Topoisomerase I (TOP1) is an enzyme that alters the topology of DNA by transiently breaking one DNA strand. TOP1-targeting anticancer agents exert their cytotoxic activity by trapping an abortive enzyme-DNA cleavable complex, converting TOP1 into a cellular poison. Camptothecin (CPT) was the first TOP1 poison identified. The poor solubility of this alkaloid, the metabolic instability of its lactone moiety and the high binding affinity to human serum albumin of its hydrolysis product are among the obstacles that hampered clinical development of this first generation of TOP1-targeting anticancer agents. Despite these shortcomings, there are two derivatives of CPT (Irinotecan, and Topotecan) in clinical use. The focus of this proposal is to advance the development of benzo[i]phenanthridines and related compounds as a novel class TOP1-targeting anticancer agents. It is our hypothesis that within this class of noncamptothecin TOP1-targeting agents, there are compounds that 1) have enhanced chemical and metabolic stability and 2) are able to overcome known mechanisms of resistance that do affect the cytotoxic activity of CPT analogues. Such attributes within a second generation of TOP1-targeting anticancer agents may provide the basis for broader clinical utility as well as improved efficacy.
The specific aims of this proposal are 1) Evaluate select benzo[i]phenanthridines, azabenzo[i]phenanthridines, and azadibenzo[c,h]cinnolines as novel TOP1-targeting agents capable of overcoming multidrug resistance associated with efflux transporters such as BCRP, as well as MDR1 (P-glycoprotein), MRP1, and LRP; 2) to assess in vivo efficacy using various human tumor cell lines, including those that express MDR1 and BCRP and 3) characterize the metabolism and bioavailability of ARC-111 (azabenzo[i]phenanthridine analogue) and ARC-31 (an azadibenzo[c,h]cinnoline). While ARC-111 and ARC-31 possess potent TOP1-targeting activity and cytotoxicity, these compounds differ in regard to their relative efficacy in vivo. Our laboratory has identified several compounds structurally-related to benzo[i]phenanthridines with similar potency to CPT in TOP1-targeting activity and cytotoxicity. The exceptional in vitro and in vivo biological activities of benzo[i]phenanthridines, azabenzo[i]phenanthridines and azadibenzo[c,h]cinnolines observed in our laboratory form the basis for the studies proposed to advance our understanding of these potentially clinically-useful agents. ? ?
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