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UCLA researchers cure leukemia in mice

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UCLA researchers have reported curing a type of acute leukemia (blood cancer) in mice without producing any toxic side-effects. The study may lead to successful treatment of leukemia in humans. The findings were published on February 24 in the journal Experimental Medicine.

The researchers note that the experimental treatment works by blocking two key metabolic pathways, which the leukemia cells need to grow and spread. Metabolism entails the internal function of cells; a number of mechanisms and chemical reactions that maintain cellular function are involved. Biosynthetic pathways are the components that allow the cell to survive and reproduce. The process results in the cells synthesizing chemicals, known as nucleotides, which they need for survival. Blockage of these nucleotide pathways by drug molecules results in halting cell growth, and subsequent death of the cancer cells. The investigators found that a key nucleotide called deoxycytidine triphosphate (dCTP) is produced by two pathways: the de novo pathway (DNP) and the nucleoside salvage pathway (NSP). With current drug treatments to block the DNP in a leukemia cell, the dCTP nucleotide is still produced by the NSP; thus, the leukemia cell can survive. To overcome this problem, the investigators created a small-molecule drug called DI-39, which blocks the NSP. As a result, when both these drugs are administered, both pathways are blocked with a one-two punch––the malignant cells cannot produce dCTP nucleotides, and they die.

For the study, the two-pronged experimental treatment was administered to mice that had acute lymphoblastic leukemia (ALL). The treatment destroyed all the ALL cells, without harming healthy blood cells; moreover, and the mice suffered no detectable side effects. “All cancer cells utilize these two pathways, and they have a strong avidity for these nucleotides to synthesize their DNA or repair it,” explained Dr. David Nathanson, assistant professor of molecular and medical pharmacology. He added, “Thus, we believe that this treatment strategy might be applicable across other hematological malignancies besides leukemia.”

The drug used for the study was developed exclusively at UCLA. “Usually people say that drug discovery and development cannot happen strictly in the academic environment, that discovery should be done in academia, and development done elsewhere, such as in industry,” explained study leader Dr. Caius Radu, associate professor of the biomedical physics interdepartmental program and molecular & medical pharmacology. He added, “With this study we show that everything can be done in the academic environment. We started this project from scratch and with the help of UCLA scientists from many different disciplines, we have taken the drug through all the steps, nearly ready for clinical trials.”

Acute lymphocytic leukemia (ALL) is a cancer of the blood in which too many lymphocytes, a type of white blood cell, are produced by the bone marrow and by organs of the lymph system. Normally, the lymphocytes fight infection; however, in ALL, the cells are immature and overabundant. They crowd out other blood cells, and may collect in the blood, bone marrow, and lymphatic tissue. Acute leukemia can grow quickly and requires treatment as soon as possible after it is found. Chromosome abnormalities (extra chromosomes and structural changes in the chromosome material) are present in the majority of patients.

ALL is more common in children than adults, with most children younger than five years of age when the cancer is found. According to the American Cancer Society, approximately 6,020 cases of ALL are expected in 2014. The average person has about a one in 750 chance of developing ALL.

The following are some of the most common symptoms of ALL; however, each individual may experience symptoms differently. Symptoms may include:

  • Bleeding
  • Bruising
  • Fever
  • Infections
  • Persistent weakness
  • Fatigue
  • Loss of appetite
  • Aches in bones and joints
  • Swollen lymph nodes
  • Weight loss
  • Night sweats
  • Swelling in the abdomen
  • Trouble breathing
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