NEW YORKRepeated low-dose administration of amifostine (Ethyol) is being
studied in a randomized, multi-center, community-based trial in an attempt to
prevent neurotoxicity caused by platinum-based chemotherapy.
David Alberts, MD, and Martee Hensley, MD, discussed the new study at the
Ethyol Emerging Neuropathy Trial Investigator Meeting.
How Amifostine Works
Dr. Alberts, professor of medicine, pharmacology, and public health, and
associate dean for research at the University of Arizona College of Medicine
and Arizona Cancer Center, Tucson, explained that amifostine is a targeted
cytoprotectant for normal cells.
"Amifostine is a prodrug that is not active in vitro unless
dephosphorylated to the sulfhydryl form, WR-1065, which undergoes oxidation to
a symmetric disulfide, WR-33278, an extremely important cationic polyamine
that protects DNA during chemotherapy and radiation therapy," he said.
Amifostine is generally not dephosphorylated by tumors because cancers tend
to have very low levels of membrane-bound alkaline phosphatase, which is
required to dephosphorylate the pro-drug. "There is a 250-fold difference
in the amount of alkaline phosphatase on the cell membranes of normal human
lung fibroblasts compared to a non-small-cell lung cancer (NSCLC) cell
line," Dr. Alberts said (Figure 1).
As a result, he said, on normal cells, dephosphorylation produces WR-1065,
"which is pulled into the cell and can absorb oxygen free radicals,
neutralize the DNA-binding moieties of platinum-containing and alkylating
agents, protect DNA against radiation damage, and induce DNA repair mechanisms,
possibly by stripping away platinum adducts."
Dr. Alberts said that several different types of normal tissue could
potentially be protected by amifostine against chemotherapy or radiation. The
drug is FDA approved specifically to protect against nephrotoxicity from
cisplatin (Platinol) in ovarian cancer and NSCLC patients, as well as to
protect against radiation-induced xerostomia, he said.