New Strategy for Restoring Tamoxifen Sensitivity Under Study

May 1, 1997
Oncology NEWS International, Oncology NEWS International Vol 6 No 5, Volume 6, Issue 5

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.

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

Carlos Arteaga, MD, associate professor of medicine and cell biologyat Vanderbilt, said that neutralization of TGF-beta-2 by anti-TGF-betaantibodies "totally inhibited progressive growth" of tamoxifen-resistanthuman breast tumors implanted into mice that were subsequently treatedwith tamoxifen. The finding suggests that "neutralization of TGF-betain this intact host had restored tamoxifen sensitivity," he added.

Dr. Arteaga and his colleagues have conducted a series of laboratoryexperiments to explore the relationship between TGF-beta-2 and breast tumorresponse to tamoxifen.

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

Subsequent studies evaluated the ability of tamoxifen to modulate tumorcells' sensitivity to NK and LAK. In LCC-1 cells, tamoxifen significantlyincreased the cytotoxic activity of NK and LAK, but LCC-2 cells remainedresistant, Dr. Arteaga said in his report of the findings at a generalsession of the San Antonio Breast Cancer Symposium.

Another series of studies evaluated the effect of tamoxifen on NK activityin mice that were tumor free or implanted with LCC-1 or LCC-2 tumors. Tamoxifeninduced NK function in the tumor-free and LCC 1-bearing animals but notin animals with LCC-2, again suggesting the overexpression of TGF-beta-2.

"With this data, we proposed a model by which tamoxifen would enhanceNK activity," Dr. Arteaga said. "At least in breast cancer sensitivesystems, this might, in part, mediate tamoxifen's antitumor activity. Incells that overexpress TGF-beta-2, the overexpression may counteract NKfunction, hence explaining tamoxifen resistance."

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

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

The experiments were repeated in animals that lack NK activity. Tumorgrowth curves overlapped in animals treated with the anti-TGF antibodyor IgG-2. The finding provided support for the concept that up-regulationof NK activity is mediated by TGF-beta-2 and is essential to tamoxifen'santitumor activity.

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

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

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