Effect of 5-alpha-reductase inhibition and dexamethasone administration on the growth characteristics and intratumor androgen levels of the human prostate cancer cell line PC-3.
The endocrine treatment of metastatic prostate cancer includes castration which reliably lowers the serum testosterone (T); however, the effect on intratumor levels of T and dihydrotestosterone (DHT) is less predictable. In vitro work demonstrated that the human prostate cancer cell line PC-3 had significant 5-a-reductase activity that could be inhibited with 17b-N,N-diethylcarbamoyl-4-aza-5a-androstan-3-one (4MA). In this study, we examined the effect of 5-a-reductase inhibition with 4MA and androgen suppression with dexamethasone on the growth characteristics and intratumor androgen levels in the PC-3 cell line in male athymic nude mice (Balb/c). The mice were randomized into six treatment groups: 1) noncastrate vehicle control, 2) 4MA, 0.25 mg/day, 3) 4MA, 1 mg/day, 4) dexamethasone, 25 micrograms/day, 5) 4MA, 1 mg/day, and dexamethasone, 25 micrograms/day, and 6) castrate control group. After 21 days of treatment the animals were sacrificed, serum collected, and tumors harvested. Each treatment produced intratumor DHT levels equivalent to the castrate group. Only the low dose 4MA caused a reduction in intratumor DHT without producing castrate levels of circulating T. The combination of dexamethasone and 4MA was less effective in lowering the intratumor DHT/T ratio than 4MA alone. No significant differences in tumor growth parameters were noted between intact control animals and any of the treatment arms. Serum T levels correlated poorly with intratumor androgen levels. Five-a-reductase inhibition produced castrate levels of intratumor DHT in the nonandrogen-dependent prostate cancer cell line PC-3. The combination of dexamethasone and 5-a-reductase inhibition with 4MA appears to be less effective in lowering intratumor androgen levels than either therapy alone.
Tuttle
R M
RM
Madigan Army Medical Center, Tacoma, Washington.
Loop
S
S
Jones
R E
RE
Meikle
A W
AW
Ostenson
R C
RC
Plymate
S R
SR
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000728:Androgens / Q000032:analysis*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology / Q000627:therapeutic use; D003907:Dexamethasone / Q000627:therapeutic use*; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D011897:Random Allocation; D013739:Testosterone / Q000032:analysis / Q000097:blood; D014407:Tumor Cells, Cultured
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D000728:Androgens; D001378:Azasteroids; D013196:Dihydrotestosterone; D013739:Testosterone; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; D003907:Dexamethasone