Clinical Trials Renew Interest in Old Drug for Children with Leukemia

Pediatric cancer specialists at The University of Texas SouthwesternMedical Center at Dallas plan to bring an old cancer-fighter offthe bench and test its effectiveness in a new generation of childrenwith leukemia.

Dr. Barton Kamen and colleagues believe that aminopterin (AMT),one of the first chemotherapy drugs used to treat children withacute lymphoblastic leukemia, shows promise as an alternativefor some children who cannot be successfully treated with thestandard chemotherapy drug, methotrexate (MTX). The researcherspublished their findings in a recent issue of Clinical CancerResearch. They are currently enrolling patients in clinicaltrials to test AMT.

"We've known for 45 years that aminopterin was a good drug,but because of concerns about toxicity, physicians stopped usingit and turned to methotrexate," explained Dr. Kamen, whois professor of pediatrics and pharmacology. "We've alsolearned, however, that methotrexate isn't a good choice for allleukemia patients, so we keep looking for treatment alternatives."

Acute lymphoblastic leukemia is the most common form of childhoodcancer; about 25% of all children diagnosed with cancer have thisform. About 70% of these patients are effectively treated andremain disease-free. Kamen's latest research suggests that AMTmay push that success rate even higher.

AMT Metabolized More Effectively Than MTX

"Some children's disease is not controlled by methotrexateso they relapse," Kamen said. "By studying how methotrexateis metabolized in the body we began to see why these childrenweren't treated successfully. That opened the door once againto explore the use of aminopterin, which we know is more potentand more effectively metabolized than methotrexate."

Kamen explained that, as a physician treating children with acutelymphoblastic leukemia, he has grown increasingly frustrated withthe lack of new, effective drugs. That frustration prompted hisexperiments with AMT. He said it has been necessary to locatea new manufacturer to supply AMT for the trials. "During40 years of use, methotrexate basically moved it off the shelf."

Kamen, holder of the Carl B. and Florence E. King Foundation DistinguishedChair in Pediatric Oncology Research and an American Cancer SocietyClinical Research Professor, compared AMT with MTX in laboratorytests using cells from children with leukemia. The researchersfound that AMT was metabolized more completely by the cells thanMTX, which explains some of the problems patients have with MTX.

Both AMT and MTX are antifolates--drugs that look like the folatevitamin, or folic acid, to a cell and usually interfere with itsfunction. Folates are required for the growth of cells, and antifolateskill 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 greatdeal about drug-induced toxicity. We're better equipped to guardagainst it and treat it." He also expects that more advancedmanufacturing methods should deliver a safer AMT product.

"Little progress has been made in finding and introducingnew drugs into the cancer armamentarium, so it's not unreasonableto go back to an old drug and apply new knowledge in treatingthis generation of young cancer patients," Kamen said.