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More Selective Antiestrogens Under Development

More Selective Antiestrogens Under Development

ABSTRACT: An expert panel of 10 international cancer researchers and practicing oncologists met in Boston to discuss the past, present, and future uses of antiestrogens in the treatment of breast cancer. The first five articles in this series, based on the symposium presentations, appeared in Oncology News International in Oct 1996 , Nov 1996 , Dec 1996 , Jan 1997 , and March 1997 ). This article on new endocrine therapies is the last in the series. The symposium was sponsored by Zeneca Pharmaceuticals.

BOSTON--New endocrine therapies are being developed for use in advanced breast cancer, as adjuvant therapy, and possibly for prevention, but they are unlikely to gain acceptance unless they have some clear advantage over tamoxifen (Nolvadex). Anthony Howell, MD, of the Christie CRC Research Centre, Christie Hospital NHS Trust, Manchester, England, described six new nonsteroidal antiestrogens in various stages of development and one steroidal agent.

"Most of these nonsteroidal drugs are based on the triphenylethylene structure of tamoxifen, except for raloxifene, which is a benzothiaphene," he said. These molecules were chemically altered to try to improve upon tamoxi-fen's effects, in terms of increased anticancer activity, decreased side effects, or increased effects on overall health (reductions in cardiovascular and skeletal events).

Dr. Howell noted that toremifene (Fareston) has been approved in many countries and appears to be close to approval in the United States. "But if you look at the preclinical and clinical data, you can't see any advantage to this drug over tamoxifen," he said, citing a head-to-head randomized trial in advanced breast cancer in which the two drugs gave the same results.

Droloxifene, which binds more avidly to the estrogen receptor than tamoxifen, is currently in phase II clinical trials in Canada. Preclinically, in the immature rat uterus assay, it had more antagonist activity than tamoxifen and reduced agonist activity.

He cited two possible advantages of droloxifene: It appears to have some cross-sensitivity with tamoxifen and thus may be active after tamoxifen failure, and it has a short half-life and thus might be useful in alternating schedules with other drugs.

There is much interest in raloxifene, he said, because it seems to be quite active on bone but not on the uterus, and thus may be useful in preventing osteoporosis. "To date, it does not look like a very active drug in terms of anticancer activity, but we await further data on that," he said.

Preclinical testing of TAT-59 from Japan and idoxifene from the Royal Marsden Hospital suggests that both may have a better profile than tamoxifen, "but they're in phase II trials at the moment," he said, "and we won't know for some time whether they are more active."

As far as side effects are concerned, most of the newer compounds look very similar. Said Dr. Howell: "In terms of long-term effects on the cardiovascular systems and on bone, we don't have any data to indicate that any of these are better than tamoxifen."

When Wakeling and Bowler were asked to develop a new antiestrogen, they bypassed the tamoxifen molecule, Dr. Howell said. These researchers went back to the estradiol molecule and added a long side chain on the 7 alpha position, to produce a so-called pure antiestrogen that has little or no agonist activity.

In immature rat uterus assays, the first such compound, ICI 187,780 completely inhibited rat uterine growth in the presence of estrogen and showed no antagonist activity in the absence of estrogen, "and this is the first glimmer of a possibly better antiestrogen coming from the laboratory," Dr. Howell said.

One dose of a similar compound, ICI 182,780, lowered estrogen-receptor positivity in biopsy specimens of women taken before and after antiestrogen treatment, whereas tamoxifen does not seem to have this effect.

Long Duration of Response

In a recently published clinical trial, ICI 182,780 was given to women who had relapsed on adjuvant tamoxifen or who had received tamoxifen at relapse and then progressed. Nineteen of these patients remain in remission after 36 months. The median duration of response has been about 25 months. Dr. Howell said that preclinical studies of the compound in nude mice predicted a long duration of response.

"The question is, Why should this drug be possibly better than tamoxifen?" he asked. Tamoxifen inhibits trans-activating function 2 (TAF2) in the ER protein, but does not inhibit TAF1, and this may be the reason for its partial agonist activity, he explained. ICI 182,780, on the other hand, seems to inhibit both TAF1 and TAF2, thus potentially causing a greater shut off of transcriptional activity in estrogen-stimulated genes.

Dr. Howell briefly mentioned that a whole series of so-called transcriptional intermediate factors (TIFs) are currently being characterized. These TIFs must be activated for gene transcription to take place.

"So I can see a tremendous future in selectively inhibiting these TIFs in different ways to make endocrine therapy more precise," he said. "Someday, after many of us have retired, the golden age of endocrine therapy might actually arise."

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