A ribonucleotide reductase inhibitor, MDL 101,731, induces apoptosis and elevates TRPM-2 mRNA levels in human prostate tumor xenografts.
MDL 101,731, (E)2'-fluoromethylene-2'-deoxycytidine, is an irreversible inhibitor of ribonucleotide diphosphate reductase and causes regression of human tumors in nude mouse models. Messenger RNA levels for testosterone-repressed prostatic message-2 (TRPM-2), a transcript that increases in human tumor xenografts undergoing programmed cell death, were 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 threefold in drug-treated animals. Apoptosis in the tumor xenografts was further indicated by in situ labeling of DNA strand breaks by incorporation of biotinylated-dUTP with terminal deoxynucleotidyl transferase. In vitro, PC-3 cells incubated with MDL 101,731 showed evidence of apoptosis based on flow cytometry and DNA laddering. These data support the hypothesis that MDL 101,731 stimulates programmed cell death in regressing PC-3 xenografts.
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215, USA.
P S
PS
Wright
D
D
Cross-Doersen
J P
JP
Th'ng
X W
XW
Guo
H A
HA
Crissman
E M
EM
Bradbury
L R
LR
Montgomery
F Y
FY
Thompson
D E
DE
Loudy
J O
JO
Johnston
A J
AJ
Bitonti
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor; D051152:Clusterin; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D018075:RNA, Complementary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D018075:RNA, Complementary; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D003841:Deoxycytidine; D012262:Ribonucleoside Diphosphate Reductase; C086432:tezacitabine