Researchers have discovered that a widely used class of drugs may be beneficial to acute myeloid leukaemia (AML) patients who are resistant to a common treatment.
According to the Swedish study, ribonucleotide reductase inhibitors – which include hydroxyurea and gemcitabine – might restore the effectiveness of cytarabine in some patients.
Cytarabine is ineffective in certain patients whose leukaemia cells express large amounts of the enzyme SAMHD1, the researchers say. This enzyme is important in breaking down the active metabolite of the drug, called ara-CTP, so these patients respond less well to the drug.
This problem leads to a significantly worse survival rate compared with patients who have low levels of SAMHD1. So Drs Nikolas Herold and Sean Rudd and their colleagues at the Karolinska Institutet in Sweden examined ways to block the effects of SAMHD1 on cytarabine treatment.
They tested the over 33,000 different substances to see their effect on SAMHD1’s ability to confer resistance to cytarabine in leukaemia cells. This resulted in the identification of three substances, hydroxyurea, gemcitabine and triapine, all ribonucleotide reductase inhibitors.
Details were published online in EMBO Molecular Medicine on 17th January.
Dr Herold said: “Adding any of these three substances significantly improved the effect of the cytarabine-treatment in cell samples with high levels of SAMHD1.
“This was true for acute myeloid leukaemia samples from both adults and children. In mice with acute myeloid leukaemia, we also saw that the median survival was significantly prolonged when cytarabine was combined with a ribonucleotide reductase inhibitor.”
Next, the team will carry out a clinical trial on humans to test the new combination treatment.
Herold added: “Hydroxyurea is an approved drug that is already used to treat AML, so we think it has great potential.
“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.”
Rudd SG, Tsesmetzis N, Sanjiv K, Paulin CB, Sandhow L, Kutzner J, Hed Myrberg I, Bunten SS, Axelsson H, Zhang SM, Rasti A, Mäkelä P, Coggins SA, Tao S, Suman S, Branca RM, Mermelekas G, Wiita E, Lee S, Walfridsson J, Schinazi RF, Kim B, Lehtiö J, Rassidakis GZ, Pokrovskaja Tamm K, Warpman-Berglund U, Heyman M, Grandér D, Lehmann S, Lundbäck T, Qian H, Henter J, Schaller T, Helleday T, Herold N (2020) “Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy”, EMBO Molecular Medicine, doi: 10.15252/emmm.201910419