Abstract 4479: Preclinical toxicology and pharmacology for BACPTDP, a camptothecin that targets hypoxic/acidic tumors.
Authors: Adams David J. , Morgan Lee Roy , Rodgers Andrew H. , Jursic Branko S. , Manikumar Govindarajan , Wani Mansukh C. 
Published: August 2014

Abstract
BACPTDP is a dipeptide prodrug of the 7-butyl-10-amino analog of camptothecin (BACPT) that is nearing clinical development. BACPTDP was selected based on its ability to exploit the tumor pH gradient that exists in tumors growing in hypoxic and acidic extracellular microenvironments. The drug has two known molecular targets: nuclear topoisomerase I and the transcription factor HIF-1α. BACPTDP has broad spectrum preclinical antitumor activity, but was particularly active against Panc-1 murine xenografts, a model for advanced pancreatic cancer (Adams, D.J., et al. Cancer Chemother. Pharmacol. 67, 855-865, 2011). The goals of the current work were to evaluate toxicology in vivo and to identify a sensitive biomarker of drug response in vitro. Results: Acute toxicity of a single intravenous bolus dose was assessed in mice and rats, where the LD10/LD50 was 15/23 mg/kg and 7.5/13 mg/kg, respectively. The cause of death in both rodent models was cardiovascular/respiratory arrest. Liver function abnormalities (AST/ALT) and bone marrow suppression were noted in rats at 5 mg/kg; neither renal nor CNS toxicity (seizures) was observed in any studies. Dog studies are pending. The phosphorylated histone γH2AX was found to be a sensitive biomarker for BACPT response in both human PBMCs and in Panc-1 cells. γH2AX could be detected in 20% of Panc-1 cells treated for 2 h at 10 nM by flow cytometry assay. Of note, when cells were cultured at 10% oxygen, the level seen by circulating tumor cells (CTCs), the effective drug concentration decreased by 25-fold. The biomarker could also be detected in 30% of HT29 colon carcinoma cells treated for 2 h with 100 nM BACPT, spiked into human blood samples and analyzed by the Veridex CellSearch technology for CTCs. This response was equivalent to that observed with a ten-fold higher concentration of topotecan. Interaction of BACPT with gemcitabine was evaluated in Panc-1, MiaPaCa-2 and BxPC-3 pancreatic cancer cell lines under atmospheric versus 10% oxygen conditions. Antiproliferative activity of BACPT alone was not significantly affected by oxygen concentration (cell line mean IC50 = 5 nM versus 2 nM, respectively). Likewise, drug interaction assessed by median effect analysis indicated that lower oxygen tension did not dramatically affect drug interaction, with additive to synergistic interactions that were independent of sequence of administration. Conclusions: these preclinical data support the development of a Phase I clinical trial to evaluate BACPTDP in pancreatic cancer as a single agent and in Phase II studies in combination with gemcitabine, the standard-of-care chemotherapy. In addition, γH2AX can serve as a sensitive biomarker of response to BACPTDP in both PBMCs and in circulating tumor cells, consistent with previously published studies with topotecan.
Citation Format: David J. Adams, Lee Roy Morgan, Andrew H. Rodgers, Branko S. Jursic, Govindarajan Manikumar, Mansukh C. Wani. Preclinical toxicology and pharmacology for BACPTDP, a camptothecin that targets hypoxic/acidic tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4479. doi:10.1158/1538-7445.AM2013-4479