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 with leukemia.
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(Drug information on 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(Drug information on 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.