Starving Breast Tumors to Death
Exemestane's mechanism of action proves superior for second-line breast cancer therapy
Exemestane or Aromasin joins the ranks of other third-generation antiaromatase agents in preventing breast cancer from spreading in postmenopausal women.
With this new drug, breast cancer cells are placed on a starvation diet. Their supply of estrogen becomes severely depleted as the drug acts on the pathway upon which male hormones are converted into female hormones by the aromatase enzyme.
The first evidence that estrogen hastens breast cancer cell growth was in 1896. A British physician removed the ovaries of a woman in an attempt to cure her of breast cancer. Although the disease later recurred, it demonstrated that estrogen is crucial to breast cancer progression.
In 1971, antiestrogens became widely available. They are drugs that interfere with the ability of estrogen to bind to its receptors. Over time, however, the cancer cells start to resist the effects of the antiestrogens and become hypersensitive to estrogen.
Antiaromatase agents, developed a few years later, block the synthesis of estrogen by binding to aromatase.
Medical oncologist Dr. Stefan Glück, on a visit from the University of Calgary, said that "if you can target this enzyme and stop it from working so a woman will not produce estrogen, then you can stop or reduce the breast cancer cell growth."
Currently, there are two types of aromatase modulators with different chemical structures. This difference is reflected in their mechanisms of action.
Exemestane, a steroidal aromatase agent, has a chemical structure similar to the substrate of the aromatase enzyme. It effectively renders aromatase impotent when it locks on to the enzyme's substrate binding site. The effect is irreversible, as this action will destroy the enzyme.
In contrast, nonsteroidal inhibitors bind reversibly to the heme part of the enzyme. If they are displaced from this binding by other substances, aromatase will resume converting androgens to estrogens.
Three international multiphase trials of antiaromatase agents have demonstrated the efficacy and safeness of exemestane as a second- or third-line and preoperative therapy for postmenopausal women with metastatic breast cancer in whom treatment with tamoxifen-the gold standard in antiestrogen therapy-had previously failed.
The patients were randomized to receive megestrol acetate, letrozole, nastrozole, or exemestane. The studies showed that exemestane was the only antiaromatase agent that had an advantage over megestrol acetate for both time to tumor progression and duration of survival. In terms of time to treatment failure, and duration of response at 24 weeks, exemestane was also shown to be superior. (Megestrol acetate is the standard second-line hormonal therapy.)
Exemestane also had no significant drug toxicity and was exceptionally tolerated by the patients.
Meanwhile, other studies indicate the aptness of exemestane as a first-line treatment for metastatic breast cancer versus tamoxifen. The phase II trial sponsored by the European Organization for Research and Treatment of Cancer showed a substantially better response rate and clinical benefit for the exemestane group than for patients given tamoxifen.
Dr. Glück pointed out that exemestane is effective only in patients with hormone receptor-positive breast cancer. It should not be given to premenopausal patients or co-administered with estrogen-containing agents. He explained that exemestane is best given to women with a slowly progressive disease, as the onset of action is slow. If given early enough, however, it could actually kill all the cancer cells and cure some of the patients, he said.
The drug's half-life is 24 hours; it is in tablet form and could be taken once daily, even by those with renal or liver problems. The recommended dose is 25 mg per day.
Pharmacia manufactures exemestane or Aromasin. The drug, the first aromatase inactivator approved for use in the United States, was launched in the Philippines February 10.
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