plomestane and atamestane

The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 and atamestane (SH 489) was evaluated on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumours in rats. The compounds were given subcutaneously at daily doses of 10 and 50 mg/kg for 4 weeks. Exemestane was also given orally, at daily doses of 100 and 200 mg/kg. Subcutaneous exemestane induced 30% (10 mg/kg) and 73% (50 mg/kg) regressions of established tumours and strongly reduced the appearance of new tumours. Conversely, atamestane, MDL 18962 and oral exemestane did not affect growth of established tumours nor influenced the appearance of new neoplasms. Aromatase activity of ovarian microsomes (OAA) was reduced by 85%-93% after subcutaneous exemestane and by 25%-59% after MDL 18962, and was unaffected after atamestane. Oral exemestane caused a reduction in OAA of 72%-74%. Serum luteinising hormone (LH) levels were reduced at both the subcutaneous doses of exemestane and at the higher dose of MDL 18962. Atamestane caused an increase in LH levels, while no effect was observed with oral exemestane. The LH-lowering effect of subcutaneous exemestane, the less marked effect of MDL 18962, and the ineffectiveness of oral exemestane were also observed after 10 days of treatment in ovariectomised rats. The antigonadotrophic effect of subcutaneous exemestane, which is probably due to its slight androgenic effect, could contribute to its antitumour activity in the DMBA tumour model in intact rats, through a counteraction of the negative feedback of oestrogens on gonadotropin secretion.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Androstadienes; Androstenedione; Animals; Antineoplastic Agents; Aromatase Inhibitors; Cell Division; Dose-Response Relationship, Drug; Endocrine Glands; Female; Luteinizing Hormone; Mammary Neoplasms, Experimental; Organ Size; Ovariectomy; Pargyline; Prolactin; Rats

Topics: Aminoglutethimide; Androstadienes; Androstenedione; Animals; Aromatase Inhibitors; Female; Gonadotropins, Equine; Humans; In Vitro Techniques; Kinetics; Microsomes; Ovary; Pargyline; Placenta; Rats; Rats, Inbred Strains

Human placental aromatase inhibitory properties of FCE 24304, MDL 18962, SH 489 and 4-hydroxyandrostenedione (4-OHA) were compared. The compounds caused time-dependent enzyme inactivation with t1/2 values of 13.9, 13.1, 45.3 and 2.1 min and Ki values of 26.0, 0.7, 2.0 and 29.0 nM respectively. The antitumor activity of FCE 24304, MDL 18962 and SH 489 was studied on the DMBA-induced mammary tumor in rats, at daily s.c. doses of 10 and 50 mg/kg. FCE 24304 induced 30 and 73% regressions of established tumors, associated with 86 and 93% decrease in total ovarian aromatase activity. SH 489 and MDL 18962 did not affect tumor growth. FCE 24304, like 4-OHA, was shown to inhibit LH hypersection in castrated rats. A gonadotropin suppressive effect could contribute to the antitumor activity of aromatase inhibitors in intact DMBA-induced tumor bearing rats.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Androstadienes; Androstenedione; Animals; Antineoplastic Agents; Aromatase Inhibitors; Female; Humans; Luteinizing Hormone; Male; Mammary Neoplasms, Experimental; Microsomes; Orchiectomy; Ovary; Pargyline; Placenta; Pregnancy; Rats; Rats, Inbred Strains; Reference Values