In Vitro and in Vivo Effect of Adriamycin Therapy on Monocyte Activation by Liposome-encapsulated Immunomodulators1

The purpose of these studies was to determine the effect of Adriamycin (ADR) on the ability of liposome-encapsulated immunomodulators to activate human blood monocytes to the tumoricidal state. We undertook these experiments because we envisioned using encapsulated activators in addition to chemotherapy to destroy pulmonary micrometastases in patients with osteosarcoma (OS). Prior to the initiation of such therapy, it was important to determine whether chemotherapy interferes with monocyte function. First, human peripheral blood monocytes were iso lated from normal donors and preincubated with ADR (0.5-500 ng/ml) for I h and then washed prior to the addition of free or liposomeencapsulated activators. After 18-24 h incubation, the activating agents were washed off and |l25I]IdUrd-labeled A375 melanoma cells were added. Lysis of radiolabeled tumor cells was quantified 72 h later. Monocytes were also incubated with ADR for 24 h in the presence of free or liposomeencapsulated activators and their cytotoxicity quantified. ADR had no effect on the ability of either free or liposome-encapsulated agents to activate monocyte tumoricidal function. We also studied the in vivoeffect of ADR therapy on monocyte function in nine patients with OS. At the time of diagnosis and 1 month after ADR therapy (75 mg/m2) patient monocytes could be activated to the tumoricidal state by liposome-encapsulated agents at levels equal to or greater than pretherapy levels. Monocytes isolated from four patients with OS I day after ADR therapy and then activated by liposomeencapsulated agents also demonstrated tumoricidal activity. These studies indicated that the monocytes isolated from osteosarcoma patients treated with ADK can be activated in vitro to kill tumor cells and that additional therapy with liposome-encapsulated immunomodulators may be com bined with ADR in the treatment of metastatic pulmonary OS.