Maddaloni V, P. N, Perfetti A, Macrì A, D. S, D. L, Genco L, R. S, Boenzi R
{"title":"个体化治疗:DPYD c.2194G>A (V732I)等位基因在氟嘧啶治疗结肠直肠癌患者中的关键作用","authors":"Maddaloni V, P. N, Perfetti A, Macrì A, D. S, D. L, Genco L, R. S, Boenzi R","doi":"10.15406/jsrt.2022.07.00151","DOIUrl":null,"url":null,"abstract":"5-Fluorouracil (5FU) is a chemotherapeutic agent belonging to the class of antimetabolite drugs, which exert a toxic action causing death of neoplastic cells. 5FU is mostly used as a standard treatment for colorectal cancer; the development of toxicity phenomena is related to the partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), limiting factor of the catabolism of fluoropyrimidines. Only 3-5% of 5-FU is converted to an active metabolite, while 85% of the drug is inactivated by DPD to 5-fluoro-dihydrouracil (5-FDHU). A reduced enzymatic activity of the DPD can be the cause for the presence of adverse drug reactions and toxicity in the patient, with multiorgan involvement, which can sometimes lead to death. The variants of the DPYD gene recommended by the AIOM (Associazione Italiana di Oncologia Medica)guidelines are: DPYD*2A (IVS14+1G>A, c.1905+1G>A); DPYD*13 (c.1679T>G); DPYD c.2846A>T, D949V; DPYD c.1236G>A (HapB3); DPYD c.2194G>A (V732I).Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and should not be treated with fluoropyrimidines, but this is a rare condition; while patients with partial deficiency should be treated with a reduced dose of the drug. Before starting treatment it’s crucial to determine the genetic profile of the patients candidates to therapy with fluoropyrimidines. In our cohort of the 370 samples analyzed by Real Time PCR, 294(~80%) are wild type for each variant screened. : DPYD c.2194G>A (V732I) alleleis significantly represented in the population examinated: considering the 15% reduction in drug administration imposed by this genotype, molecular profiling is essential before starting therapy with 5FU.In our study we also found a rare variant DPYD F632F rs17376848 c.1896 T> C in a patient, whose relevancefor therapeutic purposes is currently of uncertain significance.","PeriodicalId":172569,"journal":{"name":"Journal of Stem Cell Research & Therapeutics","volume":"1 1","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2022-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Personalized therapy: the crucial role of the DPYD c.2194G>A (V732I) allele in the treatment of colorectal cancer patients candidates for therapy with fluoropyrimidines\",\"authors\":\"Maddaloni V, P. 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The variants of the DPYD gene recommended by the AIOM (Associazione Italiana di Oncologia Medica)guidelines are: DPYD*2A (IVS14+1G>A, c.1905+1G>A); DPYD*13 (c.1679T>G); DPYD c.2846A>T, D949V; DPYD c.1236G>A (HapB3); DPYD c.2194G>A (V732I).Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and should not be treated with fluoropyrimidines, but this is a rare condition; while patients with partial deficiency should be treated with a reduced dose of the drug. Before starting treatment it’s crucial to determine the genetic profile of the patients candidates to therapy with fluoropyrimidines. 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引用次数: 0
摘要
5-氟尿嘧啶(5-Fluorouracil, 5FU)是一类抗代谢药物,具有致肿瘤细胞死亡的毒性作用。5FU主要用作结直肠癌的标准治疗;毒性现象的发生与氟嘧啶分解代谢的限制因子二氢嘧啶脱氢酶(DPD)的部分或完全缺乏有关。只有3-5%的5-FU转化为活性代谢物,而85%的药物被DPD灭活为5-氟-二氢尿嘧啶(5-FDHU)。DPD酶活性降低可能是患者出现药物不良反应和毒性的原因,可累及多器官,有时可导致死亡。AIOM (Associazione Italiana di Oncologia Medica)指南推荐的DPYD基因变体为:DPYD*2A (IVS14+1G>A, c.1905+1G>A);DPYD * 13 (c.1679T > G);DPYD c.2846A>T, D949V;DPYD c.1236G>A (HapB3);DPYD c.2194G>A (V732I)。完全DPD缺乏症患者存在危及生命或致命毒性的高风险,不应使用氟嘧啶治疗,但这是一种罕见的情况;而部分缺乏症患者应减少药物剂量。在开始治疗之前,确定适合氟嘧啶治疗的患者的基因谱是至关重要的。在Real Time PCR分析的370个样本中,筛选出的每个变异有294个(约80%)为野生型。: DPYD c.2194G>A (V732I)等位基因在所检查的人群中显著存在:考虑到该基因型施加的药物给药减少15%,在开始5FU治疗之前,分子分析是必不可少的。在我们的研究中,我们还发现了一种罕见的DPYD F632F rs17376848 c.1896患者的T> C,其与治疗目的的相关性目前尚不确定。
Personalized therapy: the crucial role of the DPYD c.2194G>A (V732I) allele in the treatment of colorectal cancer patients candidates for therapy with fluoropyrimidines
5-Fluorouracil (5FU) is a chemotherapeutic agent belonging to the class of antimetabolite drugs, which exert a toxic action causing death of neoplastic cells. 5FU is mostly used as a standard treatment for colorectal cancer; the development of toxicity phenomena is related to the partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), limiting factor of the catabolism of fluoropyrimidines. Only 3-5% of 5-FU is converted to an active metabolite, while 85% of the drug is inactivated by DPD to 5-fluoro-dihydrouracil (5-FDHU). A reduced enzymatic activity of the DPD can be the cause for the presence of adverse drug reactions and toxicity in the patient, with multiorgan involvement, which can sometimes lead to death. The variants of the DPYD gene recommended by the AIOM (Associazione Italiana di Oncologia Medica)guidelines are: DPYD*2A (IVS14+1G>A, c.1905+1G>A); DPYD*13 (c.1679T>G); DPYD c.2846A>T, D949V; DPYD c.1236G>A (HapB3); DPYD c.2194G>A (V732I).Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and should not be treated with fluoropyrimidines, but this is a rare condition; while patients with partial deficiency should be treated with a reduced dose of the drug. Before starting treatment it’s crucial to determine the genetic profile of the patients candidates to therapy with fluoropyrimidines. In our cohort of the 370 samples analyzed by Real Time PCR, 294(~80%) are wild type for each variant screened. : DPYD c.2194G>A (V732I) alleleis significantly represented in the population examinated: considering the 15% reduction in drug administration imposed by this genotype, molecular profiling is essential before starting therapy with 5FU.In our study we also found a rare variant DPYD F632F rs17376848 c.1896 T> C in a patient, whose relevancefor therapeutic purposes is currently of uncertain significance.