RESUMEN
OBJECTIVES: Rhabdomyosarcoma (RMS) accounts for 50% of soft tissue sarcomas and 7% of pediatric malignancies. Cyclophosphamide (CPA) is the cornerstone of therapy and is a prodrug that is activated by the highly polymorphic drug-metabolizing enzyme CYP3A5. We aim to examine the possible CYP3A5 polymorphism association with CPA efficacy, survival outcomes, and toxicity in Egyptian pediatric RMS patients. METHODS: The three non-functional SNPs, CYP3A5*3 rs776746 (C_26201809_30), CYP3A5*6 rs10264272 (C_30203950_10), and CYP3A5*7 rs41303343 (C_32287188_10) were genotyped by real-time PCR. We conducted a cohort retrospective study of 150 pediatric RMS patients treated with CPA-based first-line treatment to analyze the association between these genotypes and CPA efficacy/toxicities in RMS patients. KEY FINDINGS: The frequency of having normal, intermediate, and poor metabolizers was 4.7%, 34%, and 61.3%, respectively. There was an association between these different phenotypes, genotypes, and CPA efficacy/toxicity. Hemorrhagic cystitis and pancytopenia were present in all patients, while nephrotoxicity incidence was 87.3%. There was a notable difference in the occurrence of hemorrhagic cystitis among CYP3A5 intermediate metabolizers *1/*3, *1/*6, and poor metabolizers *3/*3, *3/*6 with a significance level of p<0.05. Neither CYP3A5*7 polymorphism nor *6/*6 genotype was identified in our study. CONCLUSION: Our results demonstrate that CYP3A5*3 (rs776746) and CYP3A5*6 (rs10264272) have a great association with CPA efficacy and toxicity in RMS patients.
Asunto(s)
Ciclofosfamida , Citocromo P-450 CYP3A , Polimorfismo de Nucleótido Simple , Rabdomiosarcoma , Humanos , Citocromo P-450 CYP3A/genética , Ciclofosfamida/efectos adversos , Masculino , Femenino , Rabdomiosarcoma/genética , Rabdomiosarcoma/tratamiento farmacológico , Niño , Egipto/epidemiología , Preescolar , Estudios Retrospectivos , Estudios de Seguimiento , Pronóstico , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Lactante , Genotipo , Adolescente , Tasa de SupervivenciaRESUMEN
BACKGROUND: Rhabdomyosarcoma (RMS) is a rare cancer that develops in soft tissue, particularly skeletal muscle tissue and occasionally hollow organs like the bladder or uterus. Vincristine (VCR) is the main therapy used in treatment of RMS, it is an alkaloid produced from vinca and it is one of the most commonly prescribed drugs in pediatric oncology for the treatment of a number of tumors. The CYP3A5 enzyme is responsible for vincristine metabolism. The effect of CYP3A5 genetic polymorphism on the efficacy and toxicity of VCR on RMS patients still needs further research. METHODS: Genotyping for CYP3A5 SNPs rs776746, rs10264272 and rs41303343 was performed using Taqman Real-Time PCR assays in a retrospective cohort study of 150 RMS pediatric patients treated with vincristine. The relationship between these genotypes and RMS survival was then examined. RESULTS: We found that patients with CYP3A5*3/*3 had the highest incidence of vincristine-induced neuropathy reaching 61.3%. Patients with CYP3A5*1/*3, CYP3A5*3/*6 and the normal metabolizers with CYP3A5*1/*1 had frequencies of 22%, 10.7%, and 4.7%. patients with the lowest frequency of 1.3% were those with the CYP3A5*1/*6 genotype. There was no correlation between the genotypes of CYP3A5*3, CYP3A5*6, CYP3A5*7, and RMS survival. Initial risk, metastasis, response, convulsions, unsteady gait and hepatotoxicity grade had a significant effect on overall survival with p<0.05. CONCLUSION: CYP3A5*1/*1 have less severe vincristine-induced neuropathy than CYP3A5 *1/*3, CYP3A5 *1/*6 and CYP3A5 *3/*3, CYP3A5 *3/*6. There is a significant influence of CYP3A5 mutation on neuropathy grade and assist of ADL as a part of neurotoxicity.
Asunto(s)
Antineoplásicos Fitogénicos , Citocromo P-450 CYP3A , Polimorfismo de Nucleótido Simple , Rabdomiosarcoma , Vincristina , Humanos , Vincristina/efectos adversos , Citocromo P-450 CYP3A/genética , Femenino , Masculino , Estudios Retrospectivos , Rabdomiosarcoma/genética , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/patología , Niño , Preescolar , Egipto , Pronóstico , Antineoplásicos Fitogénicos/efectos adversos , Estudios de Seguimiento , Tasa de Supervivencia , Genotipo , Lactante , AdolescenteRESUMEN
INTRODUCTION: Breast cancer (BC) is the most common malignancy among women; supporting the need for identification of novel prognostic biomarkers, circulating microRNAs (miRNAs) could serve as such in various cancers. The aim of this study was to explore the association between miRNAs 182 and 375 with BC stages and its receptors, based on their expression using real time PCR. MATERIALS AND METHODS: Detailed medical history was taken and blood samples were withdrawn from 80 female subjects divided over the studied groups. Patients ranged in age from 24 to 80 years and were classified as follows: group I included 10 noncancerous postmenopausal control subjects; group II included 32 postmenopausal patients with BC; group III included 10 noncancerous premenopausal control subjects; group IV included 24 premenopausal patients with BC; and group V included 6 patients with benign breast tumors. RESULTS: miRNA 182 expression was significantly higher in group II, group IV, and group V (3.36 ± 0.14, 2.52 ± 0.34, and 4.93 ± 0.3,9 respectively); miRNA 375 expression was significantly higher in group II, group IV, and group V (4.41 ± 0.40, 3.12 ± 0.35, and 11.28 ± 2.37, respectively) (P < .05). Both miRNAs were significantly associated with each other and with receptors used for the prognosis of BC even after multiple regression analysis. CONCLUSION: Accordingly, miRNAs 182 and 375 could be potential noninvasive markers used for the follow up of BC patients.