Abstract C251: Dianotecan: A novel water-soluble CPT prodrug as a potential anticancer agent with less susceptility to multidrug resistance than irinotecan.

Abstract Camptothecin (CPT) and its derivatives are topoisomerase I inhibitors. Among these, irinotecan and topotecan have shown significant clinical activity against a broad range of malignancies. Irinotecan is approved for use in the treatment of advanced colorectal cancer, as first-line therapy in combination with 5-FU or as a salvage agent after failure of 5-fluorouracil-based chemotherapy. However, recent studies have revealed that SN-38 (the active metabolite of irinotecan) is the substrate of BCRP (ABCG2), an ATP-binding cassette (ABC) transport protein which confers multidrug resistance and is also characterized as the marker of stem and progenitor cells. In tumor cell lines over-expressing BCRP, selective BCRP efflux of SN-38 leads to decrease in cellular drug accumulation, resulting in drug resistance phenotype. Here we report discovery of a novel water-soluble CPT prodrug (dianotecan) which can be efficiently metabolized to CPT in vivo after i.v. Injection. In the tumor xenograft studies, dianotecan has been established as a potent inhibitor against a number of human solid tumors including HT-29, S1, NCI-446, MCF-7. Significantly, dianotecan has demonstrated anti-tumor efficacy far superior to irinotecan in the xenograft studies using the BCRP-overexpressing S1-M1-80 cell line. These findings suggest dianotecan, as a potential anticancer agent, is less susceptible to multidrug resistance than irinotecan. The preclinical data of dianotecan will be discussed in the poster. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C251. Citation Format: Wenqiang Zhou, Li-Wu Fu. Dianotecan: A novel water-soluble CPT prodrug as a potential anticancer agent with less susceptility to multidrug resistance than irinotecan. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C251.