Meta-analysis of the association between NUDT15 gene polymorphism and 6-MP toxicity during chemotherapy in childhood acute lymphoblastic leukemia / 国际儿科学杂志

Objective:To evaluate systematically the association between the c. 415>C polymorphism of NUDT15 gene and the toxicity of 6-mercaptopurine(6-MP)in children with acute lymphoblastic leukemia(ALL).Methods:The literatures in domestic and foreign databases were retrieved: PubMed, EmBase, Cochrane Library, CNKI, CBM, VIP Chinese Sci-tech Journal Database, and Wanfang Database.The language was limited to Chinese or English.A case-control study or cohort study of 6-MP treatment in pediatric ALL related to the toxicity of the NUDT15 gene c. 415>C polymorphism was included.The time of search was set from the establishment of the database to October 1st, 2020.Two researchers screened the literature independently, extracted data from the literature that met the inclusion criteria, and evaluated the quality of the included studies.The association between locus polymorphism and toxicity during 6-MP chemotherapy was analyzed by Meta analysis with Rev Man 5.3 and Stata 12.0 software.Results:Nine studies were finally included, eight of which were cohort studies and one was a case-control study, with a total of 1 068 patients.The results showed that under the five genetic models, the mutation at c. 415>C of NUDT15 gene was significantly associated with the risk of leukopenia and neutropenia( P<0.01), while hepatotoxicity was with no significant association between the occurrence risk of damage( P>0.05). Conclusion:The mutation at c. 415>C of NUDT15 gene significantly increased the incidence of leukopenia and neutropenia during 6-MP chemotherapy, while there was no significant effect on the occurrence of hepatotoxicity.

Severe recurrent nocturnal hypoglycemia during chemotherapy with 6-mercaptopurine in a child with acute lymphoblastic leukemia

Various endocrine dysfunctions occur during chemotherapy, including hypoglycemia. However, reports of hypoglycemia associated with 6-mercaptopurine (6-MP) are rare. Herein, we report an 8-year-old boy with severe symptomatic hypoglycemia likely due to 6-MP during chemotherapy. He had been diagnosed with acute lymphoblastic leukemia 3 years previously and was in the maintenance chemotherapy period. Treatment included oral dexamethasone, methotrexate, and 6-MP, of which only 6-MP was administered daily. Hypoglycemic symptoms appeared mainly at dawn, and his serum glucose dropped to a minimum of 37 mg/dL. Laboratory findings showed nothing specific other than increased serum cortisol, free fatty acids, ketone, alanine aminotransferase, and aspartate aminotransferase. Under the hypothesis of hypoglycemia due to chemotherapy drugs, we changed the time of 6-MP from evening to morning and recommended him to ingest carbohydrate-rich foods before bedtime. Hypoglycemia improved dramatically, and there was no further episode during the remaining maintenance chemotherapy period. To the best of our knowledge, this is the first report of this type of hypoglycemia occurring in an Asian child including Korean.

APEX1 Polymorphism and Mercaptopurine-Related Early Onset Neutropenia in Pediatric Acute Lymphoblastic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients. MATERIALS AND METHODS: Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients. RESULTS: Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01). CONCLUSION: We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia.

NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

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.

Association between polymorphism of NDUT15 gene and leucopenia induced by 6-mercaptopurine in children with acute lymphoblastic leukemia / 临床儿科杂志

Objective To investigate the association between single nucleotide polymorphisms (SNP) (rs116855232 in NDUT15 gene)and acute lymphocytic leukemia(ALL)in Chinese Han children.Methods A total of 133 children with ALL were recruited in this study, and were divided into two groups based on white blood cell count (WBC) as of WBC≤2.0×109 group and WBC>2.0×109group. Genotypes of each patient were detected using PCR-RFLP. WBC, initial and average dose of 6-mercaptopurine (6-MP) were collected. Results In this study, we found 4 patients with TT genotype, 31 patients with CT genotype and 98 patients with CC genotype; and there is a difference in genotypes between the two groups in initial stage (P=0.007) and in maintenance therapy stage (P=0.005). In maintenance therapy stage, patients with TT genotype received a lower dose of 6-MP than that for patients with other genotypes(P<0.01).Conclusions The polymorphism of rs116855232 in NDUT15 gene was associated with leucopenia induced by 6-mercaptopurine in children with ALL, and patients with TT genotype were suggested to use a lower dose of 6-MP to avoided serious leucopenia.

Effect of Immunomodulators and Biologic Agents on Malignancy in Patients with Inflammatory Bowel Disease / 대한소화기학회지

Immunosuppressive agents and biological agents are widely used for therapy in patients with inflammatory bowel disease (IBD). However, these therapies may be associated with an increased risk of malignancy. There is evidence that exposure of the therapeutic agents such as thiopurine and anti-tumor necrosis factor for IBD is associated with an increased risk of lymphoproliferative disorders, skin cancers, or uterine cervical cancers. This article reviews the malignancies associated with the use of immunosuppressive agents and biological agents in IBD.

Uso de azatioprina en enfermedad de Crohn ¿En qué estamos? / Current state of the use of azathioprine in Crohn’s disease

Crohn´s disease (CD) is an intestinal pathology that may have a torpid and disabling course. One of the purposes of the pharmalogical therapy is to prevent progression of the disease and keep the patient in clinical remission. Thiopurines (azathioprine (AZT)/6-mercaptopurine (6-MP)) correspond to a group of drugs so far recommended in all current consensus for maintaining remission of the disease. Recent publications have questioned its effectiveness as a maintenance treatment. We reviewed the literature to date and the aforementioned publications trying to clarify the current status of the use of AZT/6-MP in CD. We emphasize the importance of thiopurine therapy guided by levels of its metabolites, 6-thioguanines and 6-metilmercaptopurines and usefulness of Allopurinol in selected cases. It is still pending to determine whether thiopurines have the potential to modify the disease at an early stage. Further studies are needed before conclusions can modify our clinical behavior to continue using AZT/6-MP in patients with CD.

La enfermedad de Crohn (EC) es una enfermedad intestinal que puede tener un curso tórpido e invalidan. Uno de los objetivos del tratamiento farmacológico es evitar la progresión de la enfermedad y mantener al paciente en remisión. Las tiopurinas (azatioprina (AZT)/6-mercaptopurina (6-MP) corresponden a un grupo de fármacos hasta ahora recomendados en todos los consensos para mantener la remisión de esta enfermedad. Publicaciones recientes han cuestionado su efectividad como tratamiento de mantención. Revisamos la literatura disponible hasta la fecha y las mencionadas publicaciones, intentando esclarecer el estatus actual del uso de AZT/6-MP en EC. Recalcamos la importancia de realizar la terapia con tiopurinas guiada según los niveles de sus metabolitos 6-tioguaninas y 6-metilmercaptopurinas y la utilidad del uso de alopurinol en casos seleccionados. Conclusión: Está pendiente determinar si las tiopurinas tienen el potencial de modificar la enfermedad tempranamente. Se requieren mayores estudios antes de sacar conclusiones que modifiquen nuestra conducta clínica en lo que respecta a seguir usando AZT/6-MP en pacientes con EC.

Optimization and validation of an RP-HPLC method for the estimation of 6-mercaptopurine in bulk and pharmaceutical formulations

A reverse phase HPLC method is described for the determination of 6-mercaptopurine in bulk and tablets. Chromatography was carried on a C18 column using a mixture of acetonitrile and 0.05 mol/L sodium acetate buffer (10:90 v/v) as the mobile phase at a flow rate of 1 mL/min-1 with detection at 324 nm. The retention time of the drug was 3.25 min. The detector response was linear in the concentration of 0.01-5 μg/mL. The limit of detection and limit of quantification were 17 and 52 ng/mL respectively. The method was validated by determining its sensitivity, linearity, accuracy and precision. The proposed method is simple, economical, fast, accurate and precise and hence can be applied for routine quality control of mercaptopurine in bulk and tablets.

Descreve-se método de CLAE em fase reversa para a determinação de mercaptopurina a granel e em comprimidos. A cromatografia foi realizada em coluna C18, utilizando mistura de acetonitrila em tampão acetato de sódio 0,05 mol/L (10:90 v/v) como fase móvel, com fluxo de 1 mL/min e detecção a 324 nm. O tempo de retenção do fármaco foi de 3,25 min. A resposta do detector foi linear na concentração de 0,01-5 μg/mL. O limite de detecção e o limite de quantificação foram de 17e 52 ng/mL, respectivamente. O método foi validado pela determinação de sua sensibilidade, linearidade, acurácia e precisão. O método proposto é simples, econômico, rápido, acurado e preciso e, então, pode ser aplicado para controle de qualidade de rotina da mercaptopurina em batelada e em comprimidos.

The Association between the Therapeutic Agent and the Compliance of the Patients with Inflammatory Bowel Diseases / 대한소화기학회지

BACKGROUND/AIMS: Adherence of the patients with inflammatory bowel diseases is important to maintain the remission. However, the patients do not always keep their appointments for treatment. The aim of this study was to investigate the clinical factors associated with adherence of patients in terms of appointment keeping. METHODS: A total of 73 subjects were retrospectively investigated from September 2005 to January 2012 at Dongguk University Ilsan Hospital (Goyang, Korea). We reviewed medical records including the age, sex, residence, medications, the disease activity, and the rate of keeping the date. A punctual visit was defined as outpatient visit on the scheduled date +/-7 days. Punctual patients for the visit were defined as their punctual visit rates exceed 90%. RESULTS: Male to female ratio was 2.4:1. Mean age was 41.5+/-15.4 years (range, 20 to 78 years). Ulcerative colitis was 53 cases (72.6%) and Crohn's disease was 20 cases (27.4%). Mean duration of disease was 42.0+/-41.6 months (range, 4 to 226 months). Mean puntual visit rate was 86.7+/-16.0% (range, 27 to 100). Thirty-eight patients (52.1%) were punctual patients for the visit. Azathioprine/6-mercaptopurine treatment was associated with punctual patients for the visit (odd ratio, 3.19; 95% confidence interval, 1.12 to 9.09; p=0.03). However, other clinical factors did not influence the punctual visit rates. CONCLUSIONS: Our study demonstrated that the use of azathioprine/6-mercaptopurine was associated with keeping the appointment for meeting the doctor. Further prospective study would be necessary.

Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil / Toxicidade da azatioprina: por que e quando? análise da prevalência de polimorfismo em Joinville, SC

CONTEXT: The use of thiopurine drugs such as azathioprine and 6-mercaptopurine has become quite common in the treatment of inflammatory bowel disease, transplantation and acute leukemias. Despite their effectiveness, these drugs are capable of causing drug-induced toxicity with the risk of death by myelosuppression. It is now known that these complications occur because of genetic polymorphisms of the thiopurinemethyltransferase (TPMT) enzyme, responsible for its metabolism. OBJECTIVE: To assess the prevalence of thiopurine methyltransferase polymorphisms in the population of Joinville, SC, Brazil. METHODS: We analyzed the frequency of four main allelic variants of the TPMT gene in 199 blood donors from Joinville, from February to April 2010. RESULTS: The normal allele ("wild-type") was found in 93.9% of subjects studied. TPMT variants were detected in 12 subjects (6.03%). CONCLUSIONS: From this study, it was estimated at 6% the risk of toxicity by the administration of azathioprine and 6-mercaptopurine to patients in Joinville.

CONTEXTO: A utilização de drogas tiopurinas como a azatioprina e a 6-mercaptopurina tem se tornado bastante frequente no tratamento de doenças inflamatórias intestinais, transplantes e leucemias agudas. Apesar de sua efetividade, estas drogas são capazes de causar toxicidade droga-induzida com risco de morte através de mielossupressão. Sabe-se hoje que estas complicações ocorrem em decorrência de polimorfismos genéticos da enzima tiopurina metiltransferase (TPMT), responsável por sua metabolização. OBJETIVOS: Avaliar a prevalência do polimorfismo do gene da TPMT na população de Joinville, SC. MÉTODOS: Foi analisada a frequência das quatro principais variantes alélicas do gene da TPMT em 199 doadores de sangue da cidade de Joinville, SC, no período de fevereiro a abril de 2010. RESULTADOS: O alelo normal ("selvagem") foi encontrado em 93,9% dos indivíduos estudados. Variantes da TPMT foram detectadas em 12 sujeitos (6,03%). CONCLUSÕES: A partir do presente estudo, pode-se estimar em cerca de 6% o risco de toxicidade na administração de azatioprina e 6-mercaptopurina a pacientes em Joinville.

Acute Pancreatitis Induced by Azathioprine and 6-mercaptopurine Proven by Single and Low Dose Challenge Testing in a Child with Crohn Disease / 대한소아소화기영양학회지

We report here a case of drug-induced acute pancreatitis proved by elimination and single, low dose challenge test in a child with Crohn disease. A 14-year-old boy with moderate/severe Crohn disease was admitted due to high fever and severe epigastric pain during administration of mesalazine and azathioprine. Blood test and abdominal ultrasonography revealed acute pancreatitis. After discontinuance of the medication and supportive care, the symptoms and laboratory findings improved. A single, low dose challenge test was done to confirm the relationship of the adverse drug reaction and acute pancreatitis, and to discriminate the responsible drug. Azathioprine and 6-mercaptopurine showed positive responses, and mesalazine showed a negative response. We introduce the method of single, low dose challenge test and its interpretation for drug-induced pancreatitis.

Inflammatory Bowel Disease and Lymphoproliferative Disorders / 대한소화기학회지

The risk of lymphoproliferative disorders (LPDs) has been reported to be increased in autoimmune diseases and chronic inflammatory diseases. Similar with other chronic inflammatory diseases such as rheumatoid arthritis, there is a concern about the risk of LPDs in patients with inflammatory bowel disease (IBD). Generally, in IBD patients, the risk of LPDs appears to be similar with or very slightly higher, compared to the general population. The association of therapeutic agents with the risk of LPDs is difficult to evaluate due to multiple other potentially involved factors and co-treatment with other agents. To date, data show that thiopurine is associated with a moderately increased risk of LPDs in patients with IBD. Evidence regarding the risk of LPDs in IBD patients using methotrexate is not sufficient, but the risk of LPDs seems low. The responsibility of anti-TNF-alpha agents on the risk of LPDs is difficult to determine, because most of IBD patients receiving anti-TNF-alpha agents are co-treated with thiopurines. Attention should be given to the high risk of hepatosplenic T-cell lymphoma in young male patients treated with anti-TNF-alpha agents together with thiopurines. The risk and benefit of immunosuppressive therapy for IBD should be carefully evaluated and individualized considering the risk of LPDs.

The Safety and Efficacy of Azathioprine and 6-Mercaptopurine in the Treatment of Korean Patients with Crohn's Disease

BACKGROUND/AIMS: This study aimed to evaluate the adverse events and efficacy of azathioprine (AZA) and 6-mercaptopurine (6-MP) in Korean patients with Crohn's disease (CD). METHODS: We retrospectively analyzed 700 patients with CD (male : female=469 : 231; median age at diagnosis, 22 years; agerange, 9-74 years) who were treated at the Asan Medical Center between January 1997 and January 2006. RESULTS: Of 700 patients, 372 (53.1%) were treated with AZA/6-MP. The cumulative rates of AZA/6-MP treatment at 1, 5, 10, and 20 years were 17.4%, 51.6%, 73.1%, and 94.5%, respectively. Of 372 patients treated with AZA/6-MP, 217 patients (58.3%) experienced 291 adverse events, requiring discontinuation of therapy in 41 patients (11%). Nausea occurred in 120 patients (32.3%) and led to discontinuation of therapy in 11 patients (3.0%). Leukopenia developed in 116 patients (31.2%), requiring dose adjustments in 100 patients (26.9%) and discontinuation of medications in 16 patients (4.3%). Other adverse events included infections (2.7%), abnormal liver function tests (2.7%), fever (0.8%), hair loss (0.8%), arthralgias (0.5%), pancreatitis (0.5%), headaches (0.5%), and skin rashes (0.3%). Complete corticosteroids withdrawal was achieved in 70.9% of the patients based on an intention-to-treat analysis. The remission rate of perianal fistulas was 32.6%. CONCLUSIONS: The risk of leukopenia by AZA/6-MP is higher in Korean patients with CD than in Western patients. Although the adverse events of AZA/6-MP are not uncommon in Korean patients with CD, the actual discontinuation rate of the treatment is low. Therefore, AZA/6-MP can be administered to most Korean patients with CD without serious adverse events.

Monitoração terapêutica da azatioprina: uma revisão: [revisão] / Therapeutic drug monitoring of azathioprine: a review: [review]

Os nucleotídeos de tioguanina (6-TGN), metabólitos ativos da azatioprina (AZA) e da 6-mercaptopurina (6-MP), atuam como antagonistas das purinas, inibindo as sínteses de DNA, RNA e a protéica, e induzindo à citotoxicidade/imunossupressão. A enzima geneticamente determinada, tiopurina metiltransferase (TPMT), está envolvida no metabolismo desses agentes e, hipoteticamente, determina a resposta clínica às tiopurinas. A baixa atividade dessa enzima diminui a metilação das tiopurinas, resultando em potencial sobredose, enquanto altos níveis de TPMT levam à superprodução do metabólito tóxico 6-metilmercaptopurina (6-MMP) e à não-efetividade terapêutica da AZA e da 6-MP. Várias mutações no gene da TPMT têm sido identificadas e correlacionadas com fenótipos de baixa atividade. Neste artigo, também se discute a monitoração terapêutica desses fármacos por meio da medida dos níveis de 6-TGN intra-eritrocitários, os quais se correlacionam com imunossupressão e mielotoxicidade. Já a 6-MMP está diretamente relacionada com hepatotoxicidade. Esses ensaios estão associados ao uso de doses adequadas dessa droga, resultando num melhor controle da doença e menor uso de corticosteróides.

Thioguanine nucleotides (6-TGN), active metabolites of azathioprine (AZA) and 6-mercaptopurine (6-MP), act as purine antagonists, inhibiting DNA, RNA, and protein synthesis and inducing cytotoxicity and immunosuppression. The genetically determined thiopurine methyltransferase enzyme (TPMT) is involved in the metabolism of these agents and, theoretically, determines the clinical response to thiopurines. Low activity of this enzyme decreases the methylation of thiopurines, what results in potential overdosing, whereas high TPMT status leads to overproduction of toxic metabolite 6-methilmercaptopurine (6-MMP) and ineffectiveness of AZA and 6-MP. Several mutations in the TPMT gene have been identified and correlated with low activity phenotypes. In this study, we also discuss the therapeutic monitoring of these drugs by means of red blood cell 6-TGN levels, which correlate with immunosuppression and mielotoxicity. 6-MMP is directly connected with hepatotoxicity. These metabolites assays are associated with the use of appropriate doses of this drug, what results in a better control of the disease and a decreased use of corticosteroids.

Pancreatitis Induced by 6-mercaptopurine and 6-thioguanine in Childhood Acute Lymphoblastic Leukemia / 대한혈액학회지

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.

The Frequency and the Course of the Adverse Effects of Azathioprine/6-Mercaptopurine Treatment in Patients with Inflammatory Bowel Disease / 대한소화기학회지

BACKGROUND/AIMS: This study was to evaluate the frequency and the course of the adverse effects of AZA/6-MP in Korean patients with inflammatory bowel disease (IBD). METHODS: Medical records of the patients with IBD treated with AZA/6-MP at Severance hospital from June 1996 to September 2006 were retrospectively analyzed. RESULTS: A total of 133 patients were studied. Male to female ratio was 1.3:1. The mean age was 31.7+/-10.9 year. Adverse effects included leukopenia occurred in 75 cases (56.4%), nausea/vomiting in 32 cases (24.1%), arthralgia in 6 cases (4.5%), hepatitis in 6 cases (4.5%), skin rash in 4 cases (3.0%), herpes zoster in 3 cases (2.3%), and headache in 1 case (0.8%). Most of leucopenia (58.7%) developed within 3 months after maximal tolerated dose of AZA/6-MP and nausea/vomiting frequently occurred within 3 months after start of AZA/6-MP treatment. Thirty-eight patients (28.6%) required the discontinuation of medication due to adverse effects. CONCLUSIONS: Leukopenia was the most common adverse effect of AZA/6-MP treatment. Leukopenia and nausea/vomiting developed frequently in the early period of treatment of AZA/6-MP in patients with IBD. AZA/6-MP should be used cautiously to scrutinize bone marrow suppression.

Role of thiopurine methyltransferase measurement prior to treatment of IBD with AZA/6-MP / 基础医学与临床

Azathioprine(AZA) and 6-mercaptopurine(6-MP) have a well-established effect as an immunosuppressive agent for inflammatory bowel disease(IBD),Myelosuppression is the most serious side effect during treatment.Thiopurine methyltransferase(TPMT) plays an important role in the metabolism of 6-MP. This article reviews the literature on the role of TPMT measurement prior to treatment of IBD with AZA/6-MP.

Gene Expression Profiling of 6-MP (6-mercaptopurine) in Liver

The KFDA (Korea Food & Drug Administration) has performed a collaborative toxicogenomics project since 2003. Its aim is to construct a toxicology database of 12 compounds administered to mice at initial phase. We chose 6-MP (6-mercaptopurine) which has been used in the treatment of childhood leukemia. It was administered at low (0.224 mg/kg) and at high (2.24 mg/kg) dose (5 mice per group) intraperitonealy to the postnatal 6 weeks mice, then the serum and liver were collected at the indicated time (6, 24 and 72 h) after scarification. Serum biochemical markers for liver toxicity were measured and histopathologic studies also were carried out. The gene expression profiling was carried out by using Applied Biosystems 1700 Full Genome Expression Mouse. By self-organization maps (SOM), we identified groups with unique gene expression patterns, some of them are supposed to be related to 6-MP induced toxicity, including lipid metabolism abnormality, inflammatory response, oxidative stress, ATP depletion and cell death. The potential toxic effects appearing as gene expression changes are dependent of the time of 6-MP but independent of the dosage of it. This study would contribute to establishment of international database as well as national one about hepatotoxicity.

Observations of the therapeutic effects and side effects of 6-mercaptopurine on refractory childhood nephrotic syndrome / 医学研究生学报

Objectives: The aim of the study was to evaluate the therapeutic effects of 6-mercaptopurine in the treatment of refractory childhood nephrotic syndrome (NS). Methods: According to the varieties of NS, 6-mercaptopurine (2 mg/kg body weight daily) combined with corticosteroid or 6-mercaptopurine (2 mg/kg body weight daily) alone after tapering of steroids were given to 28 consecutive children with primary NS in our hospital. Results: One month after the use of 6-mercaptopurine, proteinuria was decreased. The duration of improvement was 9～28 days, with mean duration of 17 days. Over-all effective rate was 85.7%. Among different varieties of NS, the best therapeutic effect was noted in steroid-dependent children; the better therapeutic effect in steroid-resistant children; and good therapeutic effect in frequently relapsing children. The effective rates were 100%, 84.6%, 81.8% respectively. All the pathological varieties of 28 children were confirmed by renal biopsy. The better therapeutic effects were noted in slight mesangial proliferative glomerulonephritis (MsPGN) and minimal change nephrotic syndrome (MCNS). The less therapeutic effect was noted in membranoproliferative glomerulonephritis (MPGN). Their therapeutic effective rates were 92.9%, 80%, 66.7% respectively. Unfortunately, drug-induced aplastic anemia was seen in 2 cases. Slight gastrointestinal reactions were present in 6 cases. There were no side reaction on the gonad. Conclusions: The great difference in the therapeutic effects is related to the different pathologic varieties of NS. With regard to the treatment of refractory NS in children, the pathological varieties should be confirmed by renal biopsy as soon as possible. Based on the renal biopsy, 6-mercaptopurine can be considered in the treatment of MsPGN and MCNS. As a result, relapses could be reduced; the duration of remission could be prolonged, and the side reactions from steroid treatment could be avoided. The use of 6-mercaptopurine for the treatment of refractory NS is one of the effective therapy.

Efecto de la quimioterapia usada para el tratamiento de la leucemia linfoblástica aguda sobre la odontogénesis en ratas: estudio preliminar / Chemotherapy effect used for the acute lymphoblastic leukemia upon rats odontogenesis

El objetivo del proyecto es evaluar las alteraciones del patrón de formación del molar inferior de rata tras la aplicación de 6-Mercaptopurina y Vincristina, usadas en la quimioterapia para el tratamiento de la leucemia linfoblástica aguda en niños. La fase preliminar busca obtener un patrón normal de odontogénesis para las condiciones del estudio y verificar que los animales toleren las dosis calculadas, para pasar a la fase experimental del proyecto. Se sacrificaron dos animales de la especie ratus Norvegicus en los días 13,15,17,19,21,23,25 y 27 de vida. Los cortes teñidos con Hematoxilina-Eosina y observados bajo microscopio de luz muestran el patrón normal de odontogénesis del segundo y tercer molar inferior. Para la tolerancia a las drogas se realizó un ensayo exploratorio clínico de casos. Se dividieron los animales en tres grupos de 5 individuos. Al primero se le administraron 0.1 mg/kg de Vincristina intraperitoneal, 2.5 mg/kg de 6-Mercaptopurina vía oral al segundo, ambos en cuatro dosis y el tercero se dejó como control. Se compararon los incrementos de peso y talla con el grupo control. Los animales toleraron el esquema y este se puede usar en la segunda fase.

The purpose of this project is to evaluate the effect of Vincristrine and 6-Mercaptopurine on the odontogenesis of second and third inferior rat molars. These drugs are used for the treatment of Acute Lymphoblastic Leukemia. This first stage was carried out to describe normal odontogenesis and to test the calculated doses of this drugs in order to go up to the second phase.Two rats were sacrificed at ages of 13, 15, 17, 19, 21, 23, 25 and 27 days. Mandibles were processed for histologycal observation under light microscope. Odontogenic pattern of the second and the third inferior molars were described. A total of 15 animals were used to test drug tolerance. Five rats received four doses of 0.1 mg/kg Vincristine intra-peritoneal injections. Five of them received four oral doses of 0..3 mg/kg 6-Mercaptopurine, whereas the others were used as controls. Weight an body length increments were compared between groups. This scheme of drug application was weighted by the hole group and can be used at the experimental phase of this project.