Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts.
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.
De Cesare
Michelandrea
M
Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy.
Perego
Paola
P
Righetti
Sabina C
SC
Pratesi
Graziella
G
Carenini
Nives
N
Rivoltini
Licia
L
Zupi
Gabriella
G
Del Bufalo
Donatella
D
Balsari
Andrea
A
Zunino
Franco
F
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013873:Thionucleotides / Q000008:administration & dosage; D014183:Transplantation, Heterologous
D019253:Proto-Oncogene Proteins c-bcl-2; C433984:ST 1481; D013873:Thionucleotides; C408162:oblimersen; D002166:Camptothecin