Consequences of telomerase inhibition and combination treatments for the proliferation of cancer cells.
Telomerase is expressed in most types of tumor cells but not in most somatic cells, suggesting that telomerase inhibitors may be a powerful new approach to cancer chemotherapy. Here we explore this hypothesis by treating cultured human tumor cells with a 2'-O-methoxyethyl oligonucleotide that binds the telomerase RNA template and acts as a potent inhibitor. Treatment of DU145 (Rb(-), p53(-)) and LNCaP (Rb(+), p53(+)) cells causes telomeres to shorten and cell proliferation to stop. Decreased cell proliferation in culture is not observed immediately but occurs after several weeks and is accompanied by telomere shortening. Antiproliferative effects are more profound for cells growing in soft agar or in colony formation assays, with 90% reduction in the colony-forming ability of LNCaP cells after less than 2 weeks of exposure to the inhibitor. Decreased growth of DU145 and LNCaP tumors and large reductions in prostate-specific antigen levels are also observed in vivo in xenograft models. Short-term treatment of cells with telomerase inhibitors does not increase the effects of standard antiproliferative agents paclitaxel, doxorubicin, etoposide, cisplatin, or carboplatin. Long-term inhibition and telomere shortening sensitize DU145 cells, but not LNCaP cells, to cisplatin or carboplatin. These results demonstrate that methoxyethyl oligomers directed against the template region of telomerase are potent agents and that significant antiproliferative effects can be observed after 2-3 weeks of treatment. Reduced cell proliferation and tumor growth support the hypothesis that telomerase inhibition can make a useful contribution to chemotherapy and should encourage broad testing of telomerase inhibitors.
Chen
Zhi
Z
Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA.
Koeneman
Kenneth S
KS
Corey
David R
DR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009843:Oligoribonucleotides; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016372:RNA, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C119446:2'-O-(2-methoxyethyl)-RNA; D004791:Enzyme Inhibitors; D009843:Oligoribonucleotides; D016372:RNA, Antisense; D016190:Carboplatin; D019098:Telomerase; D002945:Cisplatin