ANTITUMOR DRUGS AND INHIBITION OF INITIATION OF DNA REPL

Roswell Park Cancer Institute Corp, Buffalo NY

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Abstract

Many of the anti-proliferative agents used to treat cancer inhibit the elongation of nascent DNA chains. In principle, targeting the molecular events involved in initiation of DNA replication at origins of DNA replication should be at least as effective as a therapeutic strategy. This possibility is relatively unexplored, largely because of the paucity of information about how initiation occurs in mammals and the lack of drugs that specifically inhibit initiation rather than elongation. We are studying the cytotoxic and replication inhibitory effects in mammals and yeast of adozelesin, a member of the cyclopropylpyrroloindole (CPI) class of experimental anti-tumor agents. CPI drugs are extremely cytotoxic and show potent anti-tumor activity in mice. We have determined that the predominant inhibitory effect of adozelesin on DNA replication in mammals and the budding yeast S. cerevisiae occurs at the level of initiation of DNA replication. In S. cerevisiae, this inhibitory effect occurs in concert with the induction of a highly conserved intra-S-phase checkpoint that requires the function of an important element of origin licensing pathways in G1 and S phase, the Origin Recognition Complex (ORC). Mutations in ORC that abrogate this checkpoint sensitive cells to the lethal effects of this drug. Surprisingly, however, the increased sensitivity of this strain is not related to replication of damaged DNA in S phase. Instead, it occurs predominantly in G1 and appears to be related to the role ORC plays in origin licensing. A similar effect may occur in mammals. These results suggest a mechanism for the anti-tumor activity of adozelesin and a new therapeutic strategy that involves targeting origin licensing. In fact, independently of our results, the molecular details of origin licensing and its relationship to cell proliferation suggest that origin licensing might be a more effective target for therapeutic intervention in cancer compared to S phase events. This project will explore these possibilities with a combined genetic and biochemical analysis of the effects of adozelesin and related drugs on initiation of DNA replication in mammalian cells.