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Alterations in Murine Host Defense Functions by Adriamycin or Liposome-encapsulated Adriamycin¹

Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263

Peritoneal exudate cells (PEC) from C57BL/6 mice were collected on different days following an i.p. injection of Adriamycin (10 mg/kg) as free drug (ADM) or encapsulated in multilamellar liposomes (ADM/Lip). Macrophages harvested from mice at various times (Days 4–14) after either drug treatment were responsive to in vitro lipopolysaccharide induction of tumoricidal activity, maximum response being seen on Day 7. In addition, 18 days after treatment, significant macrophage tumoricidal activity was observed only in the ADM/Lip-treated group. When supernatants from cultures of PEC obtained 7 days after treatment were assayed for interleukin 1 following lipopolysaccharide stimulation, activity was found with both ADM- and ADM/Lip-treated cells. Without lipopolysaccharide stimulation, only PEC from ADM-treated mice elaborated factor(s) with interleukin 1-like activity. Both ADM and ADM/Lip induced significant PEC-natural killer (PEC-NK) activity by Day 4, while the ADM/Lip treatment sustained PEC-NK activity more effectively than free drug at later time points (7 or 11 days posttreatment). Drug-induced PEC-NK activity (Day 7) was (a) ablated by treatment in vitro with anti-asialo GM₁ antibody and complement, and (b) associated with a population of PEC nonadherent to plastic. A transient suppression of splenic NK activity was seen 4 days following either ADM or ADM/Lip administration with recovery to control level by Day 7.

These data demonstrate that following ADM or ADM/Lip administration some of the changes necessary for macrophage tumoricidal activation must have occurred in vivo. Liposome encapsulation of ADM extended the duration of ADM-induced augmentation of certain host defenses.

¹ Supported by CA-15142, CA-24538, and CA-37304, National Cancer Institute, USPHS.

² This work was done in partial fulfillment of the Ph.D. degree requirements in the Program of Pharmacology, Roswell Park Graduate Division, State University of New York at Buffalo.

³ To whom requests for reprints should be addressed, at Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, 666 Elm Street, Buffalo, NY 14263.

Received 2/13/87. Revised 6/29/87. Accepted 10/ 2/87.

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