TY - JOUR
T1 - Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts
AU - De Cesare, Michelandrea
AU - Perego, Paola
AU - Righetti, Sabina C.
AU - Pratesi, Graziella
AU - Carenini, Nives
AU - Rivoltini, Licia
AU - Zupi, Gabriella
AU - Del Bufalo, Donatella
AU - Balsari, Andrea
AU - Zunino, Franco
PY - 2005/5
Y1 - 2005/5
N2 - The anti-apoptotic protein Bcl-2 has been implicated in the intrinsic resistance of melanoma to chemotherapy. The aim of this study was to investigate the effects of anti-Bcl-2 oligonucleotide oblimersen on the antitumour activity of gimatecan, a novel lipophilic camptothecin currently undergoing clinical phase II studies. Results showed a reduced sensitivity of melanoma cells to gimatecan following Bcl-2 transfection and inversely, increased cell sensitivity to gimatecan in combination with oblimersen. In in vivo studies performed in two melanoma xenografts expressing different Bcl-2 levels, the antitumour activity of oblimersen itself was modest, but the combination with gimatecan produced a significant therapeutic advantage. The combination therapy inhibited tumour growth and delayed regrowth of the two tumours tested. The enhancement of antitumour activity was observed at doses that were tolerated well. The effects of oblimersen on antitumour activity and toxicity of gimatecan were dose-dependent. The capability of oblimersen to improve the efficacy of gimatecan supports the therapeutic potential of the drug combination in the treatment of human melanoma.
AB - The anti-apoptotic protein Bcl-2 has been implicated in the intrinsic resistance of melanoma to chemotherapy. The aim of this study was to investigate the effects of anti-Bcl-2 oligonucleotide oblimersen on the antitumour activity of gimatecan, a novel lipophilic camptothecin currently undergoing clinical phase II studies. Results showed a reduced sensitivity of melanoma cells to gimatecan following Bcl-2 transfection and inversely, increased cell sensitivity to gimatecan in combination with oblimersen. In in vivo studies performed in two melanoma xenografts expressing different Bcl-2 levels, the antitumour activity of oblimersen itself was modest, but the combination with gimatecan produced a significant therapeutic advantage. The combination therapy inhibited tumour growth and delayed regrowth of the two tumours tested. The enhancement of antitumour activity was observed at doses that were tolerated well. The effects of oblimersen on antitumour activity and toxicity of gimatecan were dose-dependent. The capability of oblimersen to improve the efficacy of gimatecan supports the therapeutic potential of the drug combination in the treatment of human melanoma.
KW - Bcl-2
KW - Gimatecan
KW - Melanoma
KW - Oblimersen
UR - http://www.scopus.com/inward/record.url?scp=21144451944&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=21144451944&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2005.03.001
DO - 10.1016/j.ejca.2005.03.001
M3 - Article
C2 - 15911246
AN - SCOPUS:21144451944
SN - 0959-8049
VL - 41
SP - 1213
EP - 1222
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 8
ER -