cardiotoxicity. Cancer 32:302–314
Lefrak EA, Pitha J, Rosenheim S, O'Bryan RM, Burgess MA, Gottlieb JA (1975) Adriamycin (NSC 123127) cardiomyopathy. Cancer Chemother Rep 6:302–208
Lopez-Berestein G, Kasi L, Rosenblum MG, Haynie T, Jahns M, Glenn H, Metha R, Mavlight GM, Hersh EM (1984) Clinical pharmacology of 99mTc-labeled liposomes in patients with cancer. Cancer Res 44:375–378
Olson F, Mayhew E, Maslow D, Rustrum Y, Szoka F (1982) Characterization toxicity and therapeutic efficacy of adriamycin encapsulated in liposomes. Eur J Cancer Clin Oncol 18:167–176
Parker RJ, Hartman KD, Sieber SM (1981) Lymphatic absorption and tissue dispostion of liposome-entrapped 14C adriamycin following intraperitoneal administration to rats. Cancer Res 41:1311–1317
Poste G (1983) Liposome targeting in vivo: problems and opportunities. Biol Cell 47:19–38
Rahman A, Kessler A, More N, Sikic B, Rowden G, Woolley P, Schein PS (1980) Liposomal protection of adriamycin-induced cardiotoxicity in mice. Cancer Res 40:1532–1537
Rahman A, Gutierrez P, Raschid S, Mhatre RL, Schein PS (1981) Pharmacokinetic of liposome-encapsulated doxorubicin. Fed Proc 40:685
Rahman A, More N, Schein PS (1982) Doxorubicin-induced chronic cardiotoxicity and its protection by liposomal administration. Cancer Res 42:1817–1825
Rahman A, Fumagalli A, Goodman A, Schein PS (1984) Potential of liposomes to ameliorate anthracycline-induced cardiotoxicity. Sem Oncol 11:45–55
Rahman A, White G, More M, Schein PS (1985) The pharmacological toxicological and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes. Cancer Res 45:796–803
Author information
Authors and Affiliations
Additional information
This work was supported by a grant from the American Heart Association (82-922) and by PHSCA 5P30 CA 1-4626
Rights and permissions
About this article
Cite this article
Rahman, A., Fumagalli, A., Barbieri, B. et al. Antitumor and toxicity evaluation of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes. Cancer Chemother. Pharmacol. 16, 22–27 (1986). https://doi.org/10.1007/BF00255281
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00255281