Supra-additive antitumor effect of sunitinib malate (SU11248, Sutent) combined with docetaxel. A new therapeutic perspective in hormone refractory prostate cancer.
OBJECTIVE
Physiological and molecular findings indicate over-expression of HER proteins and dysregulation of neo-angiogenesis during progression of advanced prostate cancer. The aim of this study was to test a novel rational therapeutic approach by combining docetaxel with an EGFR-targeting agent (cetuximab) and with an anti-angiogenic agent (sunitinib, SUTENT).


METHODS
Mice bearing well-established PC3 prostate tumors (mean tumor volume/treatment group approximately 250 mm(3)) were treated every week with vehicle alone (controls), sunitinib (40 mg/kg/day, 5 days/week for 3 weeks, 0.2 ml p.o.), cetuximab (0.2 mg/kg/day, 5 days/week for 3 weeks, 0.2 ml i.p.) and docetaxel (10 mg/kg, 1 day/week for 3 weeks, 0.2 ml i.p.).


RESULTS
Each drug, administered as a single-agent, demonstrated comparable and moderate effects on tumor growth with approximately 50 % inhibition at the end of the 3-week dosing schedule. Computed combination ratio (CR) values for tumor growth determined on days 61, 68 and 75 after cell implantation indicated supra-additive effects for the sunitinib-docetaxel (1.53, 1.15 and 1.47, respectively) and sunitinib-cetuximab combinations (1.2, 1.32 and 1.14, respectively), and suggested additive effects only for the sunitinib-cetuximab-docetaxel combination (CR = 1). The effects on tumor growth were accompanied by a parallel diminution in tumor cell proliferation (Ki 67) and tumor vascularization (von Willebrandt factor). There were significantly higher pro-apoptotic effects (caspase-3 cleavage) observed for the sunitinib-docetaxel and sunitinib-docetaxel-cetuximab as compared to the other conditions.


CONCLUSIONS
The supra-additive anti-tumor effect observed with the sunitinib-docetaxel combination might support innovative strategies in the management of advanced prostate cancer.
Guérin
O
O
Nice General Hospital, Nice, France.
Formento
P
P
Lo Nigro
C
C
Hofman
P
P
Fischel
J L
JL
Etienne-Grimaldi
M C
MC
Merlano
M
M
Ferrero
J M
JM
Milano
G
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D000068818:Cetuximab; D000077143:Docetaxel; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000556:secondary; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077210:Sunitinib; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D012333:RNA, Messenger; D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen; D000068818:Cetuximab; D000077210:Sunitinib