Summary
Liposomes containing cytosine arabinoside (ara-C) release drug slowly and can be used to maintain a locally high concentration of ara-C in the peritoneal cavity for intracavitary chemotherapy. However, a significant amount of active drug does reach the systemic circulation and contributes to systemic toxicity. We have devised a novel method of decreasing toxicity and increasing intraperitoneal half-life by pretreatment with “blank” liposomes containing no active drug. This technique has resulted in prolongation of intraperitoneal half-life of the liposomal ara-C from 21 h to 165 h, enabling maintenance of a therapeutic drug concentration even at 11 days after initial injection. One hundred percent cures (60-day survival) were achieved with a single-dose therapy begun 1 day after i. p. implantation of 106 L1210 leukemia cells.
Similar content being viewed by others
References
Dedrick RL, Myers CE, Gungnay PM, DeVita VT (1978) Pharmacokinetic rationale for peritoneal drug administration in treatment of ovarian cancer. Cancer Treat Rep 62: 1
Ellens H, Rustum Y, Mayhew E, Ledesma E (1982) Distribution and metabolism of liposome-encapsulated and free 1-β-D-arabinofuranosylcytosine (Ara-C) in dog and mouse tissues. J Pharmacol Exp Ther 222: 324
Ganapathi R, Krishan A, Wodinsky I, Zubrod CG, Lesko LJ (1980) Effect of cholesterol content on antitumor activity and toxicity of liposome-encapsulated 1-β-D-arabinofuranosylcytosine in vivo. Cancer Res 40: 630–633
Graham FL, Whitmore GF (1970) The effect of 1-β-arabinofuranosyl-cytosine on growth, viability, and DNA synthesis of mouse L-cells. Cancer Res 30: 2627
Juliano RL, Stamp D (1978) Pharmacokinetics of liposomeencapsulated antitumor drugs. Biochem Pharmacol 27: 21
Kaledin VI, Matienko NA, Nikolin VP, Yevgeny VG, Budker VG (1981) Intralymphatic administration of liposome-encapsulated drugs to mice: possibility for suppression of the growth of tumor metastases in the lymph nodes. JNCI 66: 881
Kanellos J, Pietersz GA, McKenzie IFC (1985) Studies of methotrexate-monoclonal antibody conjugates for immunotherapy. JNCI 75: 319
Kim S, Turker MS, Chi EY, Shifra S, Martin GM (1983) Preparation of multivesicular liposomes. Biochim Biophys Acta 728: 339
King ME, Pfeifle CE, Howell SB (1984) Intraperitoneal cytarabine therapy in ovarian carcinoma. J Clin Onc 2: 662
Kobayashi T, Tsukagoshi S, Sakurai Y (1975) Enhancement of the cancer chemotherapeutic effect of cytosine arabinoside entrapped in liposomes on mouse leukemia L-1210. Gann 66: 719
Kobayashi T, Kataoka T, Tsukagoshi S, Sakurai Y (1977) Enhancement of anti-tumor activity of 1-β-D-arabinofuranosylcytosine by encapsulation in liposomes. Int J Cancer 20: 581
Liburdy R, Magin RL (1985) Microwave-stimulated drug release from liposomes. Radiation Res 103: 266
Markman M, Cleary S, Lucas WE, Howell SB (1985) Intraperitoneal chemotherapy with high-dose cisplatin and cytosine arabinoside for refractory ovarian carcinoma and other malignancies principally involving the peritoneal cavity. J Clin Onc 3: 925
Markman M, Cleary S, Pfeifle C, Howell SB (1986) Cisplatin administered by the intracavitary route as treatment for malignant mesothelioma. Cancer 58: 18
Mayhew E, Rustum YM, Szoka F, Papahdjopoulos D (1979) Role of cholesterol in enhancing the antitumor activity of cytosine arabinoside entrapped in liposomes. Cancer Treat Rep 63: 1923
Parker RJ, Priester ER, Sieber SM (1982) Comparison of lymphatic uptake, metabolism, excretion, and biodistribution of free and liposome-entrapped [14C]cytosine β-D-arabinofuranoside following intraperitoneal administration to rats. Drug Metab Disp 10: 40
Patel KR, Baldeschwieler JD (1984) Treatment of intravenously implanted Lewis lung carcinoma with liposome-encapsulated cytosine arabinoside and non-specific immunotherapy. Int J Cancer 34: 415
Raabo E, Terkildsen TC (1960) On the enzymatic determination of blood glucose. Scand J Clin Lab Invest 12: 402
Rustum YM, Mayhew E, Szoka F, Campbell J (1981) Inability of liposome encapsulated 1-β-D-arabinofuranosylcytosine nucleotides to overcome drug resistance in L1210 cells. Eur J Cancer Clin Oncol 17: 809
Skipper HE, Schabel FM, Wilcox WS (1967) Experimental evaluation of potential anticancer agents. XXI. Scheduling of arabinosylcytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemother Rep 51: 125
Yatvin MB, Muhlensiepen H, Porschen W, Weinstein JN, Feinendegen LE (1981) Selective delivery of liposome-associated cis-dichlorodiammineplatinum (II) by heat and its influence on tumor drug uptake and growth. Cancer Res 41: 1602
Author information
Authors and Affiliations
Additional information
Supported in part by Public Health Service grants CA-01082, CA-35309, and CA 23100 from the National Cancer Institute, National Institute of Health, DHHS. This work was conducted in part by the Clayton Foundation for Research, California Division. Stephen B. Howell is a Clayton Foundation Investigator
Rights and permissions
About this article
Cite this article
Kim, S., Kim, D.J. & Howell, S.B. Modulation of the peritoneal clearance of liposomal cytosine arabinoside by blank liposomes. Cancer Chemother. Pharmacol. 19, 307–310 (1987). https://doi.org/10.1007/BF00261478
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00261478