By Karla Gale
NEW YORK (Reuters Health) – Amifostine, a drug currently approved in the US for its cytoprotective properties in cancer therapy, also exerts significant antimetastatic and antimutagenic effects at doses lower than those of similar agents.
According to Dr. David J. Grdina, of the University of Chicago, amifostine has great potential, both in the treatment of cancer and for prophylactic purposes following accidental radiation exposure.
Dr. Grdina and associates implanted murine sarcoma cells into the right thighs of 5 groups of mice, 10 animals per group. Amifostine 50 mg/kg or saline was administered 1 day after tumor cell inoculation, then every third day until the tumors were removed after reaching a size of 8 mm in diameter.
Amifostine was administered immediately after surgery and again 2 days later, the authors note in a Fast Track article in the International Journal of Cancer for January 10.
On the 23rd day after tumor removal, 77% of control mice exhibited pulmonary metastases, with an average number of 12.8 per mouse. In the amifostine-treated animals, metastases were significantly reduced to 57% with an average of 2.9 per mouse (p < 0.05 for each measure).
Plasma levels of angiostatin, a protein inhibitor of angiogenesis, were significantly elevated in mice without tumors and those with tumors, compared with the placebo-treated controls.
In vitro experiments showed that the active thiol form of amifostine reduced the enzymatic activities of matrix metalloproteinase (MMP)-2 and MMP-9 after 18 hours of exposure. MMPs degrade extracellular matrix, facilitating tumor cell invasion and metastasis formation, the researchers note.
These results were opposite of what the research team feared, namely, that the cytoprotective properties of amifostine would enhance the formation of metastases, Dr. Grdina told Reuters Health.
"After observing that it inhibited new metastases, we went to the literature and found that N-acetylcysteine and captopril exert similar effects because of their thiol portions, which chelate the zinc in the active site of MMPs, and which inhibit many enzymes involved in the metastatic process," he said.
The investigative team is particularly excited about amifostine, he added, because its thiol group is attached to a polyamine molecular platform, which allows it to more readily enter cells at lower concentrations.
The group's previous work has shown that amifostine can be given up to 3 hours after exposure to radiation to reduce its mutagenic effect. It was for this reason that amifostine research was originally funded by the Department of Energy, Dr. Grdina said.
"We were pursuing its use as a way to protect radiation workers, for example, if they needed to clean toxic waste or if there were an accident at a nuclear reactor. This would be a way to lower the risk of cancer from radiation exposure," Dr. Grdina said. "With the fall of the Soviet Empire and the end of the Cold War, radiation exposure was no longer considered a major issue, so we switched our emphasis to medical problems."
Now, he pointed out, the US government is concerned about nuclear terrorism, this time in the context of so-called "suitcase bombs."
"Soldiers guarding a radioactive environment could be given amifostine at higher concentrations to take advantage of its cytoprotective as well as its antimutagenic effects," he added.
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