Glucosphingolipids as sites of action in the chemotherapy of cancer.

Searches for abnormalities in tumors have revealed a dismayingly large number of metabolic changes, both increases and decreases in the content of qualitatively normal substances. Substances having a novel chemical structure have been found only rarely. The possibility should be considered that these apparently new compounds, despite their variety and inconsistency of appearance, are somehow responsible for the unrestrained growth, malignancy, and invasiveness characteristic of cancer. A corollary possibility should also be considered: certain admittedly normal substances found in tumors in relatively high concentrations can, if they reach a triggering concentration, begin the cancerous process. This paper presents selected clues about a class of compounds in the above categories, the glycosphingolipids based on G1cCer.S They are called “glucosphingolipids” in the title and “glycolipids” in the text.§ These substances are formed from N-acyl sphingols (ceramides) by a transferase which attaches glucose to the C-l of the sphingol. Other transferases subsequently attach additional sugar groups to the GlcCer. The most-studied glycolipids are the ones containing sialic acid, the gangliosides. Acetyl groups can be present in amide and ester linkage, and glycolyl groups can be present in amide linkage. Many researchers have come to believe that glycolipids are “closely involved” in one or more aspects of cancer cell metabolism and this article summarizes some of their reports. On the basis of literature reading and initial success with a drug that inhibits glycolipid synthesis in mouse Ehrlich ascites tumor cells, we have come to believe that glycolipids are causally involved in cancer. Our hypothesis starts with the recent discoveries that some types of cancer