CHARACTERIZATION OF THE EFFECTS OF AN AROMATASE INHIBITOR (19-ACETYLENIC ANDROSTENEDIONE)
ON ESTROGEN LEVELS IN NORMAL MALES
J.O. Johnston, M.B. Cramer, C.H. Taylor, B.D. McLees, K. Heck, C. Longcope,
and G.B. Gordon. Marion Merrell Dow Research lnstitute, Cincinnati, OH (JOJ,
MBC, CHT. BDM, KH); University of Massachusetts, Worcester, MA(CL); and
The Johns Hopkins School of Medicine, Baltimore, MD(GBG).
Breast cancer is the most frequent malignancy among Western women. Many
breast cancers respond to treatments designed to reduce the amount of estrogens
available to the tumor. This concept is potentially applicable to other
estrogen-associated disorders such as endometrial cancer and the stromal
component of benign prostatic hypertrophy. Estrogen formation occurs in
tissues other than the gonads such as muscle and fat. Thus, in postmenopausal
women inhibition of peripheral estrogen biosynthesis can reduce the amount
of circulating estrogens that are available to the tumor. Estrogens are
formed from androgens by the cytochrome P450 complex known as aromatase.
Our approach has been to develop enzyme-activated irreversible inhibitors.
One such compound is 19-acetylenic androstenedione (19-AA or MDL 18,962).
This compound is a pseudo-substrate that forms a reactive intermediate during
enzymatic catalysis and alkylates an active-site nucleophilic residue. This
report describes a Phase I clinical evaluation of 19-AA. Eighteen normal
male volunteers received a single intravenous dose of 19-AA in an open tolerance
protocol conducted at the Clinical Research Unit of the Johns Hopkins Hospital.
Subjects received no treatment on Days 1 and 2. A single dose of 19-AA in
PEG400/saline was given at 8:00 AM of Day 3. Volunteers were observed and
samples collected until Day 6. Drug tolerance was assessed at 0.01, 0.04,
0.1, 0.2, and 0.4 mg/kg. Each subject received a single dose of 19-AA. The
drug infusions were well tolerated with lightheadedness developing in 6
of 18 subjects. Mild to moderate reversible increases of transaminases (SGOT
or SGPT) were seen in 6 of 18 subjects. A dose relationship was not seen.
Serum estrone (E1) and estradiol (E2) levels were significantly reduced
by treatment with 19-AA at the 4 highest dose levels (Ppretreatment baseline
values). No significant dose response was observed, possibly due to the
small sample size. Serum estrogen data from 0.1-0.4 mg/kg 19-AA treatment
groups (n=12) were evaluated. Compared to baseline values, 19-AA infusion
significantly decreased E1 (41% and 44% at 12 and 24 hr after dosing, respectively)
and E2 (56% and 36% at the same time points). The sources of variability
for the 48 hr mean baseline serum estrogens levels (E1=38-52 pg/mL; E2=30-34
pg/mL) were contributed by intersubject (E1=83%; E2=76%), sample, including
diurnal variations (E1=9%, E2=17%) and assay (E1=8%, E2=7%) variability.
The diurnal variations were characterized by morning 8:00 AM peaks and by
evening 8:00 PM nadirs. This diurnal variation has not previously been well
characterized in males or postmenopausal females and needs to be considered
in study design. In summary, 19-AA appears to lower serum estrone and estradiol
levels in normal male volunteers. Further clinical studies are ongoing.
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