The selective estrogen receptor modulator trioxifene (LY133314) inhibits metastasis and extends survival in the PAIII rat prostatic carcinoma model.
Trioxifene (LY133314) is a selective estrogen receptor modulator (SERM) with competitive binding activity against estradiol for estrogen receptor alpha (ERalpha) and antagonistic activity against ERalpha-mediated gene expression. The PAIII rat prostatic adenocarcinoma (PCa) is an androgen receptor-negative, ERalpha- and ERbeta-positive, spontaneously metastatic rodent tumor cell line. After s.c. implantation of 10(6) PAIII cells in the tail, s.c. administration of trioxifene (2.0, 4.0, 20.0, or 40.0 mg/kg-day) for 30 days produced significant (P < 0.05) inhibition of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximum nodal weight decreases, 86% and 88% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by trioxifene treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by trioxifene administration in a dose-related manner (maximal reduction, 98% from control values). Continual administration of the compound significantly (P < 0.05) extended survival of PAIII-bearing rats. Trioxifene inhibited the proliferation of PAIII cells at micromolar levels in vitro but did not slow growth of the primary tumor growth in the tail. Trioxifene administration also produced regression of male accessory sex organs. In PAIII-tumor-bearing animals, trioxifene administration produced a maximal regression of 76% for ventral prostate and 64% for seminal vesicle (P < 0.05 for both). SERMs may be preferable to estrogens given their efficacy in experimental PCa models and relative lack of side effects observed in clinical trials. Our data support the contention that trioxifene represents a SERM with potential antimetastatic efficacy for the treatment of androgen-independent, metastatic PCa.
Neubauer
Blake Lee
BL
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. neubauer_blake_l@lilly.com
McNulty
Ann M
AM
Chedid
Marcio
M
Chen
Keyue
K
Goode
Robin L
RL
Johnson
Mac A
MA
Jones
C David
CD
Krishnan
Venkatesh
V
Lynch
Rebecca
R
Osborne
Harold E
HE
Graff
Jeremy R
JR
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005837:Genitalia, Male / Q000187:drug effects; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011944:Receptors, Androgen / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology*; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011759:Pyrrolidines; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D008156:Luciferases; C014934:trioxifene