Research Project
3491432
We propose a new series of small molecular weight, natural products that are similar to higher plant toxins in their mechanisms of action, inhibiting protein synthesis at the level of the ribosome. All inhibit in vivo translation in cell free systems. Some are cytotoxic to eucaryotic cells at low concentrations (ID50 100 pg/ml) and thus behave like the "intact" dimeric toxins ricin and abrin; others are not cytotoxic at relatively high concentrations (10 ug/ml) and are similar to the ribosomal inactivating protein (RIPs) such as gelonin. Monoclonal antibodies (MA) are proposed as vehicles to facilitate binding and internalization of the non-cytotoxic (RIP-like) molecules and to enhance selectivity of the cytotoxic (intact toxin-like) molecules. We will conjugate two of the RIP-like molecules that differ only in one site of acetylation and one toxin-like molecule to an anti- melanoma MA and test for inhibition of protein synthesis and overall cytotoxicity and selectivity with antigen-positive and antigen-negative melanoma cells. Their conjugates may have equivalent potency but not suffer the poor delivery due to nonspecific uptake as occurs for higher molecular weight toxins. They are also not likely to suffer from drug-induced cross- resistance, as occurs with drugs currently used in chemotherapy. Should either or both of these approaches prove feasible, it will be possible to construct several generations of a wide range of related anti-tumor agents that have unique mechanisms of action that will be important new agents for the treatment of cancer.
