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New Strategy for Restoring Tamoxifen Sensitivity Under Study

New Strategy for Restoring Tamoxifen Sensitivity Under Study

NASHVILLE, Tenn--Inhibition of transforming growth factor-beta (TGF-beta) may enhance the activity of tamoxifen (Nolvadex) in breast cancer and restore tamoxifen sensitivity to resistant cells, according to results of laboratory experiments at the Vanderbilt Cancer Center and Georgetown's Lombardi Cancer Center.

Carlos Arteaga, MD, associate professor of medicine and cell biology at Vanderbilt, said that neutralization of TGF-beta-2 by anti-TGF-beta antibodies "totally inhibited progressive growth" of tamoxifen-resistant human breast tumors implanted into mice that were subsequently treated with tamoxifen. The finding suggests that "neutralization of TGF-beta in this intact host had restored tamoxifen sensitivity," he added.

Dr. Arteaga and his colleagues have conducted a series of laboratory experiments to explore the relationship between TGF-beta-2 and breast tumor response to tamoxifen.

First, they studied the effects of tam-oxifen on the LCC-1 and LCC-2 breast cancer cell lines, the latter of which are tamoxifen resistant and also overexpress TGF-beta-2. The studies showed that LCC-2 cells are highly resistant to both natural killer (NK) and lymphokine-activated killer (LAK) cells, consistent with the overexpression and immunosuppressive potential of TGF-beta-2.

Subsequent studies evaluated the ability of tamoxifen to modulate tumor cells' sensitivity to NK and LAK. In LCC-1 cells, tamoxifen significantly increased the cytotoxic activity of NK and LAK, but LCC-2 cells remained resistant, Dr. Arteaga said in his report of the findings at a general session of the San Antonio Breast Cancer Symposium.

Another series of studies evaluated the effect of tamoxifen on NK activity in mice that were tumor free or implanted with LCC-1 or LCC-2 tumors. Tamoxifen induced NK function in the tumor-free and LCC 1-bearing animals but not in animals with LCC-2, again suggesting the overexpression of TGF-beta-2.

"With this data, we proposed a model by which tamoxifen would enhance NK activity," Dr. Arteaga said. "At least in breast cancer sensitive systems, this might, in part, mediate tamoxifen's antitumor activity. In cells that overexpress TGF-beta-2, the overexpression may counteract NK function, hence explaining tamoxifen resistance."

To evaluate the model, the investigators introduced LCC-2 tumors into mice. The tumors were allowed to grow to a size of 100 mm3. The animals then received 25 mg of tamoxifen and were randomized to anti-TGF antibody or an IgG-2 control. Animals given the antibody had total inhibition of tumor growth.

"When we looked at NK function in LCC-2 tumors in the setting of tamoxifen, we found that those animals treated with the antibody now had up-regulation of NK, which was not present in the animals treated with the control IgG-2," Dr. Arteaga said. "The finding suggested that the up-regulation of NK function was important for restoration of tamoxifen action."

The experiments were repeated in animals that lack NK activity. Tumor growth curves overlapped in animals treated with the anti-TGF antibody or IgG-2. The finding provided support for the concept that up-regulation of NK activity is mediated by TGF-beta-2 and is essential to tamoxifen's antitumor activity.

Taken together, the data lead to the following conclusions, Dr. Arteaga said:

  1. Tamoxifen-stimulated host immune functions may, in part, mediate the antitumor effects of antiestrogens.
  2. Tumor cell overexpression of immunosuppressive cytokines, such as TGF-beta-2, may lead to tamoxifen inhibition.
  3. Inhibition of TGF-beta-2 overex-pression in breast tumor cells may enhance tamoxifen-mediated antitumor effects.
 
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