Therapy of spontaneous lung metastasis of murine renal adenocarcinoma by systemic administration of liposomes containing the macrophage activator CGP 31362.

نویسندگان

  • C P Dinney
  • C D Bucana
  • T Utsugi
  • I J Fidler
  • A C von Eschenbach
  • J J Killion
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Liposomes Containing Lipopeptide CGP 31362 Reticulum Cell Sarcoma Hepatic Metastases in Mice Treated Inducible Nitric Oxide Synthase and Regression of M5076 Direct Correlation between Expression of Endogenous

The purpose of this study was to determine whether the activation of inducible nitric oxide synthase (¡NOS)can serve as a target for immunotherapeutic agents for treatment of murine reticulum cell sarcoma métas tases. Liver métastaseswere established by the i.v. injection of M5076 cells into syngeneic C57BL/6 mice. Multiple systemic administrations of multilamellar vesicle-liposomes (MLV) co...

متن کامل

Direct Correlation between Expression of Endogenous Inducible Nitric Oxide Synthase and Regression of M5076 Reticulum Cell Sarcoma Hepatic Métastases in Mice Treated with Liposomes Containing Lipopeptide CGP 313621

The purpose of this study was to determine whether the activation of inducible nitric oxide synthase (¡NOS)can serve as a target for immunotherapeutic agents for treatment of murine reticulum cell sarcoma métas tases. Liver métastaseswere established by the i.v. injection of M5076 cells into syngeneic C57BL/6 mice. Multiple systemic administrations of multilamellar vesicle-liposomes (MLV) co...

متن کامل

Treatment of experimental lung metastasis with local thoracic irradiation followed by systemic macrophage activation with liposomes containing muramyl tripeptide.

The purpose of these studies was to determine whether the combination of a low-dose local thoracic irradiation (LTI) followed by systemic activation of macrophages with liposomes containing muramyl tripeptide phosphatidylethanolamine (MTP-PE) would significantly decrease established experimental fibrosarcoma lung metastases. Male C3Hf/Kam mice were given i.v. injections of 1 X 10(5) fibrosarcom...

متن کامل

Involvement of macrophages in the eradication of established metastases following intravenous injection of liposomes containing macrophage activators.

Liposomes containing encapsulated lymphokines or muramyl dipeptide (MDP), when injected i.v. into C57BL/6 mice, produced significant destruction of established lung and lymph node metastases from a s.c. highly metastatic B16-BL6 melanoma. We present evidence that eradication of the metastases is mediated by the activation of host macrophages to the tumoricidal state. Results from three separate...

متن کامل

Preparation and in-vitro Evaluation of an Antisense-containing Cationic Liposome against Non-small Cell Lung Cancer: a Comparative Preparation Study

The current methods for treatment of cancers are inadequate and more specific methods such as gene therapy are in progress. Among different vehicles, cationic liposomes are frequently used for delivery of genetic material. This investigation aims to prepare and optimize DOTAP cationic liposomes containing an antisense oligonuclotide (AsODN) against protein kinase C alpha in non-small cells lung...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Cancer research

دوره 51 14  شماره 

صفحات  -

تاریخ انتشار 1991