The research was published in the journal EMBO Molecular Medicine.
Leukemia is a family of blood cancers that results in high numbers of white blood cells. There are both chronic and acute types of the disease. Acute myeloid leukemia (AML), one of the most common forms, affects more than 20,000 people in the U.S. annually and has a high mortality rate, particularly in older patients.
One of the most-used AML drugs is cytarabine (ara-C), which interferes with DNA replication. But, many patients do not response to ara-C because their leukemia cells express high levels of the enzyme SAMHD1. SAMHD1 breaks down ara-CTP, the active metabolite of cytarabine. As a result, these patients have much worse survival rates than ones with low levels of SAMHD1.
Ara-C,” the authors of a new study wrote, “remains the backbone treatment of acute myeloid leukemia (AML) as well as other hematological and lymphoid malignancies but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown.”
Researchers at the Karolinska Institute in Sweden evaluated more than 33,000 compounds on SAMHD1 to determine which ones could inhibit the effects of SAMHD1 on cytarabine. They identified three different compounds called ribonucleotide reductase inhibitors (RNRi) that decreased SAMHD1’s effectiveness at deactivating ara-CTP. The three compounds are hydroxyurea, gemcitabine and triapine.
“Adding any of these three substances significantly improved the effect of the cytarabine-treatment in cell samples with high levels of SAMHD1,” said Nikolas Herold, an investigator at the Department of Women’s and Children’s Health at the Karolinska Institute. “This was true for AML samples from both adults and children. In AML-mice, we also saw that the median survival was significantly prolonged when cytarabine was combined with an RNA-inhibitor.”
As it turns out, hydroxyurea is a cheap drug that is used to treat blood disorders like AML, but it is not typically used in combination with cytarabine. Gemcitabine is a powerful drug used to treat a lot of different forms of cancer, but has toxicity issues if dosed repeatedly. Triapine is currently being investigated in clinical trials for cancer. The researchers indicate that in animal studies, the combination therapies didn’t show excessive side effects beyond ones already observed in cytarabine treatment.
They hope to move ahead with a clinical trial studying the combination of standard AML hydroxyurea in newly diagnosed patients. It will be run in collaboration with the Swedish AML-group and is expected to begin recruiting patients in the new couple weeks.
The research was published in the journal EMBO Molecular Medicine.
“Hydroxyurea is an approved drug that is already used to treat AML, so we think it has great potential,” Herold said. “If our research results can be confirmed in clinical trials, the treatment of AML could be significantly improved also in developing countries with limited resources since hydroxyurea is patent-free and doesn’t cost more than ibuprofen.”
The scientists also demonstrated how the RNR-inhibitors act on SAMHD1 levels. The RNR-inhibitors change the intracellular makeup of deoxynucleoside triphosphates (dNTP). SAMHD1 requires dNTPs to active its enzymatic activity. As a result, the RNR-inhibitors prevent SAMHD1’s ability to break down ara-CTP.
