Comparative antitumor effects of hormonal ablation, estrogen agonist, estrogen cytotoxic derivative, and antiestrogen in the PAIII rat prostatic adenocarcinoma.
The effects of hormonal ablation, estrogen, estrogen-derived cytotoxic agent, and estrogen antagonist therapies used clinically were evaluated on in vitro colony formation, in vivo growth, and lymphatic and pulmonary metastasis of the PAIII tumor. Ventral prostatic and seminal vesicle weights were evaluated in the same animals to assess androgen-related responses. Estradiol, estramustine phosphate, and testosterone had no effects on PAIII colony formation in vitro. Castration, hypophysectomy, estradiol benzoate, and estramustine phosphate treatment of PAIII-bearing Lobund Wistar rats produced significant (P less than 0.05) regression of male accessory sex organs. Of these treatments, only hypophysectomy had significant (P less than 0.05) inhibitory effects on primary PAIII growth and lymphatic and pulmonary metastasis. LY117018 [6-hydroxy-2-(p-hydroxyphenyl)benzo(b)thien-3-yl-p-2-(l-pyrrolidin yl)ethoxy phenyl ketone] has antiestrogenic activity but produces no significant agonist responses. LY117018 had no effect upon PAIII colony formation in vitro. Following s.c. implantation of PAIII cells, LY117018 (2.0, 10.0, or 20.0 mg/kg s.c.) had no effect on primary tumor growth in the tail. In vitro LY117018 administration produced marked antimetastatic effects. In a dose-dependent manner, LY117018 inhibited PAIII metastasis to the gluteal (97%) and iliac lymph nodes (88%) (P less than 0.05 for both). LY117018 also maximally inhibited pulmonary metastasis by 86% (P less than 0.05). Maximal regression of 42% for ventral prostatic and 35% for seminal vesicle weights were also seen after LY117018 administration (P less than 0.05 for both). Co-administration of estradiol benzoate had no antagonistic effect upon the antitumor responses produced by LY117018. The mechanism of action of LY117018 is not known. The failure of estradiol benzoate to affect PAIII growth and metastasis supports the contention that the responses to LY117018 are not attributable to simple antagonism of estrogen action. LY117018 may be exerting its antitumor effects through autocrine, paracrine, or endocrine mechanisms. LY117018 represents a class of agents with potential utility in treating metastatic cancer of the prostate.
Neubauer
B L
BL
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Best
K L
KL
Goode
R L
RL
Heiman
M L
ML
Hoover
D M
DM
Robertson
D W
DW
Sarosdy
M F
MF
Shaar
C J
CJ
Tanzer
L R
LR
Merriman
R L
RL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000311:Adrenal Glands / Q000033:anatomy & histology; D000818:Animals; D047072:Aromatase Inhibitors; D001835:Body Weight / Q000187:drug effects; D002722:Chlorobenzenes / Q000494:pharmacology; D004958:Estradiol / Q000627:therapeutic use; D004961:Estramustine / Q000031:analogs & derivatives / Q000494:pharmacology; D007016:Hypophysectomy; D008297:Male; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012669:Seminal Vesicles / Q000033:anatomy & histology; D013737:Testis / Q000033:anatomy & histology; D013876:Thiophenes / Q000494:pharmacology
D047072:Aromatase Inhibitors; D002722:Chlorobenzenes; D011743:Pyrimidines; D011759:Pyrrolidines; D013876:Thiophenes; C076350:LY 183648; C076351:LY 186564; D004961:Estramustine; D004958:Estradiol; C025430:LY 117018