ANTITUMOR-ACTIVITY OF NOVEL OCTALACTIN A ANALOGS IN MURINE LEUKEMIA-CELLS IN-VITRO

Octalactin A and B (code names KI and K2) are eight-membered-ring lact ones from a marine bacterium. KI is reportedly cytotoxic. Since access to this natural product is severely limited, the entire synthesis of K1 has been achieved in K. Buszek's laboratory, and several of its str uctural and stereochemical analogs (code names K3-K9) have been tested for their ability to prevent murine L1210 leukemic cells from synthes izing macromolecules and growing in vitro. At 50 mu M, K1 is inactive and the eight-membered lactone K4, an oxocene, is the only compound fo und to inhibit tumor cell growth by about 90% in the L1210 system. The long-term inhibition of L1210 cell growth by K4 is concentration depe ndent (IC50 around 10 mu M) and not reversible following drug removal. The delayed and weaker cytotoxic effects of K4 suggest that the inhib ition of tumor cell proliferation observed 1-4 days after K4 treatment is not solely caused by drug cytotoxicity. When compared to It spectr um of representative anticancer drugs, higher concentrations of K4 mus t be used to maximally inhibit tumor cell growth. In contrast to its a ntiproliferative activity, 50 mu M K4 fails to alter the rates of DNA, RNA and protein synthesis in L1210 cells This discrepancy between the ability of K4 to inhibit macromolecule synthesis and leukemic cell gr owth suggests that other molecular targets are involved in the antitum or action of this drug At 50 mu M, K4 inhibits the polymerization of p urified tubulin by about 45%, and therefore may be a novel microtubule de-stabilizing drug weaker than vincristine. Even though other mechan isms may be involved in its antitumor action, the ability of K4 to par tially disrupt microtubule dynamics indirectly suggests that this synt hetic oxocene may be a cell cycle-specific anticancer drug that blocks mammalian cells in M-phase.