Enhancement of antitumor activity of polyethylene glycol-coated liposomal doxorubicin with soluble and liposomal interleukin 2.
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.
Cabanes
A
A
Sharet Institute of Oncology, Hadassah Hebrew University Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Even-Chen
S
S
Zimberoff
J
J
Barenholz
Y
Y
Kedar
E
E
Gabizon
A
A
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers; D005260:Female; D007167:Immunotherapy; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D007376:Interleukin-2; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin