06-18-2004, 06:41 PM #1
Aromatase inhibitors and their antitumor effects
Here's some interesting information about the effects of nolvadex and letrozole
The potential of aromatase (estrogen synthetase) within the breast to provide a significant source of estrogen mediating tumor proliferation is suggested by studies reporting 4-6 fold higher estrogen levels in tumors than in plasma of postmenopausal breast cancer patients. Recent studies in our laboratory have identified aromatase and mRNAarom in tumor epithelial cells using immunocytochemistry and in situ hybridization. In addition, significant aromatase activity, which was stimulated 7-fold by dexamethasone, was measured in metastatic cells isolated from a breast cancer patient. Increase in proliferation was measured by proliferating cell nuclear antigen (PCNA) immunostaining in tumor sections and by thymidine incorporation into DNA in response to testosterone was observed in histocultures of breast cancer samples. This latter effect could be inhibited by 4-OHA. These results imply that intratumoral aromatase has functional significance and may be an important target for successful inhibitor treatment of breast cancer patients. To investigate treatment strategies with aromatase inhibitors and antiestrogens, we developed an intratumoral aromatase model to simulate the hormone responsive postmenopausal breast cancer patient. Tumors of estrogen receptor positive, human breast carcinoma cells (MCF-7) transfected with the human aromatase gene are grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to stimulate tumor formation. We have utilized this model to investigate the effects of the antiestrogens, tamoxifen and ICI 182,780, and the aromatase inhibitors, letrozole and arimidex , alone and in combination, on tumor growth. Both the aromatase inhibitors and the antiestrogens were effective in suppressing tumor growth. However, letrozole was significantly more effective than the antiestrogens, tamoxifen or ICI 182,780. When the aromatase inhibitors were combined with the antiestrogen tamoxifen, tumor growth was suppressed to about the same extent as with the aromatase inhibitors alone. Furthermore, the results do not suggest a benefit in combining tamoxifen with the pure antiestrogen ICI 182,780. Thus, sequential use of these agents is likely to be more advantageous to the patient in terms of longer duration of effective treatment.
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