Sisplatin kemoterapisine bağlı bulantı-kusmada granisetron etkisinin CYP1A1 ve CYP3A4 polimorfizmi ile ilişkisi
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Tarih
2022
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info:eu-repo/semantics/openAccess
Özet
Bu çalışmada Sisplatin ile tedavi edilen kanser vakalarında kemoterapiye bağlı
gelişen bulantı-kusmada antiemetik bir ilaç olan Granisetron etkisinin CYP1A1 ve
CYP3A4 polimorfizmi ile ilişkisi araştırılmıştır
NEU Meram Tıp Fakültesi ve KTO Karatay Üniversitesi Medicana Tıp
Fakültesi Tıbbi Onkoloji Kliniğine başvuran, daha önce kemoterapi almamış, ≥18
yaş ve Karnofsky performans skalası ≥%50 olan; Sisplatin bazlı tek ajan veya
kombinasyon kemoterapisi olarak 50 mg/m² ya da üzerindeki dozda kemoterapötik
ajan alan 50 hasta çalışmaya dahil edilmiştir. Bu hastalara Sisplatin öncesi bulantı-kusmanın önlenmesi amacıyla premedikasyonda Granisetron (3 mg) ve
Deksametazon (8 mg) intravenöz olarak uygulanmıştır. Hastalar gecikmiş bulantı-kusmanın engellenmesi amacıyla kemoterapi sonrası 4 gün daha Granisetron’u oral
yolla kullanmaya devam etmişlerdir. Her hasta sitotoksik ilaç başlanmasından
itibaren 5 gün boyunca günlük olarak takip edilmiştir. Kanser tedavisi sırasında
kemoterapi ilişkili bulantı ve kusma (CINV) şiddetini değerlendirmek için hastalara
FLIE işlevsel yaşam indeksi skalası kullanılmıştır. Tedavinin hemen öncesinde
hastalardan alınan kan örneklerinden izole edilen DNA örneği kullanılmıştır.
Çalışmada, CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943) CYP3A4*22
(rs35599367) polimorfizmlerin belirlenmesinde PZR tabanlı RFLP tekniğinin yanı
sıra gen polimorfizmlerinin validasyon amaçlı gerçek zamanlı PZR’a dayalı HRM
tekniği de kullanılmıştır.
Elde edilen sonuçlara göre örneklerin ilgili polimorfizmler bakımından
genotip frekansları CYP1A1*2A (rs4646903) için %80 Wild Type, %18 Heterozigot,
%2Homozigot, CYP1A1*2C (rs1048943) için %92 Wild Type, %8 Heterozigot, CYP3A4*22 (rs35599367) için %96 Wild Type, %4 Heterozigot varyant aleli olarak
bulunmuştur. Bu çalışmada Sisplatin tedavisi alan kanser hastalarında kemoterapiye
bağlı olarak gelişen bulantı - kusmayı önlemek için uygulanan Granisetron
tedavisinin etkinliği ile CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943),
CYP3A4*22 (rs35599367) polimorfizmleri arasında anlamlı bir ilişki tespit
edilmemiştir. Örnek grubunda Granisetron tedavisinin etkinliğini değiştirecek
herhangi bir genotipik farklılık bulunmamaktadır.
In this study, 50 patients, ≥18 years old with Karnofsky performance scale ≥50% received Cisplatin-based chemotherapy as a single agent or combination at a dose of 50 mg/m2 or more before admission to the medical oncology clinics of Meram Medical Faculty of NEU and Medicana Medical Faculty of KTO Karatay University, were included. In order to prevent nausea and vomiting before Cisplatin, Granisetron (3 mg) and Dexamethasone (8 mg) were administered intravenously in premedication to these patients. Patients continued to use Granisetron orally for 4 days after chemotherapy to prevent delayed nausea and vomiting. Each patient was followed up daily for 5 days from the initial dose of the cytotoxic drug. FLIE Functional Living Index was used to evaluate the severity of chemotherapy-related nausea and vomiting (CINV) during cancer treatment. CINV is one of the most common side effects observed after chemotherapy. Granisetron is an antiemetic drug that is a 5-hydroxytryptamine (5HT3) receptor blocker used to prevent chemotherapy-induced nausea and vomiting. It is known that CINV persists in 30-50% of patients taking Granisetron. Unlike 1A-HT3RA, Granisetron is metabolized by the liver through Ndemethylation, aromatic ring oxidation and conjugation mediated by the P450 isoenzymes CYP3A and CYP1A1. There is no study showing the association between the effect of Granisetron on CINV and the enzyme polymorphism. In this study, polymorphisms that may change the effectiveness of Granisetron therapy were investigated. A DNA sample isolated from blood samples taken from patients was used just before the treatment. In this study, the PCR-based RFLP technique was used to determine the CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943), CYP3A4*22 (rs35599367) polymorphisms, as well as the real-time PCR-based HRM technique for the validation of gene polymorphisms. According to the results, samples in terms of genotype frequencies of relevant polymorphisms CYP1A1*2A (rs4646903) for 80 % of the Wild type, 18 % Heterozygous, %2 Homozigot, CYP1A1*2C (rs1048943) for 92% of Wild Type, 8% Heterozygous, CYP3A4*22 (rs35599367) for at 96% for the Wild type, 4% of the variant allele was found to be heterozygous. In this study, a significant relationship between effectiveness of Granisetron treatment on chemotherapy induced nausea and vomiting in cancer patients receiving Cisplatin treatment and polymorphisms of CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943), CYP3A4*22 (rs35599367) has not been determined. There were no genotypic differences in the sample group that would change the effectiveness of Granisetron therapy. The polymorphism of the CYP3A4 gene rs270574 did not show a significant effect on the cases. when evaluated for the interaction of Cisplatin and Granisetron analyzed. As a conclusion; to prevent nausea and vomitting related with chemotherapy in cancer patients receiving Cisplatin therapy, no significant relationship found between the effectiveness of Granisetron therapy and the polymorphisms of CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943), CYP3A4*22 (rs35599367.
In this study, 50 patients, ≥18 years old with Karnofsky performance scale ≥50% received Cisplatin-based chemotherapy as a single agent or combination at a dose of 50 mg/m2 or more before admission to the medical oncology clinics of Meram Medical Faculty of NEU and Medicana Medical Faculty of KTO Karatay University, were included. In order to prevent nausea and vomiting before Cisplatin, Granisetron (3 mg) and Dexamethasone (8 mg) were administered intravenously in premedication to these patients. Patients continued to use Granisetron orally for 4 days after chemotherapy to prevent delayed nausea and vomiting. Each patient was followed up daily for 5 days from the initial dose of the cytotoxic drug. FLIE Functional Living Index was used to evaluate the severity of chemotherapy-related nausea and vomiting (CINV) during cancer treatment. CINV is one of the most common side effects observed after chemotherapy. Granisetron is an antiemetic drug that is a 5-hydroxytryptamine (5HT3) receptor blocker used to prevent chemotherapy-induced nausea and vomiting. It is known that CINV persists in 30-50% of patients taking Granisetron. Unlike 1A-HT3RA, Granisetron is metabolized by the liver through Ndemethylation, aromatic ring oxidation and conjugation mediated by the P450 isoenzymes CYP3A and CYP1A1. There is no study showing the association between the effect of Granisetron on CINV and the enzyme polymorphism. In this study, polymorphisms that may change the effectiveness of Granisetron therapy were investigated. A DNA sample isolated from blood samples taken from patients was used just before the treatment. In this study, the PCR-based RFLP technique was used to determine the CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943), CYP3A4*22 (rs35599367) polymorphisms, as well as the real-time PCR-based HRM technique for the validation of gene polymorphisms. According to the results, samples in terms of genotype frequencies of relevant polymorphisms CYP1A1*2A (rs4646903) for 80 % of the Wild type, 18 % Heterozygous, %2 Homozigot, CYP1A1*2C (rs1048943) for 92% of Wild Type, 8% Heterozygous, CYP3A4*22 (rs35599367) for at 96% for the Wild type, 4% of the variant allele was found to be heterozygous. In this study, a significant relationship between effectiveness of Granisetron treatment on chemotherapy induced nausea and vomiting in cancer patients receiving Cisplatin treatment and polymorphisms of CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943), CYP3A4*22 (rs35599367) has not been determined. There were no genotypic differences in the sample group that would change the effectiveness of Granisetron therapy. The polymorphism of the CYP3A4 gene rs270574 did not show a significant effect on the cases. when evaluated for the interaction of Cisplatin and Granisetron analyzed. As a conclusion; to prevent nausea and vomitting related with chemotherapy in cancer patients receiving Cisplatin therapy, no significant relationship found between the effectiveness of Granisetron therapy and the polymorphisms of CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943), CYP3A4*22 (rs35599367.
Açıklama
Doktora Tezi
Anahtar Kelimeler
Bulantı-Kusma, Granisetron, Polimorfizm, Sisplatin, Cisplatin, Granisetron, Nausea and Vomiting, Polymorphism
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Güler, S. (2022). Sisplatin kemoterapisine bağlı bulantı-kusmada granisetron etkisinin CYP1A1 ve CYP3A4 polimorfizmi ile ilişkisi. (Yayımlanmamış doktora tezi). Necmettin Erbakan Üniversitesi, Sağlık Bilimleri Enstitüsü, Tıbbi Farmakoloji Anabilim Dalı, Konya.
