AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment ...AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.展开更多
BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there ar...BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.展开更多
6-Thioguanine(6TG)is a widely used chemotherapeutic agent for the treatment of a variety of human diseases including acute lymphoblastic leukemia.After entry into cells,6TG is metabolically converted into 6-thioguanos...6-Thioguanine(6TG)is a widely used chemotherapeutic agent for the treatment of a variety of human diseases including acute lymphoblastic leukemia.After entry into cells,6TG is metabolically converted into 6-thioguanosine(^(S)G)nucleotide that can be incorporated into the genome during DNA replication.^(S)G in genomic DNA could induce cell death by triggering the post-replicative mismatch repair(MMR)pathway.Meanwhile,incorporation of 6TG into the Cp G sites could perturb the global DNA methylation and gene regulation.However,the effect of 6TG on RNA modifications is still unknown.Adenosine-toinosine(A-to-I)editing in RNA is one of the most common post-transcriptional modifications in mammals and there is growing evidence showing the significant alteration of A-to-I RNA editing in tumor tissues compared to normal tissues.In the current study,we examined the incorporation of 6TG into RNA and investigated its effect on A-to-I editing of bladder cancer-associated protein(BLCAP)transcript in acute lymphoblastic leukemia cells.The results demonstrated that ^(S)G could be incorporated into various RNA species,with m RNA having the most abundant ^(S)G.In addition,the results showed 6TG treatment elevated A-to-I editing in BLCAP transcript through upregulating adenosine deaminase 2 acting on RNA(ADAR2),which eventually contributes to the decreased cell viability.This study highlights a new mechanism of the cytotoxicity of 6TG in inducing cell death.展开更多
文摘AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.
基金Supported by the National Natural Science Foundation of China,No.82020108031,No.81973398,and No.82104290Guangdong Provincial Key Laboratory of Construction Foundation,No.2020B1212060034Guangdong Basic and Applied Basic Research Foundation,No.2022A1515012549 and No.2023A1515012667.
文摘BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.
基金supported by the National Natural Science Foundation of China(Nos.22074110,21635006,21721005)。
文摘6-Thioguanine(6TG)is a widely used chemotherapeutic agent for the treatment of a variety of human diseases including acute lymphoblastic leukemia.After entry into cells,6TG is metabolically converted into 6-thioguanosine(^(S)G)nucleotide that can be incorporated into the genome during DNA replication.^(S)G in genomic DNA could induce cell death by triggering the post-replicative mismatch repair(MMR)pathway.Meanwhile,incorporation of 6TG into the Cp G sites could perturb the global DNA methylation and gene regulation.However,the effect of 6TG on RNA modifications is still unknown.Adenosine-toinosine(A-to-I)editing in RNA is one of the most common post-transcriptional modifications in mammals and there is growing evidence showing the significant alteration of A-to-I RNA editing in tumor tissues compared to normal tissues.In the current study,we examined the incorporation of 6TG into RNA and investigated its effect on A-to-I editing of bladder cancer-associated protein(BLCAP)transcript in acute lymphoblastic leukemia cells.The results demonstrated that ^(S)G could be incorporated into various RNA species,with m RNA having the most abundant ^(S)G.In addition,the results showed 6TG treatment elevated A-to-I editing in BLCAP transcript through upregulating adenosine deaminase 2 acting on RNA(ADAR2),which eventually contributes to the decreased cell viability.This study highlights a new mechanism of the cytotoxicity of 6TG in inducing cell death.
