asialo-gm1-ganglioside and Carcinoma--Renal-Cell

Advanced metastatic renal cell carcinoma has been shown to be responsive to immunotherapy but the response rate is still limited. We have investigated the therapeutic potential of systemic interleukin-4 (IL-4) administration for the treatment of pulmonary metastases in the murine Renca renal adenocarcinoma model. Renca cells were injected iv in Balb/c mice to induce multiple pulmonary tumor nodules. From Day 5, Renca-bearing mice were treated with two daily injections of recombinant murine IL-4 for 5 consecutive days. IL-4 treatment induced a significant reduction in the number of lung metastases in a dose-dependent manner and significantly augmented the survival of treated animals. Immunohistochemistry studies, performed on lung sections, showed macrophage and CD8+ T cell infiltration in the tumor nodules 1 day after the end of IL-4 treatment. The CD8 infiltration increased by Day 7 after IL-4 treatment. Granulocyte infiltration was not detectable. To clarify further the role of the immune system in IL-4 anti-tumor effect, mice were depleted of lymphocyte subpopulations by in vivo injections of specific antibodies prior to treatment with IL-4. Depletion of CD8+ T cells or AsGM1+ cells abrogated the effect of IL-4 on lung metastases, whereas depletion of CD4+ T cells had no impact. These data indicate that CD8+ T cells and AsGM1+ cells are involved in IL-4-induced regression of established renal cell carcinoma.

Topics: Animals; Antigens, Differentiation, T-Lymphocyte; Antigens, Ly; Carcinoma, Renal Cell; CD8-Positive T-Lymphocytes; Female; G(M1) Ganglioside; Immunologic Factors; Interleukin-4; Kidney Neoplasms; Lung Neoplasms; Lymphocyte Depletion; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Macrophages; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Recombinant Proteins; Thy-1 Antigens; Time Factors

The effect of the streptococcal preparation OK-432, which is one of the biological response modifiers, was examined in BALB/c mice using a transplantable murine renal cell carcinoma (Renca) of spontaneous origin, and an analysis of effector cells was performed. The tumor grew progressively and metastasized consistently to the abdominal lymph nodes and then to distant organs following the inoculation of Renca cells in the left renal subcapsular site in BALB/c mice, and the survival time of the mice was under 42 days. In this tumor model, i.p. administration of OK-432 after tumor inoculation significantly extended the survival time and significantly inhibited the formation of the inoculated tumor itself. Removal of the left kidney on the 7th day after tumor inoculation neither extended the survival time nor augmented the effect of OK-432. Splenic cells obtained on the 7th day after tumor inoculation from Renca-bearing mice treated with OK-432 were capable of lysing syngeneic Renca cells, NK-sensitive allogenic YAC-1 cells, and LAK-sensitive EL-4 cells in a 4-hour 51Cr-release assay in vitro. Those obtained from healthy mice treated with OK-432 also showed cytotoxic activity against Renca cells. The cytotoxicity of splenic cells from Renca-bearing mice treated with OK-432 was lost almost completely for both Renca and YAC-1 cells after in vitro treatment with anti-asialo GM1 antibody, and was partially lost after in vitro treatment with anti-Thy-1,2 antibody. Additionally, in vivo i.p. administration of anti-asialo GM1 antibody significantly counteracted the effect of OK-432 on survival. These findings demonstrated that Renca cells were NK-sensitive and that the i.p. administration of OK-432 was beneficial for the prevention of the spontaneous metastasis of Renca carcinoma. As the effectors, NK cells played a dominant role and activated T cells were also involved.

Topics: Animals; Carcinoma, Renal Cell; Female; G(M1) Ganglioside; Glycosphingolipids; Injections, Intraperitoneal; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation; Picibanil

We have studied the role of natural killer activity during the growth and dissemination of a transplantable renal adenocarcinoma (Renca) of spontaneous origin in BALB/c mice. The pattern of growth of this tumor accurately mimics that of adult human renal cell carcinoma in terms of clinical stages I-IV, particularly with regard to spontaneous metastasis to lung and liver. Renca is moderately sensitive to lysis by natural killer cells from normal mice and is more efficiently lysed by natural killer cells from mice treated with the biological response modifier maleic anhydride divinyl ether, a pyran copolymer. Our studies demonstrate that selective depression of natural killer activity by administration of antiserum specific for the neutral glycosphingolipid asialo GM1 correlated with increased formation of spontaneous metastases in the lungs, liver, and lymph nodes. Conversely, augmentation of natural killer activity by the biological response modifier decreased the formation of spontaneous metastases in lungs, liver and lymph nodes. Further, the suppression of natural killer activity and subsequent increased formation of metastases were accompanied by a significantly reduced survival time, whereas the augmented natural killer activity and decreased incidence of metastases in biological response modifier-treated mice were accompanied by an increase in time of survival. These results demonstrate a significant role for natural killer cells in the control of spontaneous metastasis during growth of this murine renal cancer.

Topics: Animals; Carcinoma, Renal Cell; Cell Line; Female; G(M1) Ganglioside; Glycosphingolipids; Immune Sera; Kidney Neoplasms; Killer Cells, Natural; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation; Pyran Copolymer