Development of a new DNA topoisomerase I inhibitor, TP300: A pH-activated water-soluble prodrug

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 768 TP300 is a new camptothecin analogue, preclinically showing potent DNA topoisomerase I inhibitory activity, whilst also having potential for less individual variation, predictable PK, good availability in cancer cells and less influence by resistance mechanisms. TP300 is a water-soluble prodrug administered using iv infusion in an acidic formulation (ca. pH 3-4). It is rapidly converted to the lipophilic active form (AF), CH0793076 at physiological pH. This pH dependent conversion means that production of AF is not subject to individual variation, as so commonly seen with prodrugs relying on enzymatic conversion. The lipophilicity of AF makes it more readily bioavailable to tumor cells. TP300 showed statistically significantly greater tumor growth inhibition compared with CPT-11 (using maximum tolerated doses) in 11/12 mouse xenograft models, which included colorectal, lung, gastric and pancreatic cancer cell lines. The effective dose range (MTD/ED50), calculated based on the HCT116 colon cancer mouse xenograft model, was 157 for TP300 and 12 for CPT-11, demonstrating a wider range of possible dosages for TP300. In cancer chemotherapy, there is a major problem with the innate or acquired resistance of cancer cells to anticancer drugs. Breast cancer resistant protein (BCRP) expression is reported as a contributory factor to cellular resistance to camptothecin analogues, like SN-38. In a SN-38-resistant cancer cell line, containing various resistance mechanisms, including BCRP, a 55-fold higher concentration of SN-38 was needed to achieve IC50 compared with the parent cell line. This contrasted to an 8.5-fold difference for AF. To study BCRP resistance more specifically, a BCRP-transfected cell line was used and only a two-fold higher concentration of AF was needed to achieve IC50 in the presence of BCRP, compared with absence of BCRP, contrasting with a 12-fold difference for SN-38. These results show that the influence of BCRP upon AF is very limited. This in vitro activity, especially against BCRP-expressing cancer cell lines has also been clearly shown using some in vivo xenograft mouse models. In mouse xenograft models (12), TP300 showed similar activity in cancer cell lines with verified BCRP expression (4) or with negative or unknown BCRP expression (8), with more than 80% tumor growth inhibition in 11/12 cell line models. This compared with CPT-11 showing <50% tumor growth inhibition in BCRP expressing cell lines. There is also encouraging preclinical data in various combination settings. A Phase I study is currently in progress.