Potent therapeutic effects of novel DNA-targeted alkylating agents, aniline N-mustards linked to DNA-affinic molecules against human tumor xenografts

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3204 A series of novel DNA-targeted alkylating agents, aniline N-mustards linked to DNA-affinic molecules (i.e., 9-anilinoacridines, acridines, quinolines) via a urea linker, were synthesized for antitumor evaluation. It demonstrates that these agents exhibit potent cytotoxicity against human lymphoblastic leukemia (CCRF/CEM) as well as the solid tumors (mammary MX-1 and colon HCT-116) cell growth in vitro with submicromolar IC50 values. The results revealed that these compounds have little or no cross-resistance to either taxol or vinblastine. It suggested that most N-mustard derivatives were neither a good substrate of membrane of p-glycoprotein nor related to mutated tubulin. The in vivo antitumor therapeutic effects of the target compounds were studied. Nude mice bearing human breast tumor MX-1 were treated with these agents at the dose of 10-150 mg/kg, Q2D×5, via intravenous injection, resulted in tumor total disappearance (or complete remission, CR) with low toxicity (9-17% body weight loss with rapid recovery). BO-1055, BO-1063, BO-1064 and BO-1066 achieved complete tumor remission, whereas BO-1049 achieved CR in parts of the mice. Remarkably, BO-1051, BO-1055, BO-1063, and BO-1065 with only one cycle 5-dose-treatments, complete remission was achieved and maintained for over 70 days without any relapse in 3 out of 3 mice. Interestingly, the apparent tumor-suppression was observed in mice on day-16 (last dose), but complete-suppression was achieved latter suggesting that the newly synthesized agents may have a long duration of action. The therapeutic effects of N-mustard compounds, BO-1049, 1051 and 1055, against human glioma U87 GM s.c. xenograft in nude mice were also examined; BO-1049 (150 mg/kg), BO-1051 (100 mg/kg), and BO-1055 (30 mg/kg), Q2D×5, i.v.-injection, resulted in complete tumor-growth suppression. Remarkably, those mice treated with BO-1051 (100 mg/kg, Q2D×5, n=3), it not only suppressed tumor growth but also continuously shrank tumor to only detectable tumor size (i.e., nearly complete remission) with only one cycle of treatment. Furthermore, this tumor shrinkage effect was observed on 10 and 12 days after the last dose of BO-1051on Day-16 (The treatment started on Day-8). Remarkably, all three compounds (BO-1049, 1051 and 1055) yielded superior therapeutic effects than cyclophosphamide (80 mg/kg, Q2D×5) in a parallel study. These results demonstrated the newly synthesized compounds possess potent antitumor therapeutic efficacy and have potential for clinical applications.