Objective: Many cytotoxic chemotherapy agents have a narrow therapeutic index. In fact, in some patients, the onset of serious adverse effects may precede any therapeutic benefit. The use of lipo somes to target drug delivery to the site of action can improve a drug's therapeutic index by increasing its efficacy while minimizing toxicity. Liposomal doxo rubicin (Doxil®, Sequus Pharmaceuticals, Inc.)* is the first liposomal chemotherapy product to be approved in the United States. The purpose of this review is to provide a basic understanding of liposomal drug delivery, describe the unique pharmacokinetic prop erties of liposomal doxorubicin (Doxil®), and, finally, comment on this novel drug's place in therapy. Data Sources: Manual and on-line (Medline) literature searches were performed. Search terms included were the brand and generic names of the product, Kaposi's sarcoma, and liposomes. The med ical information department of Sequus Pharmaceuti cals was contacted.
Study Selection: If available, controlled clinical trials with scientific merit were reviewed. Nonran domized studies, case reports, review articles, and letters to editors were considered if appropriate.
Conclusions: Liposomal chemotherapy is one of many attempts to improve cytotoxic chemotherapy by maximizing tumor cell kill while minimizing pa tient adverse effects. Liposomal doxorubicin (Doxil®) is the first of such products approved for use in the United States and has a unique formulation and advantageous pharmacokinetic profile. Liposomal doxorubicin (Doxil®) is both a safe and effective agent in the treatment of advanced AIDS-related Ka posi's sarcoma. The efficacy of liposomal doxorubicin (Doxil®) in the treatment of refractory solid tumors such as breast cancer, lung cancer, colorectal cancer, renal cell cancer, ovarian cancer, and sarcoma has not been demonstrated uniformly. Limited data are avail able regarding the cardiotoxicity potential of this agent; currently no definitive conclusions can be made. Further investigation will be needed to find the ideal dose, dose schedule, and monitoring parameters for the use of liposomal doxorubicin (Doxil®) in patients with solid tumors.
Bangham ADLiposomes: Realizing their promise. Hosp Pract. 1993;27:51-62.
2.
Ostro MJLiposomes. Sci Am.1987;256:103-111.
3.
Lasic D. Liposomes : Synthetic lipid microspheres serve as multipurpose vehicles for the delivery of drugs, genetic material and cosmetics. Am Scientist. 1992;80:20-31.
4.
Gabizon A.Liposomal anthracyclines. Hematol Oncol Clin North Am. 1994;8:431-450.
5.
Perez-Soler R.Liposomes as carriers of antitumor agents: Toward a clinical reality. Cancer Treat Rev.1989 ;16:67- 82.
6.
Ostro MJ, Cullis PRUse of liposomes as injectable-drug delivery systems. Am J Hosp Pbarm.1989;46: 1576-1587.
7.
Mayer LD, Bally MB, Hope MJ, et al. Techniques for encapsulating bioactive agents into liposomes . Chem Pbys Lipids.1986;40:333-345.
Dorr RT, Von Hoff DD. Cancer Chemotherapy Handbook, 2nd edition. Norwalk, CT: Appleton & Lange , 1994;396-411.
10.
Gabizon A., Catane R., Uziely B., et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes . Cancer Res.1994;54:987-992.
11.
Anon.1996Updated Evaluation, Pharmacy and Therapeutics Review, Liposomal doxorubicin . The Formulary, 1996 (Feb.)
Working PK, Newman MS, Huang SK, et al. Pharmacokinetics, biodistribution and therapeutic efficacy of doxorubicin encapsulated in Stealth® liposomes (liposomal doxorubicin (Doxil®) . J Liposome Res.1994;4(1):667-687.
14.
Bogner JR, Kronawitter U., Rolinski B., et al. Liposomal doxorubicin in the treatment of advanced AIDS-related Kaposi sarcoma. J Acquir Immune Defic Syndr. 1994;7(5):463- 468.
15.
Krown SE, Metroka JCKaposi's sarcoma in the acquired immune deficiency syndrome: A proposal for uniform evaluation, response, and staging criteria. J Clin Oncol.1989;7:1201-1207.
16.
Hengge UR, Brockmeyer NH, Baumann M., et al. Liposomal doxorubicin in AIDS-related Kaposi's sarcoma. Lancet. 1993;342:497.
17.
Hengge UR, Brockmeyer NH, Rabhofer R., et al. Fatal hepatic failure with liposomal doxorubicin. Lancet. 1993;341:383.
18.
Harrison M. , Tomlinson D., Stewart S.Liposomal-entrapped doxorubicin: An active agent in AIDS-related Kaposi's sarcoma. J Clin Oncol.1995;13: 914-920.
19.
Goebel FD, Goldstein D., Goos M., et al. Efficacy and safety of Stealth liposomal doxorubicin in AIDS-related Kaposi's sarcoma. [The International SL-DOX Study Group.]Br J Cancer1996 Apr;73(8):989-94.
20.
Gill PS, Wernz, J., Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol.1996;14: 2353-2364.
21.
Uziely B., Jeffers S., Isacson R., et al. Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol.1995;13:1777-1785.
22.
Gabizon A., Isacson R., Libson E., et al. Clinical studies of liposome-encapsulated doxorubicin. Acta Oncol.1994;33(7):779-786.
23.
Gordon KB, Tajuddin A., Guitart J., et al. Hand-Foot syndrome associated with liposome-encapsulated doxorubicin toxicity. Cancer1995;75:2169-2173.
24.
Fabian CJ, Molina R., Slavik M., et al. Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion. Invest New Drugs.1990 ;8:57- 63.
25.
Herman EH, Rahman A., Ferrans VJ, et al. Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation. CancerRes.1983 ;43:5427-5432.
26.
Rahman A., Kessler A., More N., et al. Liposomal protection of adriamycin-induced cardiotoxicity in mice. Cancer Res.1980;40:1532-1537.
27.
Rahman A., Fumagalli A., Barbieri B., et al. Antitumor and toxicity evaluation of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes. Cancer Chemother Pbarmacol.1986;16:22-27.
28.
Rahman A., White G., Moore N., et al. Pharmacological, toxicological and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes. Cancer Res.1985;45:796-803.
29.
Berry G., Billingham M., Alderman E., et al. Reduced cardiotoxicity of liposomal doxorubicin (Doxil) (pegylated liposomal doxorubicin) in AIDS Kaposi's sarcoma patients compared to a matched control group of cancer patients given doxorubicin. Proc Am Soc Clin Oncol.1996;15:303.
30.
Rahman A., Treat J., Rah JK, et al. A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin. J Clin Oncol.1990;8: 1093-1100.
31.
Conley BA, Egorin MJ, Whitacre MY, et al. Phase I and pharmacokinetic trial of liposome-encapsulated doxorubicin . Cancer Chemother Pbarmacol.1993; 33:107-112.
32.
Cowens JW, Creaven PJ, Greco WR, et al. Initial clinical (phase I) trial of TLC D-99 (Doxorubicin Encapsulated in Liposomes). Cancer Res.1993;53: 2796-2802.
33.
Early E., Shorter S., Sugarman A., et al. Phase I trial of dose-intense liposomal encapsulated doxorubicin (LED) with G-CSF in patients with advanced soft tissue sarcoma. Proc Am Soc Clin Oncol.1996;15: 524.
34.
Treat J., Greenspan A., Forst D., et al. Antitumor activity of liposome-encapsulated doxorubicin in advanced breast cancer: Phase II Study. J Natl Cancer Inst.1990;82:1706-1710.
35.
Gabizon A., Peretz T., Sulkes A., et al. Systemic administration of doxorubicin-containing liposomes in cancer patients: A Phase I study. Eur J Cancer Clin Oncol.1989;25:1795-1803.
36.
Owen RR, Sells RA, Gilmore IT, et al. A phase I clinical evaluation of liposome-entrapped doxorubicin (Lip-Dox) in patients with primary and metastatic hepatic malignancy. Anticancer Drugs. 1992; 3:101-107.
37.
Madhavan S. , Northfelt DWLack of vesicant injury following extravasation of liposomal doxorubicin. J Natl Cancer Inst.1995;87:1556-1557.
38.
Doxil® (Sequus). Redbook. Montvale, NJ: Medical Economics, 1996;234.
