Enhancement of antitumor activity of polyethylene glycol-coated liposomal doxorubicin with soluble and liposomal interleukin 2.

Abstract

Polyethylene glycol-coated liposomal doxorubicin (Doxil) has a sustained release profile and a mild myelosuppressive effect that may enable a beneficial interaction with lymphocyte-activating cytokines, such as interleukin 2 (IL-2). Previous studies have shown that liposome entrapment of IL-2 potentiates its immunomodulatory effects and reduces the need for frequent dosing. We assessed the therapeutic effect of Doxil (8 mg/kg) followed by free or liposomal IL-2 (50,000 Cetus Units x 3) in mice bearing M109 lung adenocarcinoma transplanted i.v. or i.p. Doxil was always administered i.v., whereas IL-2 was given i.v. in the i.v. M109 model and i.p. in the i.p. M109 model. The optimal combined treatment was significantly more effective than liposomal chemotherapy alone, producing tumor-free, long-term survivors in 100% (i.v. M109) and 94% (i.p. M109) of the mice, compared with 50% and 56%, respectively, for Doxil alone. The efficacy boost of IL-2 appeared to be formulation dependent, with free IL-2 and IL-2 in small unilamellar vesicles most active in the i.v. tumor model, and IL-2 in multilamellar vesicles most active in the i.p. tumor model. The combination of Doxil with free or liposomal IL-2 was devoid of any conspicuous toxicity. Cytokine treatment without chemotherapy was completely ineffective. Liposome-based chemoimmunotherapy is a synergistic and highly efficacious approach to eradicate metastatic and regionally spread tumors.

• Authors: A Cabanes, S Even-Chen, J Zimberoff, Y Barenholz, E Kedar, A Gabizon
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 5 Issue 3 Pg. 687-93 (Mar 1999) ISSN: 1078-0432 [Print] United States
• PMID: 10100723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Carriers
• Interleukin-2
• Liposomes
• Polyethylene Glycols
• Doxorubicin

Topics

• Adenocarcinoma (drug therapy, mortality, secondary)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use)
• Disease Models, Animal
• Doxorubicin (administration & dosage)
• Drug Carriers
• Female
• Immunotherapy
• Injections, Intraperitoneal
• Injections, Intravenous
• Interleukin-2 (administration & dosage)
• Liposomes
• Lung Neoplasms (drug therapy, mortality, pathology)
• Mice
• Mice, Inbred BALB C
• Neoplasm Metastasis
• Neoplasm Transplantation
• Polyethylene Glycols
• Survival Analysis
• Treatment Outcome
• Tumor Cells, Cultured