Table of Contents
Advances in Toxicology
Volume 2014 (2014), Article ID 283749, 12 pages
http://dx.doi.org/10.1155/2014/283749
Research Article

Compound-Specific Toxicities Detected in CFU-GM, Rat Kidney NRK Cells, Rat Bladder RBLAK Cells, and Rat Liver Slices following Batracylin or N-Acetyl Batracylin Exposure

Lab of Investigative Toxicology, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Lab for Cancer Research, Frederick, MD 21702, USA

Received 30 April 2014; Revised 3 July 2014; Accepted 4 August 2014; Published 8 September 2014

Academic Editor: Rosa Busquets

Copyright © 2014 Facundo M. Cutuli and Holger P. Behrsing. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The investigational anticancer agent batracylin (BAT; 8-aminoisoindolo [1,2-b]quinazolin-10(12H)-one; NSC320846) causes γ-H2AX foci development in exposed tumor cells and has demonstrated activity against solid tumors and adriamycin-resistant leukemia. Reports indicate BAT has wide interspecies variation of adverse effects, including myelosuppression, kidney, bladder, and liver damage, including biliary hyperplasia. The effects of BAT and its metabolite N-acetyl batracylin (NAB) were evaluated in the CFU-GM bone marrow toxicity assay, rat kidney (NRK) cells, bladder epithelial (RBLAK) cells, and rat precision cut liver slices (PCLS). Exposure effects were evaluated biochemically and histologically. Human, dog, and rat exhibited similar CFU-GM IC90 values for BAT (21–29 μM). The ATP assay and γ-H2AX staining showed time- and concentration-dependent toxicity in RBLAK (more severe than NRK at <72 hr) NRK and cells (μM after 96 hr BAT exposure). BAT (5 μM and 25 μM) caused biochemical and histology changes to PCLS by day 3 and 25 μM produced centrilobular hepatotoxicity. NAB (≤5 μM) produced no toxicity in CFU-GM, NRK, or RBLAK cells. However, both BAT and NAB caused biliary epithelial cell proliferation in PCLS. Our studies demonstrated species similarities in sensitivity to BAT-induced myelosuppression, and implicate the metabolite NAB in biliary hyperplasia.