Antitumor effects of SEF19, a new nonsteroidal aromatase inhibitor, on 7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats.
The antitumor and endocrine effects of a new nonsteroidal aromatase inhibitor, 2-(imidazol-1-yl)-4,6-dimorphorino-l, 3, 5-triazine (SEF19) were examined in female Sprague-Dawley rats bearing estrogen dependent 7,12-dimethylbenz[a]anthracene(DMBA)-induced mammary tumors, and the effects were compared with those of CGS20267. The rats bearing DMBA-induced mammary tumors within 6-15 weeks after the DMBA administration were divided into the treatment groups once a week every week, and they were treated with SEF19, CGS20267 and vehicle for 4 weeks. One hundred rats were sacrificed 4 hours after the last administration, and the remaining 60 rats were sacrificed after a 4-week recovery period. During the treatment and recovery period, the tumor size was generally smaller in the SEF19 and CGS20267-treated subgroups than in the control subgroup. Tumor sizes in the subgroups treated with high doses of SEF19 (25 mg/kg/day and 50 mg/kg/2 days) were reduced to the size of the CGS20267-treated subgroup. The CGS20267-treated rats showed decrease in the serum estradiol level and an increase in the serum testosterone level. Their uterine weights were reduced. SEF19 treatment failed to show any effect on the serum levels of estrone, estradiol, testosterone and androstenedione, but it suppressed uterine weight in a dose-dependent manner. After the recovery period, no effect was detected in the serum concentrations of steroid hormones and the weight of the organs. At every dose used in the present study the aromatase inhibitory activity of SEF19 was weaker than that of CGS20267, but the inhibitory effect on mammary tumor growth of SEF19 at high doses was comparable to that of CGS20267. We conclude that the antitumor effect of SEF19 is not due to aromatase inhibition but mainly to its direct cytotoxicity.
Iino
Y
Y
Department of Emergency and Critical Care Medicine, Gunma University School of Medicine, Japan.
Karakida
T
T
Sugamata
N
N
Andoh
T
T
Takei
H
H
Takahashi
M
M
Yaguchi
S
S
Matsuno
T
T
Takehara
M
M
Sakato
M
M
Kawashima
S
S
Morishita
Y
Y
D015127:9,10-Dimethyl-1,2-benzanthracene; D000735:Androstenedione / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D047072:Aromatase Inhibitors; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000097:blood; D004970:Estrone / Q000097:blood; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D000077289:Letrozole; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D009570:Nitriles / Q000627:therapeutic use; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000033:anatomy & histology; D013739:Testosterone / Q000097:blood; D014227:Triazines / Q000627:therapeutic use*; D014230:Triazoles / Q000627:therapeutic use; D014599:Uterus / Q000033:anatomy & histology
C107532:2-(imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009570:Nitriles; D014227:Triazines; D014230:Triazoles; D004970:Estrone; D013739:Testosterone; D000735:Androstenedione; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D000077289:Letrozole