Pediatric cancer specialists at The University of Texas Southwestern
Medical Center at Dallas plan to bring an old cancer-fighter off
the bench and test its effectiveness in a new generation of children
Dr. Barton Kamen and colleagues believe that aminopterin (AMT),
one of the first chemotherapy drugs used to treat children with
acute lymphoblastic leukemia, shows promise as an alternative
for some children who cannot be successfully treated with the
standard chemotherapy drug, methotrexate (MTX). The researchers
published their findings in a recent issue of Clinical Cancer
Research. They are currently enrolling patients in clinical
trials to test AMT.
"We've known for 45 years that aminopterin was a good drug,
but because of concerns about toxicity, physicians stopped using
it and turned to methotrexate," explained Dr. Kamen, who
is professor of pediatrics and pharmacology. "We've also
learned, however, that methotrexate isn't a good choice for all
leukemia patients, so we keep looking for treatment alternatives."
Acute lymphoblastic leukemia is the most common form of childhood
cancer; about 25% of all children diagnosed with cancer have this
form. About 70% of these patients are effectively treated and
remain disease-free. Kamen's latest research suggests that AMT
may push that success rate even higher.
AMT Metabolized More Effectively Than MTX
"Some children's disease is not controlled by methotrexate
so they relapse," Kamen said. "By studying how methotrexate
is metabolized in the body we began to see why these children
weren't treated successfully. That opened the door once again
to explore the use of aminopterin, which we know is more potent
and more effectively metabolized than methotrexate."
Kamen explained that, as a physician treating children with acute
lymphoblastic leukemia, he has grown increasingly frustrated with
the lack of new, effective drugs. That frustration prompted his
experiments with AMT. He said it has been necessary to locate
a new manufacturer to supply AMT for the trials. "During
40 years of use, methotrexate basically moved it off the shelf."
Kamen, holder of the Carl B. and Florence E. King Foundation Distinguished
Chair in Pediatric Oncology Research and an American Cancer Society
Clinical Research Professor, compared AMT with MTX in laboratory
tests using cells from children with leukemia. The researchers
found that AMT was metabolized more completely by the cells than
MTX, which explains some of the problems patients have with MTX.
Both AMT and MTX are antifolates--drugs that look like the folate
vitamin, or folic acid, to a cell and usually interfere with its
function. Folates are required for the growth of cells, and antifolates
kill cells by interfering with their metabolism.
Kamen believes that the early concerns about AMT can be addressed.
"In 40 years at the bedside and bench, we've learned a great
deal about drug-induced toxicity. We're better equipped to guard
against it and treat it." He also expects that more advanced
manufacturing methods should deliver a safer AMT product.
"Little progress has been made in finding and introducing
new drugs into the cancer armamentarium, so it's not unreasonable
to go back to an old drug and apply new knowledge in treating
this generation of young cancer patients," Kamen said.