Targeting telomerase activity by BIBR1532 as a therapeutic approach in germ cell tumors.
Germ cell tumors (GCT) possess a high activity of telomerase, a ribonucleoprotein complex compensating the erosion of telomeres during cell division by adding TTAGGG-repeats to the telomeric ends of chromosomes. Cisplatin, the most important drug in the treatment of GCT, preferentially acts on G-rich regions like telomeres. Inhibiting telomerase in tumors can result in telomere shortening and senescence and could increase the efficacy of chemotherapy in refractory patients. The study evaluated the promise of the small molecule telomerase inhibitor BIBR1532 as single agent and assessed a possible synergism with cisplatin in a preclinical model of GCT.GCT-derived cell line 2102EP was cultured with or without 10 microM of BIBR1532. Cell expansion was quantified in population doublings (PD). Telomere length was analyzed by fluorescence in situ hybridization and flow cytometry (flow-FISH). The sensitivity of the cells towards cisplatin was determined by MTT-assay. Telomerase activity was assessed by TRAP assay. After 300 PD, telomere length diminished from 18.5 kb +/- 0.59 kb to 8.9 +/- 0.1 kb in BIBR1532 treated 2102 EP cells as compared to 14.5 +/- 0.0 kb in untreated control cells. Treated cells did not show altered growth kinetics compared to untreated counterparts. Despite effective shortening of telomeres, the sensitivity of the treated cells towards cisplatin did not increase. Concomitant treatment with BIBR1532 and cisplatin did not result in accelerated telomere shortening. Telomere length can be shortened significantly by telomerase inhibition in GCT cell line models. However, possibly in view of their extensive telomere "reserve," telomerase inhibition did neither result in increased sensitivity of 2102 EP cells to cisplatin nor did co-treated cells show accelerated telomere shortening.
Mueller
Sandra
S
Department of Oncology, Hematology, Immunology and Rheumatology, Medical Center, University of Tuebingen, Tuebingen, Germany.
Hartmann
Ulrike
U
Mayer
Frank
F
Balabanov
Stefan
S
Hartmann
Joerg T
JT
Brummendorf
Tim H
TH
Bokemeyer
Carsten
C
D062365:Aminobenzoates / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D009373:Neoplasms, Germ Cell and Embryonal; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects
D062365:Aminobenzoates; D000970:Antineoplastic Agents; C458523:BIBR 1532; D009281:Naphthalenes; D019098:Telomerase; D002945:Cisplatin