Relation between cytokine promoter gene polymorphism and toxicity of 5-fluorouracil plus cisplatin chemotherapy

Abstract

Abstract. Variability in the efficacies and toxicities of anticancer agents is a major problem. We hypothesized that polymorphisms in cytokine gene promoters may underlie genetic susceptibility to chemotherapy-induced toxicities in the Japanese. DNA was extracted from 100 patients undergoing 5-fluorouracil plus cisplatin chemotherapy. We used a caseonly design to evaluate the relation between toxicities and cytokine promoter gene polymorphisms. The following polymorphisms were genotyped: tumor necrosis factor (TNF)-·-1031T/C, interleukin (IL)-1ß-511C/T, IL-6-634C/G, IL-10-819T/C, IL-18-137G/C, macrophage migration inhibitory factor -173G/C, and 86-basepair variable numbers of tandem repeat in intron 2 of the IL-1 receptor antagonist. The frequency of the IL-6-634 GC and GG genotypes was significantly higher in patients with grades 1-4 leukopenia (P=0.003; Crude-odds ratios (Cr-OR) =4.0), neutropenia (P=0.0051; Cr-OR=3.6), or thrombocytopenia (P<0.0001; Cr-OR=6.1) than in patients without these toxicities. Similarly, the frequency of the IL-1ß-511 TC and TT genotypes and the frequency of the TNF-·-1031 TT genotype were significantly higher in patients with grades 1-4 thrombocytopenia (P=0.015; Cr-OR=2.9) and stomatitis (P=0.02; Cr-OR=3.1), respectively. Multivariate analysis of factors such as age, sex, disease type, purpose of the chemotherapy, use of radiotherapy, and cytokine promoter gene polymorphisms showed polymorphisms to be significant predictors of toxicity. Our results suggest that polymorphisms in cytokine gene promoters may be associated with susceptibilities to leukopenia, neutropenia, thrombocytopenia and stomatitis in patients treated with 5-fluorouracil plus cisplatin.

The C-Reactive Protein to Albumin Ratio as a Predictor of Severe Side Effects of Adjuvant Chemotherapy in Stage III Colorectal Cancer Patients

“…In the state of chronic inflammation, several cytokines could cause weight loss and malnutrition, which could result in severe side effects during chemotherapy [16, 17]. Indeed, the present study demonstrated that high CAR levels were correlated with grade 3 or 4 adverse events during AC on multivariate analysis.…”

“…Chronic and high inflammation means hypercytokinemia that might lead to weight loss and malnutrition. Several studies reported that hypercytokinemia could produce severe side effects during chemotherapy [13–16]. Furthermore, a good nutritional status slows weight loss, stabilizes body composition, and could improve quality of life in patients with advanced CRC, which reduces chemotherapy-associated side effects [17].…”

Hematotoxicity: In Vitro and Ex Vivo Compound Profiling

“…For several compounds [28][29][30][31][32][33][34][35][36][37][38][39], one of the polymorphic enzymes increases exposure to the toxic form of the compound and thereby induces hematotoxicity in the patient, due to higher exposure levels and not due to a specific mechanism of toxicity within the patient populations.…”

Emerging drugs for chemotherapy-induced mucositis

“…It is now clear that genetic factors influence mucositis risk in at least two ways: first, because of genetic defects, patients may have reduced levels of enzymes needed to metabolize chemotherapeutic drugs [37] ; and second, the genetic control of the pathways associated with mucositis may vary among patients [11,38,39] . In the future, pretreatment testing should assist in predicting which patients are at risk for mucositis.…”