ABSTRACT
Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.
Subject(s)
Acyclovir/pharmacology , Antiviral Agents/pharmacology , Cytomegalovirus Infections/prevention & control , Ganciclovir/analogs & derivatives , Pyrophosphatases/genetics , Acyclovir/therapeutic use , Adolescent , Adult , Aged , Animals , Antibiotic Prophylaxis , Antiviral Agents/therapeutic use , Biological Variation, Population/genetics , Cell Line , Child , Child, Preschool , Crystallography, X-Ray , Cytomegalovirus/drug effects , Cytomegalovirus/genetics , Cytomegalovirus/isolation & purification , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/etiology , Cytomegalovirus Infections/virology , DNA, Viral/blood , DNA, Viral/isolation & purification , Disease Models, Animal , Drug Resistance, Viral , Female , Ganciclovir/pharmacology , Ganciclovir/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Host Microbial Interactions/genetics , Humans , Infant , Infant, Newborn , Male , Middle Aged , Muromegalovirus/isolation & purification , Muromegalovirus/pathogenicity , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Pyrophosphatases/metabolism , Pyrophosphatases/ultrastructure , Treatment Outcome , Young AdultABSTRACT
Outcomes of patients with Shwachman-Diamond syndrome (SDS) who developed myeloid malignancies are poor because of refractory disease and high hematopoietic stem cell transplantation-related mortality. We herein report a case of a 7-year-old girl with SDS who developed acute myeloid leukemia with monosomy 7. She was successfully treated with chemotherapy followed by unrelated cord blood transplantation with reduced-intensity conditioning consisting of fludarabine, melphalan, and high-dose cytarabine without significant toxicity. Reduced-intensity conditioning presented in this report might be a preferable option for SDS patients with acute myeloid leukemia, although further evaluation in a larger number of similar cases is necessary.
Subject(s)
Fetal Blood/transplantation , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/therapy , Shwachman-Diamond Syndrome/complications , Transplantation Conditioning , Antineoplastic Agents, Alkylating/therapeutic use , Child , Cytarabine/therapeutic use , Female , Humans , Immunosuppressive Agents/therapeutic use , Melphalan/therapeutic use , Myeloablative Agonists/therapeutic use , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
A device is developed for concentrating a dilute solution without losing the components with boiling points slightly higher than the solvent. The device consists of an evaporator, receptor, and approximately 100 capillaries. A dilute solution is introduced into the evaporator and heated at a lower temperature than the boiling point of the solvent with the addition of a helium gas flow. As a result, mostly only the solvent evaporates, passes through the capillaries, and enters into the receptor. The low-boiling-point components in the solute, with boiling points slightly higher than the solvent, are trapped at the inlet of the capillaries. These components are then recovered by a small amount of solvent supplied from the receptor through the capillaries, with the main components of the solute concentrated at the bottom of the evaporator. A diesel fuel is separated into aliphatic and aromatic fractions by high-pressure liquid chromatography using a silica gel column. These fractions are then analyzed by low-resolution field ionization mass spectrometry, following concentration using the described device. The analytical results show that the final composition of the fractions is almost the same as that of the aliphatic or aromatic hydrocarbons in the original fuel.
