High efficacy of docetaxel with and without androgen deprivation and estramustine in preclinical models of advanced prostate cancer.
BACKGROUND
To assess the activity of docetaxel in combination with hormonal therapy in preclinical models of prostate cancer.


METHODS
Since prostate cancer has a predilection for the bone, we assessed the antitumor activity of docetaxel in in vivo models of both bone metastasis and localized prostate cancer, using MDA PCa 2b and PC3 cells in SCID mice.


RESULTS
Dramatic antitumor efficacy was observed regardless of whether the tumor cells were implanted in the prostate or in the bone. Antitumor activity was also evident in both osteolytic and osteoblastic lesions. Reasoning that docetaxel efficacy might be enhanced if it were to be used earlier in the course of the disease, we studied the sequence of docetaxel and androgen ablation (part of standard treatment for early-stage prostate cancer) in the MDA PCa 2b xenograft model. The activity was similar whether docetaxel and androgen ablation were used alone, simultaneously, or in sequence, indicating a lack of synergism or antagonism. Finally, we studied the combination of docetaxel and estramustine on androgen-sensitive and androgen-independent cell lines in vitro and in vivo. Estramustine did not increase the activity of docetaxel in these models.


CONCLUSIONS
These results provide a strong preclinical rationale for the clinical development of docetaxel for the treatment of both locally advanced and disseminated prostate cancer.
Fizazi
Karim
K
Department of Medicine, Institut Gustave Roussy, Villejuif, France. fizazi@igr.fr
Sikes
Charles R
CR
Kim
Jeri
J
Yang
Jun
J
Martinez
Luis A
LA
Olive
Matilde C
MC
Logothetis
Christopher J
CJ
Navone
Nora M
NM
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000628:therapy; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004961:Estramustine / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000601:surgery / Q000628:therapy*; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine