Association between the low-dose irinotecan regimen-induced occurrence of grade 4 neutropenia and genetic variants of UGT1A1 in patients with gynecological cancers.

The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22-38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.

[Effect of capecitabine therapy on the blood levels of antiepileptic drugs - report of two cases].

We report the cases of 2 breast cancer patients who received capecitabine(CAP)and concomitant anticonvulsant therapy with either phenytoin(PHT)or valproate(VPA)for brain metastasis. The effect of CAP on the blood levels of the 2 anticonvulsants was different and it depended on the variation in metabolism of each drug. Case 1 involved a 59-year-old woman with recurrent breast cancer. After radiation therapy for brain metastases, the patient received PHT(400mg/day)to prevent convulsions. After 5 days of PHT administration, CAP therapy was initiated, and her blood PHT levels increased to 33.8 mg/mL. Although the PHT dose was reduced to 300mg/day, the blood PHT levels markedly increased to 45.5 mg/mL 7 days after the withdrawal of CAP. Case 2 involved a 60-year-old woman with breast cancer who underwent surgery for brain metastases and subsequently received controlled-release VPA tablets(400mg/day). No remarkable change was observed in her blood VPA levels during CAP treatment or after CAP withdrawal(the blood VAP level after 7 days of treatment was, 78.4 mg/mL; after 14 days of treatment, 73.2 mg/mL; and 7 days after withdrawal, 79.7 mg/mL). CAP has been reported to inhibit nucleic acid synthesis and/or folic acid activity rather than cytochrome P450(CYP)directly. CAP had a significant effect on the blood levels of PHT, which is metabolized via the CYP pathway. However, VPA levels remained unchanged because VPA metabolism involves other pathways, such as the beta-oxidation and conjugation pathways.

Single-nucleotide polymorphisms and copy number variations of the FCGR2A and FCGR3A genes in healthy Japanese subjects.

FcγRII and FcγRIII are low-affinity Fcγ receptors that are encoded by the FCGR2A and FCGR3A genes, respectively. These genes contain functional single-nucleotide polymorphisms (SNPs), which alter the binding affinities of these receptors for the γ chain of the Fc fragment of immunoglobulin G. The known SNPs in FCGR2A and FCGR3A are rs1801274 (A>G; H131R) and rs396991 (T>G; F158V), respectively. It is also known that there are copy number variations (CNVs) in the genetic locus (1q23) where FCGR2A and FCGR3A are located. However, the frequencies of these SNPs and CNVs have not been determined in the Japanese population. The aim of this study was to investigate SNPs and CNVs in FCGR2A and FCGR3A among 113 healthy individuals. The SNPs and CNVs in FCGR2A and FCGR3A were determined using the TaqMan® SNP Genotyping and the TaqMan® Copy Number assays. Our results revealed that the incidence of FCGR2A (rs1801274) genotypes were as follows: A/A, 69.9%; A/G, 29.2%; and G/G, 0.9%. The incidence of the FCGR3A (rs396991) genotypes were as follows: T/T, 56.7%; T/G, 38.9%; and G/G, 4.4%). No CNVs were detected for FCGR2A. To the best of our knowledge, this finding has not been previously reported in the Japanese population. By contrast, CNVs were observed in FCGR3A (3 subjects were found to harbour a gene deletion and 5 subjects had 3 copies of the gene). Using simple commercially available assays we were able to confirm previous findings regarding FCGR2A and FCGR3A alleles and CNVs. These assays may provide a basis for the investigation of the role of these genes in the efficacy of antibody-based drugs, such as trastuzumab and rituximab, in Japanese subjects.

The association between heterozygosity for UGT1A1*6, UGT1A1*28, and variation in the serum total-bilirubin level in healthy young Japanese adults.

AIMS: Considerable variations in the serum total-bilirubin concentrations are observed in healthy subjects. Both sex and the UGT1A1 homozygous genotypes,*6/*6 and *28/*28, are known to influence this variation. However, currently, there is no consensus on the relationship of the heterozygous genotypes *1/*6, *1/*28, or *6/*28 and interindividual variation in the serum total-bilirubin levels. In the present study, we sought to clarify the involvement of heterozygous alleles *6 and *28 in the interindividual difference in the serum total-bilirubin levels among healthy young Japanese adults. METHODS: We enrolled 92 healthy Japanese aged 20-30 years (37 men and 55 women). The serum total-bilirubin levels were compared between men and women and with different UGT1A1 genotypes. Multiple regression analysis was used to investigate the relationships between individual differences in the serum total-bilirubin levels, UGT1A1 genetic variants, and sex. RESULTS: Serum total-bilirubin levels were significantly lower in women than in men. There were also significant differences in the serum total-bilirubin levels between the *1/*1 and *1/*28 genotype, the *1/*1 and *6/*28 genotype, the *1/*6 and *1/*28 genotype, and also the *1/*6 and *6/*28 genotype. Multiple regression analysis showed significant relationships between the serum total-bilirubin level, the UGT1A1 genotypes *1/*28 and *6/*28, and sex. This model explained 42.3% of the interindividual variation in serum total-bilirubin levels. CONCLUSIONS: We found that the UGT1A1 genotypes *1/*28 and *6/*28 as well as sex contributed to interindividual variations in the serum total-bilirubin levels. In contrast, UGT1A1*1/*6 showed only minimal involvement in individual differences in serum total-bilirubin levels.