ganglioside--gd1b and Glioma

In spite of their low incidence, central nervous system tumors have elevated morbidity and mortality, being responsible for 2.3% of total cancer deaths. The ganglioside O-acetylated GD1b (O-Ac GD1b; neurostatin), present in the mammalian brain, and the semi-synthetic O-butyrylated GD1b (O-But GD1b) are potent glioma proliferation inhibitors, appearing as possible candidates for the treatment of nervous system tumors. Tumoral cell division inhibitory activity in culture correlated with growth inhibition of glioma xenotransplants in Foxn1(nu) nude mice and intracranial glioma allotransplants. Both O-Ac GD1b and O-But GD1b inhibited in vivo cell proliferation, induced cell cycle arrest, and potentiated immune cell response to the tumor. Furthermore, the increased stability of the butyrylated compound (O-But GD1b) enhanced its activity with respect to the acetylated ganglioside (neurostatin). These results are the first report of the antitumoral activity of neurostatin and a neurostatin-like compound in vivo and indicate that semi-synthetic O-acetylated and O-butyrylated gangliosides are potent antitumoral compounds that should be considered in strategies for brain tumor treatment.

Topics: Acetylation; Animals; Antineoplastic Agents; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Separation; Flow Cytometry; Gangliosides; Glioma; Glycosphingolipids; Immunohistochemistry; Male; Mice; Mice, Nude; Rats; Rats, Sprague-Dawley; Xenograft Model Antitumor Assays

Ganglioside sialic acid content was examined in the U87-MG human glioma grown as cultured cells and as a xenograft in severe combined immunodeficiency (SCID) mice. The cultured cells and the xenograft possessed N-glycolylneuraminic acid (NeuGc)-containing gangliosides, despite the inability of human cells to synthesize NeuGc. Human cells express only N-acetylneuraminic acid (NeuAc)-containing gangliosides, whereas mouse cells express both NeuAc- and NeuGc-containing gangliosides. Small amounts of NeuGc ganglioside sialic acid (2-3% of total ganglioside sialic acid) were detected in the cultured cells, whereas large amounts (66% of total ganglioside sialic acid) were detected in the xenograft. The NeuGc in gangliosides of the cultured cells was derived from gangliosides in the fetal bovine serum of the culture medium, whereas that in the U87-MG xenograft was derived from gangliosides of the SCID host. The chromatographic distribution of U87-MG gangliosides differed markedly between the in vitro and in vivo growth environments. The neutral glycosphingolipids in the U87-MG cells consisted largely of glucosylceramide, galactosylceramide, and lactosylceramide, and their distribution also differed in the two growth environments. Asialo-GM1 (Gg4Cer) was not present in the cultured tumor cells but was expressed in the xenograft, suggesting an origin from infiltrating cells (macrophages) from the SCID host. The infiltration of mouse host cells and the expression of mouse sialic acid on human tumor cell glycoconjugates may alter the biochemical and immunogenic properties of xenografts.

Topics: Animals; G(M2) Ganglioside; G(M3) Ganglioside; Gangliosides; Glioma; Humans; Mice; Mice, Inbred C57BL; Mice, SCID; N-Acetylneuraminic Acid; Neoplasm Transplantation; Neuraminic Acids; Transplantation, Heterologous; Tumor Cells, Cultured