A RIBONUCLEOTIDE REDUCTASE INHIBITOR, MDL-101,731, INDUCES APOPTOSIS AND ELEVATES TRPM-2 MESSENGER-RNA LEVELS IN HUMAN PROSTATE TUMOR XENOGRAFTS

MDL 101,731, (E)2'-fluoromethylene-2'-deoxycytidine, is an irreversibl e inhibitor of ribonucleotide diphosphate reductase and causes regress ion of human tumors in nude mouse models. Messenger RNA levels for tes tosterone-repressed prostatic message-2 (TRPM-2), a transcript that in creases in human tumor xenografts undergoing programmed cell death, we re analyzed by in situ hybridization. Xenografts derived from a human prostate tumor cell line (PC-3) regressed following treatment with MDL 101,731 and the relative levels of TRPM-2 mRNA increased up to threef old in drug-treated animals. Apoptosis in the tumor xenografts was fur ther indicated by in situ labeling of DNA strand breaks by incorporati on of biotinylated-dUTP with terminal deoxynucleotidyl transferase. In vitro, PC-3 cells incubated with MDL 101,731 showed evidence of apopt osis based on flow cytometry and DNA laddering. These data support the hypothesis that MDL 101,731 stimulates programmed cell death in regre ssing PC-3 xenografts. (C) 1996 Academic Press, Inc.