The Development Of Indolequinone-Based Anticancer Agents For The Treatment Of Pancreatic Cancer

A6 A large series of indolequinone containing compounds were synthesized and examined for their ability to induce cytotoxicity in human pancreatic cancer cell lines. Many of these compounds were very efficient mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1), however, no correlation between NQO1 inhibition and cytotoxicity in human pancreatic cancer cells was observed. From this large series of indolequinones MAC220 (6-methoxy-1,2-dimethyl-3-(4-nitrophenoxymethyl)indole-4,7-dione, NJ824 (2-hydroxymethyl-5-methoxy-1-methyl-3-(4-nitrophenoxymethyl)indole-4,7-dione; and MAC511 (6-methoxy-1-methyl-3-(4-nitrophenoxymethyl)indole-4,7-dione) were selected for their ability to induce cytotoxicity and inhibit colony formation in human pancreatic cancer cell lines. The antitumor activities of MAC220 and NJ824 were further evaluated in mouse xenograft experiments. In these studies human pancreatic cancer (MiaPaCa-2) xenografts were established in mice followed by daily dosing (IP) with MAC220 (2.5-10mg/kg) or NJ824 (0.5-2.5mg/kg) for 10 days. In these studies treatment with MAC220 or NJ824 resulted in a significant reduction in tumor volume compared to DMSO treated controls. Treatment with MAC220 or NJ824 did not result in any apparent toxicities and no significant changes in body weights were observed during or after drug treatment. These data indicate that MAC220 and NJ824 have antitumor activity in vivo against human pancreatic cancer. To establish whether MAC220, NJ824 and MAC511 had antitumor activity against other human cancers these compounds were evaluated in the NCI 60 human cancer cell line screen. Preliminary results from these studies demonstrated potent growth inhibitory activities against a wide range of human cancers especially renal cancers and melanomas. Studies are currently underway to identify the molecular target(s) and the mechanism of action of these compounds and to develop structural analogs with superior antitumor activities.