[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
114 Preclinical studies with a glutathione S-transferase P1-1 (GSTP1-1) activated prodrug. Lilliam A. Rosario1,2, Miechelle L. O'Brien1,3, Steven R. Schow4, Colin J. Henderson5, C. Roland Wolf5 and Kenneth D. Tew1. 1Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA; 2Food and Drug Administration, Rockville, MD; 3New York Medical College, Valhalla, NY; 4Telik, Inc., South San Francisco, CA; 5Imperial Cancer Research Fund, University of Dundee, Edinburgh, UK.
Based on the published data that a number of solid tumors and drug-resistant cell lines express high levels of glutathione S-transferase P1-1 (GSTP1-1), a novel nitrogen mustard prodrug, TLK286 [-glutamyl--amino-(2-ethyl-N,N,N',N'-tetrakis (2-chloroethyl) phosphorodiamidate)-sulfonyl-propionyl-(R)-(-) phenylglycine] was rationally designed and synthesized. Therapeutically active alkylating species are released by preferential activation by GSTP1-1. Prior to Phase I clinical trial, preclinical studies were designed to confirm the novel mechanism of action. Patterns of DNA damage caused by TLK286 were consistent with the nitrogen mustard component. Mouse embryo fibroblasts from GSTP1-1-/- cells were 2-fold resistant to TLK286 compared with wild type. While NIH3T3 cells transfected with -glutamylcysteine synthetase and multidrug resistance protein 1 (MRP1) were 6-fold resistant to TLK286, concomitant transfection of GSTP1-1 reduced the resistance factor to 3.7. A 5-fold resistant cell line (HL60/TLK) was established by chronic long-term exposure to the prodrug. Resistance was not easily established, but eventually, a 5-fold resistant clone was isolated and was shown to down-regulate expression of GSTP1-1. Overall, these results confirm the GSTP1-1 specificity of the drug. Quantitatively similar levels of cross-resistance to melphalan were found, however, there was no collateral resistance to adriamycin, taxol, mitoxantrane or cisplatin. In addition, neither in vitro selected cisplatin resistant ovarian cancer cell lines (A2780/C200) nor a cell line established from an ovarian cancer patient resistant to cisplatin (OVCAR4) showed cross-resistance to TLK286. Since ovarian cancer also expresses high levels of GSTP1-1 this may be a candidate disease for Phase II studies... |
