Topoisomerase I (Topo I), a well-established anticancer target, is a nuclear enzyme producing a single-strand DNA break to allow transcription. Camptothecin Topo I inhibitors are important drugs for colon cancer, leukemias and ovarian cancer. Potent non-camptothecin Topo I inhibitors were identified in the naphthyridinones class. One of these, ARC-111, binds tightly and selectively to the DNA:topo I complex. ARC-111, topotecan and irinotecan/SN38 were compared. Mouse and human bone marrow were subjected to colony forming unit -granulocyte/macrophage (CFU-GM) assays over a 5-log concentration range. The IC90s for topotecan and SN38 for mouse CFU-GM were 518 nM and 331 nM respectively. For human CFU-GM, the IC90s for topotecan and SN38 were 19 nM and 26 nM, resulting in mouse to human differentials of 27- and 13-fold. ARC-111 was more potent, with IC90s of 28 nM for mouse CFU-GM and 6 nM for human CFU-GM; thus only a 4.5-fold differential between species. The cytotoxicities of topotecan, SN38 and ARC-111 were compared in 8 human tumor cell lines of varied histologies and resistance mechanisms. The response to topotecan was most affected by expression of efflux pumps (MDR1 and BCRP). Human bone marrow CFU-GM was much more sensitive to topotecan than were RPMI-8226, KBV-1 or NCI-H460 cells. SN38 cytotoxicity was less affected by MDR1 or BCRP. SN38 cytotoxicity to human bone marrow CFU-GM and to several human tumor cell lines werevery similar. HT29 colon cancer cells, however, were markedly sensitive to SN38. ARC-111 was a more potent cytotoxic agent than topotecan or SN38. ARC-111 cytotoxicity was at similar levels for human bone marrow CFU-GM and the 8 human tumor cell lines. Efficacy of ARC-111 was compared with irinotecan in human HCT116 colon cancer xenografts. Irinotecan was administered at 60 mg/kg/day; iv; Q4Dx3, and ARC-111 was administered at 2 mg/kg/day; iv; QODx3x2wk. Tumor growth delays (TGD) were 17 d for both irinotecan and ARC-111. A similar study was performed with the human HT29 colon cancer xenograft, and the TGD for irinotecan and for ARC-111 were 10 d for irinotecan and 9 d for ARC-111. ARC-111 was compared with docetaxel in human NCI-H460 non-small cell lung carcinoma xenografts. Docetaxel (20 mg/kg/day; iv; QODx3) and ARC-111 administration each resulted in a TGD of 21 d. ARC-111 was compared with gemcitabine in human MiaPaCa2 pancreatic cancer xenograft. Gemcitabine (90 mg/kg/day; iv; Q3Dx4) administration resulted a TGD of 7 d as did ARC-111. Current Topo I inhibitors have broad antitumor activity in human tumor xenografts that is not achieved in the clinic. This may be due to the relative resistance of mouse bone marrow to the cytotoxicity of these agents. ARC-111 has a smaller difference in cytotoxicity between mouse and human bone marrow. Thus, it may be possible to achieve similar blood levels of ARC-111 in patients as in mice allowing improved antitumor activity.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA