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[CANCER RESEARCH (SUPPL.) 42, 3268s, August 1982]
0008-5472/82/0042-0000$02.00
Introduction to the Conference, Aromatase: New Perspectives for
Breast Cancer^
Richard J. Santen
Division of Endocrinology, The Milton S. Hershey Medical Center. The Pennsylvania State University, Hershey, Pennsylvania 1 7033
Basic and clinical data suggest that human breast cancers drugs with desired mechanistic effects can then be rationally
can be divided into hormone-dependent and hormone-inde developed. These must be tested in biological systems and
pendent subtypes. The biological behavior and responsiveness compared with alternative therapy approaches.
to treatment of these two subgroups are different. Measure The development of aromatase inhibitors for treatment of
ment of estrogen and progesterone receptors serves to char hormone-dependent breast cancer has generally followed the
acterize mammary tumors as hormone dependent or hormone deductive approach. Because of this, the conference on aro
independent with an overall accuracy of approximately 80%. matase was structured upon an outline of the deductive strat
Clinical and biochemical data suggest that one-third of human egy. Several years ago, Dr. Peniti Siiteri first raised the hy
tumors fall into the hormone-dependent category and two- pothesis that aromatase, the rate-limiting step for estrogen
thirds are the independent subtype. Thus, of the 110,000 new biosynthesis, is important for the growth of breast and endo-
cases of breast carcinoma diagnosed in the United States metrial cancers (1). The speakers in the first two sessions,
entitled "Physiology, Biochemistry and Biological Signifi
yearly, approximately 35,000 will be hormone dependent. A
cance" and "Epidemiological Considerations: Aromatase,
variety of data suggest that estrogen is the major hormonal
stimulus for growth of the hormone-dependent type of breast Obesity, and Breast Carcinoma," discussed the concepts re
carcinoma. The enzyme aromatase is the rate-limiting step in lated to this unifying hypothesis. The next several sessions
estrogen production. Consequently, it is logical to consider covered experimental data regarding biochemical, biological,
that this enzyme could play a key role both in the pathogenesis and structure-function studies of aromatase. The design of a
of hormone-dependent breast cancer and in its treatment. number of competitive and suicide aromatase inhibitors was
The conference, Aromatase: New Perspectives for Breast then reviewed in the sessions entitled "Pharmacological Inhib
itors of Aromatase: Biochemical Studies," and "Pharmacolog
Cancer, was organized to bring together a group of investiga
tors with breadth and depth of expertise regarding aromatase. ical Inhibitors of Aromatase: In Vivo Studies."
The speakers represented the disciplines of anatomy, biochem Several speakers outlined the efficacy of available aromatase
istry, physiology, endocrinology, obstetrics-gynecology, on inhibitors for treatment of breast carcinoma in animal models
cology, pharmacology, medicinal chemistry, and surgery. The and in patients in the sessions entitled "Aromatase Inhibitors
multidisciplinary interchange which ensued stimulated new in as Treatment of Animal Breast Carcinoma Models,"
sights into the significance of aromatase and the potential of "Aromatase in Human Breast Carcinoma—Biochemistry: In
reversible and irreversible inhibitors of this enzyme. Vitro Inhibitors," and "Aromatase Inhibitors as Treatment of
Human Breast Carcinoma." The use of aromatase inhibitors
During the conference, development of pharmacological
methods to block estrogen synthesis as potential treatment of was compared with other ways of antagonizing the biological
breast cancer was discussed. For the design of any new effects of estrogens in breast carcinoma in additional sessions:
anticancer agent, two alternative investigative strategies, the "Antiestrogens as Alternative Means of Inhibiting Estrogen
Action," "Randomized Trials of Aromatase Inhibitors versus
inductive and deductive approaches, can be used. The first, or
inductive, approach has been most commonly used in the last Antiestrogens," "Aminoglutethimide in Tamoxifen-resistant
Patients," "Aromatase Inhibition versus Surgical Ablation,"
15 years to develop new anticancer drugs. With this method,
and "A Combination of Agents to Inhibit Estrogenic Actions as
the need to develop cytotoxic antitumor drugs was first identi
fied as a targeted goal. Multiple compounds were then Treatment of Breast Carcinoma."
screened in animals using the destruction of experimental The data presented at this workshop conference provided a
tumors as the end point of therapeutic efficacy. Promising framework for further study of the significance of aromatase
agents were then introduced into Phase I clinical trials in and the importance of developing ideal inhibitors. Important
patients. After the antitumor activity of certain compounds was target areas for further studies were identified. These included
established, hypotheses were then developed to explain the establishment of the significance of estrogen production di
exact mechanism of action of these agents. This strategy has rectly in breast cancer tissue, further epidemiological studies
led to the development of a wide variety of useful therapeutic of aromatase and its relevance for development of breast
agents. cancer, the development of better treatment regimens with
The second strategy, the deductive approach, best describes available aromatase inhibitors to reduce side effects and tox-
the history of development of aromatase inhibitors. This strat icity, and the development of more potent or selective aroma
egy requires as the first step the development of a hypothesis. tase inhibitors to allow inhibition of ovarian as well as extra-
Experimental data are then collected to substantiate the hy glandular estrogen production.
pothesis and to develop a broad understanding of the biological
and biochemical mechanisms involved. Specific inhibitors or References
1 Presented at the Conference "Aromatase: New Perspectives for Breast 1. Siiteri, P. K . et al. Steroid abnormalities in endometrial or breast carcinoma:
Cancer.' December 6 to 9, 1981, Key Biscayne. Fla. a unifying hypothesis. J. Steroid Biochem.. 7: 897-903, 1976.
3268s CANCER RESEARCH VOL. 42
