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Despite the onslaught of anticancer drugs bent on killing them, certain leukemia cells thrive by generating an enzyme critical to their survival, University of Florida researchers report in the current issue of The Biochemical Journal.

The findings could someday lead to new strategies aimed at conquering drug resistance in cancer patients.

Since the 1960s, doctors have used a powerful combination of chemotherapy drugs to treat acute lymphoblastic leukemia, or A.L.L., one of the disease鈥檚 four main forms and the most common childhood cancer. The concoction is so effective that in more than 98 percent of children the disease goes into remission. Yet a quarter eventually relapse and no longer respond to the treatment.

Experiments in cell cultures demonstrated why this might happen: Within 12 hours of being bathed with chemotherapy drugs, some leukemic cells in culture ramped up production of the protective enzyme and continued producing it for months. The result? The number of cancer cells killed by treatment dwindled, and drug-resistant cells multiplied.

UF scientists, led by Michael Kilberg, Ph.D., a UF professor of biochemistry and molecular biology, also recently identified the DNA sequence that鈥檚 responsible for switching on the gene that increases the amount of the enzyme the resistant cells produce.

鈥淣ow we are developing gene therapy techniques to use that piece of DNA as a therapeutic tool,鈥� said Kilberg, who is affiliated with the UF Shands Cancer Center. 鈥淚deally we鈥檇 like to be able to interrupt the activation of that gene in the leukemic cell. Therefore, the child who has become resistant to treatment would be sensitive again.鈥�

Currently, patients whose cancer has recurred and is resistant to treatment frequently resort to bone marrow transplantation, their only remaining option and one that is not always successful.

鈥淭he outcome for children who relapse within the first few years after diagnosis is particularly poor, with only 5 to 10 percent being long-term survivors,鈥� said Stephen Hunger, M.D., chief of the division of pediatric hematology/oncology at UF鈥檚 College of Medicine. 鈥淏one marrow transplantation is an important treatment option for children with relapsed A.L.L., but many patients still die post-transplant.鈥�

One of the drugs doctors give leukemia patients is an enzyme that breaks down one of 20 common amino acids that all cells need for growth and cell division, Kilberg said.

鈥淢ost cells have an enzyme inside them that鈥檚 the opposite of the one you鈥檙e giving as a drug -- it makes the amino acid,鈥� he said.

鈥淭his particular kind of leukemia, however, has very low levels of that enzyme, so it usually can鈥檛 manufacture the amino acid very well. When you give the enzyme that breaks down the amino acid, those cells can鈥檛 divide and grow, so they undergo programmed cell death.鈥�

When leukemia recurs, however, the drug-resistant cancer cells have somehow evolved the ability to sense that the amino acid essential to life is in short supply. They then activate the gene responsible for producing the enzyme that makes it, Kilberg said.

鈥淭his happens in all cells, and it helps nonleukemic cells survive the drug treatment,鈥� Kilberg said. 鈥淏ut it鈥檚 particularly bad when it happens in the leukemic cell, because now that cell isn鈥檛 killed by the enzyme we give 鈥� now it can make the amino acid it needs and the drug is totally ineffective.鈥�

In recent years, scientists have favored two main theories regarding the development of drug resistance, said Bruce M. Camitta, M.D., a professor of pediatrics at the Medical College of Wisconsin in Milwaukee.

鈥�(One theory is that) resistant cells are present at the time of initial diagnosis and are 鈥榮elected鈥� as chemotherapy eliminates nonresistant cells. (The other is that) resistant cells arise as a result of mutations during the course of treatment,鈥� Camitta said.

鈥淐urrently, the best approach to either of these scenarios is early intensive multidrug chemotherapy to eliminate resistant cells or to decrease chances for mutation to resistance.

鈥淯F researchers have meticulously documented what was previously only partially shown,鈥� he added. 鈥淚t should now be possible to prevent or to treat resistance by designing inhibitors specific for the (amino acid-producing enzyme).鈥�

Kilberg said UF scientists are seeking to show that in principle any tumor cell can be made sensitive to the enzyme doctors give by interfering with the cell鈥檚 ability to produce the crucial amino acid.

鈥淭he really exciting part of this is if we can show this works in the leukemic cell -- and we鈥檙e nowhere near that yet -- then in principle the same approach could work for any tumor cell,鈥� Kilberg said.

Kilberg鈥檚 research could pave the way for new ways to combat drug resistance, Hunger said.

鈥淲e need to identify new drugs that are active against this disease and learn how to use existing drugs more effectively,鈥� Hunger said. 鈥淒r. Kilberg鈥檚 work provides information that may be useful in developing strategies to overcome this resistance. More effective ways to use (the enzyme) will also be useful for adults with A.L.L., and both children and adults with non-Hodgkin鈥檚 lymphoma.鈥�

Kilberg collaborated with Bradley S. Fletcher, M.D., Ph.D., an instructor in pharmacology and experimental therapeutics; former UF graduate student Ara M. Aslanian; and Randy McClellan, a postdoctoral fellow in pediatrics.

鈥淲e鈥檙e still in the early stages of understanding the basic science,鈥� Kilberg said. 鈥淚 always worry about people getting false hopes about therapy being just around the corner. We鈥檝e got a long way to go. Like many basic science studies you have to walk before you can run. We鈥檙e really trying to provide a strong biochemical basis for this therapy.鈥�

The UF Shands Cancer Center is an interdisciplinary initiative connecting clinical and basic researchers at the 网红黑料 Science Center鈥檚 Gainesville and Jacksonville campuses, Shands at UF and Shands Jacksonville who perform original scientific research and enhance clinical strategies for the diagnosis, treatment and prevention of cancer.