3-nitrotyrosine and Pleural-Effusion--Malignant

Clinical application of interleukin (IL)-2-based immunotherapy of cancer has been limited by a major side-effect known as 'capillary leak syndrome', resulting from nitric oxide (NO) overproduction. A galactoside-specific lectin from Viscum album L. (VAA) has been reported to induce certain lymphokines and upregulate IL-2 receptors on lymphocytes. Present study was, therefore, designed to compare the effects of combination therapy with IL-2 (10(4) Cetus units/mouse, intraperitoneal (i.p). every 8 h, given as 5 day rounds per week, for one or two rounds) and VAA (1 ng/kg subcutaneous (s.c.), biweekly) with those of IL-2 or VAA therapy alone in C3H/HeJ female mice bearing s.c. transplants of a highly metastatic C3L5 mammary adenocarcinoma. IL-2 therapy alone reduced tumour growth and metastasis, but caused significant water retention indicative of capillary leakage in the kidneys after both rounds of therapy, whereas pleural effusion was only evident after the first round and not the second round. A sharp rise in the systemic NO levels after the first round, followed by a decline after the second round of IL-2 therapy suggested a causal relationship of increased NO levels to pleural effusion. A strong immunostaining for nitrotyrosine (a marker for the production of peroxynitrite) was noted in the renal tubules at the end of both rounds of therapy suggestive of a causal association of this toxic NO-metabolite with capillary leakage in the kidneys. Addition of VAA to IL-2 therapy had no effect on any of the above parameters. Unexpectedly, however, VAA therapy alone stimulated tumour growth as well as lung metastases. NO induction in the C3L5 cells by VAA was excluded as a possible reason for this stimulation. Present results suggest the need for exercising caution in the use of VAA as an immunoadjuvant in human cancer therapy.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Animals; Capillary Permeability; Female; Interleukin-2; Kidney; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Nitric Oxide; Plant Preparations; Plant Proteins; Pleural Effusion, Malignant; Recombinant Proteins; Ribosome Inactivating Proteins, Type 2; Toxins, Biological; Tumor Cells, Cultured; Tyrosine