Gefitinib-trastuzumab combination on hormone-refractory prostate cancer xenograft.
New drugs and new combinations of drugs have recently shown promising clinical activity in hormone refractory prostate cancer. We studied the association of gefitinib with trastuzumab on the androgen-refractory prostate cancer cell line DU145 expressing both epidermal growth factor receptor (EGFR) and HER-2. Drug combinations with radiotherapy (RT) were considered along with the analysis of factors linked to cell proliferation and apoptosis. The antitumour effects of gefitinib were more pronounced than those observed with trastuzumab. In mice receiving the gefitinib-trastuzumab combination, reduction in tumour volume was inferior to that predicted by the observed impact of the agents alone. The presence of trastuzumab markedly attenuated the relative increase on p27 expression and the Bax:Bcl2 ratio induced by gefitinib. The combination gefitinib-RT had similar antitumour effects as those predicted by the impact of the individual treatments, whereas the effect of the trastuzumab-RT combination was inferior to that predicted by the individual effects. The present data should be borne in mind when designing new clinical schedules for treatment of hormone-refractory prostate cancer including the use of HER inhibitors.
Formento
Patricia
P
Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France.
Hannoun-Levi
Jean-Michel
JM
Gérard
Françoise
F
Mazeau
Christiane
C
Fischel
Jean-Louis
JL
Etienne-Grimaldi
M C
MC
Gugenheim
Jean
J
Milano
Gérard
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D000068878:Trastuzumab; D000077156:Gefitinib