cgp-31362 and Lung-Neoplasms

The purpose of these experiments was to evaluate the possibility that the systemic administration of liposomes containing synthetic macrophage activation CGP 31362 or CGP 19835 in mice which were simultaneously receiving injections of gamma-interferon or interleukin 2 would lead to enhanced regression of spontaneous lung metastases produced by syngeneic renal adenocarcinoma. The kidneys of BALB/c mice were given injections of renal adenocarcinoma cells, and 10 days later the kidney with local tumor was surgically resected. These mice were then given injections i.v. with liposomes and with gamma-interferon (s.c.) or interleukin 2 (i.p.). Systemic administration of MLV-CGP 31362 and MLV-CGP 19835A significantly reduced the number of lung metastases in nephrectomized mice. Both lung tumor burden and regional recurrence were further reduced by the s.c. injection of gamma-interferon or i.p. injection of interleukin 2. Long-term survivors were observed only in the groups of animals treated with liposomes containing macrophage activators and with lymphokines. Evaluation of host responsiveness to this immunotherapy revealed in situ activation of alveolar macrophages by administration of MLV-CGP 31362 or MLV-CGP 19835A, which was enhanced in mice also treated with interleukin 2. Normal levels of natural killer cell activity were reduced in the spleens of tumor-bearing mice but were restored subsequent to treatment with MLV-CGP 31362. These results indicate the potential usefulness of treating metastatic renal cell carcinoma by systemic administration of liposomes containing synthetic macrophage activators in combination with parental injections of lymphokines.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adenocarcinoma; Animals; Drug Carriers; Drug Screening Assays, Antitumor; Immunotherapy; Interferon-gamma; Interleukin-2; Kidney Neoplasms; Killer Cells, Natural; Liposomes; Lung Neoplasms; Macrophages; Mice; Mice, Inbred BALB C; Nephrectomy; Oligopeptides; Peptide Fragments; Phosphatidylethanolamines; Rats; Specific Pathogen-Free Organisms

We determined whether the intravenous administration of multilamellar vesicle liposomes (MLV) containing a lipopeptide analogue of a fragment from the cell wall of gram-negative bacteria (CGP 31362) can render BALB/c mouse alveolar macrophages tumoricidal in situ and reduce the incidence of spontaneous lung metastasis of syngeneic renal carcinoma (RENCA) cells. Alveolar macrophages (a) incubated in vitro with MLV containing CGP 31362 (MLV-31362) and (b) harvested from mice injected i.v. with MLV-31362 were rendered cytotoxic against the RENCA cells. Maximum cytotoxic activity of the macrophages was induced by injecting 5 mumol MLV consisting of 250 mg phospholipids and 0.5 mg CGP 31362. The single i.v. injection of 5 mumol MLV-31362 produced activation of macrophages that lasted for up to 4 days. Repeated i.v. injections of MLV-31362 produced a continuous antitumor activity in alveolar macrophages. To study the lipopeptide's effects on metastasis, we injected the left kidneys of BALB/c mice with RENCA cells. The kidney with growing tumor was resected 10 days later and, after a further 2 days, groups of mice were injected i.v. with MLV-31362 or with MLV-HBSS (twice weekly for 3 weeks). Treatment with MLV-31362 significantly decreased the median number of spontaneous lung metastases. These data demonstrate that the systemic administration of MLV-31362 can activate murine lung macrophages in situ and reduce the incidence of spontaneous RENCA lung metastases.

Topics: Adjuvants, Immunologic; Animals; Carcinoma, Renal Cell; Drug Carriers; Liposomes; Lung Neoplasms; Macrophage Activation; Mice; Mice, Inbred BALB C; Oligopeptides; Peptide Fragments; Tumor Cells, Cultured

Current therapies for renal cell carcinoma have been limited by the unresponsiveness of metastatic disease to conventional treatments. Although the use of biological response modifiers as adjuvant therapy has generally not been successful against disseminated disease, in situ activation of macrophages to a tumoricidal state by liposome-encapsulated immunomodulators has been shown to eradicate metastatic cancer in murine tumor models. We, therefore, designed experiments to evaluate the ability of a new macrophage activator, CGP 31362, a synthetic bacterial cell wall analogue, to cause regression of spontaneous lung metastases in mice whose primary renal adenocarcinoma was removed by nephrectomy. Delivery of the CGP 31362 to the lungs was accomplished by its encapsulation in multilamellar phospholipid liposomes (MLV-CGP 31362). Therapy with repeated i.v. injections of MLV-CGP 31362 significantly reduced the number of lung metastases in nephrectomized mice. Therapeutic efficacy of MLV-CGP 31362 was influenced by the encapsulation ratio of CGP 31362 to total phospholipid, the dose of injected liposomes, and the frequency of administration. Optimal therapy was achieved by combining the use of i.v. MLV-CGP 31362 with the s.c. injection of recombinant murine gamma interferon. Administration of MLV-CGP 31362 prior to removal of the primary tumor and continuing postoperatively was superior to postoperative therapy alone. Several lines of evidence indicate that in situ activation of macrophages was responsible for the therapeutic effects of MLV-CGP 31362: (a) macrophages harvested from the lungs of treated mice had significant tumoricidal activity against cultured renal carcinoma cells, (b) activated macrophages, as defined by the MRP-14 marker, were present in lung tumor nodules of treated mice but not untreated mice, and (c) the in situ activation of alveolar macrophages was consistent with the in vivo deposition of 60% of radiolabeled MLV-CGP 31362 liposomes in the lungs following i.v. injection. The results reported here represent the first in vivo evaluation of MLV-CGP 31362 and offer additional evidence that macrophage combination with therapies that reduce tumor burden.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Animals; Carcinoma, Renal Cell; Drug Administration Schedule; Interferon-gamma; Kidney Neoplasms; Lipids; Liposomes; Lung Neoplasms; Macrophage Activation; Mice; Mice, Inbred BALB C; Oligopeptides; Peptide Fragments; Recombinant Proteins