Measurement of thiopurine metabolites is helpful to monitor adverse effects and assess compliance in patients on thiopurine treatment. The purpose of this study was to develop and validate an analytical method for measurement of thiopurine metabolites, thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN), in RBCs. We developed and validated a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the quantification of 6-TGN and 6-MMPN and evaluated the stability of the thiopurine metabolites in RBC and whole blood states without any preprocessing at various storage conditions. The linear range was 0.1–10 µmol/L and 0.5–100 µmol/L for 6-TGN and 6-MMPN, respectively. The mean extraction recovery at the two concentrations was 71.0% and 75.0% for 6-TGN, and 102.2% and 96.4% for 6-MMPN. Thiopurine metabolites in preprocessed RBC samples were stable at 25℃ and 4℃ after storage for 4 hours and at −70℃ for up to 6 months. However, 6-TGN decreased by 30% compared with the initial concentration when stored at −20℃ for 180 days. In whole blood states, 6-TGN decreased by about 20% at four days after storage at 4℃. We validated a reliable LC-MS/MS method and recommend that the patient's whole blood sample be preprocessed as soon as possible.
Compliance ; Humans ; Mass Spectrometry ; Methods* ; Nucleotides ; Thioguanine

A polymer gel dosimeter was fabricated. A 3-dimensional dosimetry experiment was performed in the small field of the photon of the cyberknife. The dosimeter was installed in a head and neck phantom. It was manufactured from the acrylic and it was used in dosimetry. By using the head and neck CT protocol of the CyberKnife system, CT images of the head and neck phantom were obtained and delivered to the treatment planning system. The irradiation to the dosimeter in the treatment planning was performed, and then, the image was obtained by using 3.0T magnetic resonance imaging (MRI) after 24 hours. The dose distribution of the phantom was analyzed by using MATLAB. The results of this measurement were compared to the results of calculation in the treatment planning. In the isodose curve on the axial direction, the dose distribution coincided with the high dose area, 0.76mm difference on 80%, rather than the low dose area, 1.29 mm difference on 40%. In this research, the fact that the polymer gel dosimeter and MRI can be applied for analyzing a small field in a 3 dimensional dosimetry was confirmed. Moreover, the feasibility of using these for the therapeutic radiation quality control was also confirmed.
Antineoplastic Combined Chemotherapy Protocols ; Cytarabine ; Head ; Magnetic Resonance Imaging ; Neck ; Polymers ; Quality Control ; Thioguanine

No abstract available.
Child* ; Cytarabine* ; Cytosine* ; Doxorubicin* ; Humans ; Leukemia, Myeloid, Acute* ; Maintenance Chemotherapy* ; Remission Induction* ; Thioguanine*

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children. Despite good remission rate has achieved nowadays, the patients still face a substantial risk of relapse. It has long been recognized that thiopurines are critical components in the treatment for prevention of recurrence in childhood ALL, the 6-mercaptopurine (6-MP) has usually been used in daily long-term maintenance therapy, and 6-thioguanine (6-TG) limited to the reinforcement of therapy. However, there is no optimal regimen for 6-TG or 6-MP. The related research advances on the clinical effectiveness of the two thiopurines are reviewed.
Child ; Humans ; Mercaptopurine ; therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; Thioguanine ; therapeutic use

Although pancreatitis is known as a common complication during the treatment of acute lymphoblastic leukemia, acute pancreatitis that's induced by 6-mercaptopurine or 6-thioguanine is very uncommon. We experienced the case of an 11-year-old boy with consecutive acute pancreatitis, and this was induced by 6-mercaptopurine and 6-thioguanine during maintenance chemotherapy of childhood acute lymphoblastic leukemia. We report here on this along with a review of the pertinent literature.
6-Mercaptopurine ; Child ; Humans ; Maintenance Chemotherapy ; Pancreatitis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Thioguanine

PURPOSE: We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. RESULTS: A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. CONCLUSION: NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.
6-Mercaptopurine ; Blood Cell Count ; Child* ; Humans ; Leukemia ; Leukopenia ; Precursor Cell Lymphoblastic Leukemia-Lymphoma* ; Thioguanine

A 13 years old girl came to our department with complaints of multiple ulcerating and non-ulcerating nodules on her back and buttocks since 1 month prior to visit. Skin biopsy specimen showed diffuse monomorphous infiltration of leukemic cells in the dermis and subcutis. Bone marrow biopsy specimen showed changes of erythroleukemia. Treatment was initiated with combined chemotherapy which was a combination of cytosine arabinoside, adriamyein and 6 thioguanine. When combined chemotherapy was finished, she was in complete remission state and the nodules cured after 1 month of combined chemotherapy.
Adolescent ; Biopsy ; Bone Marrow ; Buttocks ; Cytarabine ; Dermis ; Drug Therapy ; Female ; Humans ; Leukemia* ; Leukemia, Erythroblastic, Acute* ; Skin ; Thioguanine ; Ulcer

Antimetabolites, Antineoplastic ; adverse effects ; Child ; Female ; Hepatic Veno-Occlusive Disease ; chemically induced ; Humans ; Male ; Thioguanine ; adverse effects

OBJECTIVETo improve the treatment of drug related childhood hepatic veno-occlusive disease (HVOD), clinical characteristics of 6 children with hematologic neoplasm from 2 hospitals of China Children's Leukemia Group (CCLG) treated with 6-thioguanine (6-TG) complicated with HVOD were analyzed.

METHODAll the drug related HVOD patients were treated with CCLG acute lymphoblastic leukemia (ALL)-2008 protocol. They were from Children's Hospital of Fudan University and Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from April 2008 to April 2009. The diagnosis was made according to the modified Seattle criteria and Baltimore criteria, including 2 or 3 of the following clinical features: hepatomegaly and upper right abdominal pain, jaundice (bilirubin ≥ 35 µmol/L), ascites or confirmed by pathology. The 6 HVOD patients' clinical manifestations, laboratory finding, imageologic and pathologic data were collected and analyzed.

RESULTOf the 6 patients, 2 were males and 4 females. Mean age of the 6 patients was 3.89 years (range from 3 years 1 month to 4 years 11 months). The original disease was acute lymphoblastic leukemia. HVOD occurred during chemotherapy protocols of CAM (CTX + Ara-C + 6-TG) or maintenance period (MTX + 6-TG). Most of 6 HVOD patients presented with pain in liver area, hepatomegaly on imaging, elevated aminotransferase and bilirubin (often ≥ 35 µmol/L), hydroperitonia was common, one with pleural fluid, illegible hepatic veins. All the patients recovered after being treated with hepatoprotective, jaundice-relieving and supportive therapeutics, some patients were treated with low molecular weight heparin. The prognoses were good.

CONCLUSIONHVOD was a serious complication of chemotherapy with 6-TG. Hepatoprotective and jaundice-relieving and low molecular weight heparin could improve the prognosis.

Antineoplastic Agents ; therapeutic use ; Child, Preschool ; Female ; Hepatic Veno-Occlusive Disease ; drug therapy ; Humans ; Leukemia ; therapy ; Male ; Thioguanine ; therapeutic use

Clinical chemotherapy refractoriness is characterized by resistance to multiple drugs. Multidrug resistance(MDR) is caused by over-reactivity of a unidirectional drug efflux pump, transmembrane glycoprotein(P-glycoprotein), which is encoded by the MDR1 gene. P-glycoprotein leads to increased drug efflux and decreased intracellular drug concentration. Clinical trials that attempt to reverse or modulate MDR have been done. Cyclosporin-A and verapamil are the most extensively studied agents and several trials of cyclosporin-A as a MDR modulator have been reported. We report a case of an 8-year-old girl with acute mixed type leukemia who failed to respond 3 times to remission-induction therapy. It led us to conclude she had multidrug resistance. We tried a fourth induction chemotherapy including cytarabine, idarubicin and 6-thioguanine to which cyclosporin-A was added. Then, she showed signs of severe bone marrow depression and fulminant perianal cellulitis. But she recovered and successfully achieved complete remission. The addition of cyclosporine could be useful in achieving complete remission for cases of acute leukemia that resist to usual chemotherapy. Futher observation including more cases will be needed to assess long-term survival and efficacy of adding cyclosporine.
Bone Marrow ; Cellulitis ; Child ; Cyclosporine ; Cytarabine ; Depression ; Drug Resistance ; Drug Resistance, Multiple ; Drug Therapy ; Female ; Humans ; Idarubicin ; Induction Chemotherapy ; Leukemia* ; P-Glycoprotein ; Thioguanine ; Verapamil