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 re lease profile and a mild myelosuppressive effect that may enable a benefici al interaction with lymphocyte-activating cytokines, such as interleukin 2 (IL-2), Previous studies have shown that liposome entrapment of IL-2 potent iates 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 x3) in mice bearing M109 lung adenocarc inoma 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 lipo somal 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%, re spectively, for Doxil alone. The efficacy boost of IL-2 appeared to be form ulation dependent, with free IL-2 and IL-2 in small unilamellar vesicles mo st 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 lipos omal IL-2 was devoid of any conspicuous toxicity. Cytokine treatment withou t chemotherapy was completely ineffective. Liposome-based chemoimmunotherap y is a synergistic and highly efficacious approach to eradicate metastatic and regionally spread tumors.