Biomedical subjects

Kuniaki Shirao

Publications and source records attributed to Kuniaki Shirao.

At least 19 recordsLinked to original sources

PubMed2006

Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma.

PURPOSE: Epidermal growth factor receptor (EGFR) is highly expressed in some gastric cancers and is implicated in cancer cell growth and proliferation. The objective of this study was to assess the in situ biologic activity of the EGFR tyrosine kinase inhibitor gefitinib in gastric tumor samples in a phase II study. METHODS: Patients with previously treated stage IV adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive gefitinib (250 or 500 mg/d). Tumor biopsies, obtained at screening and on day 28 of treatment, were assessed for biomarker expression using immunohistochemistry and analysis of apoptosis. RESULTS: One hundred sixteen tumor samples from 70 patients were available, 70 were baseline and 46 were on-therapy biopsies. At baseline, levels of EGFR expression significantly correlated with levels of phosphorylated EGFR (pEGFR; P < .001) and Ki67 expression (P = .011), but not with phosphorylated mitogen-activated protein kinase (pMAPK). After gefitinib treatment, levels of pEGFR in tumor cells were significantly reduced (P = .001); this was not the case for pMAPK and phosphorylated Akt (pAkt). However, in some cases gefitinib inhibited pAkt and these tumors had enhanced apoptosis. Likewise, there was a significant correlation between increased exposure to geftinib and enhanced apoptosis. CONCLUSION: Gefitinib reached the tumors at concentrations sufficient to inhibit EGFR activation in advanced gastric carcinoma patients, although this did not translate into clinical benefit. Overall, intratumoral phosphorylation of MAPK and Akt was not significantly inhibited by gefitinib. However, the finding that decreases in pAkt correlated with enhanced apoptosis deserves further exploration.

Adult↗

PubMed2006

A phase II Study of the global dose and schedule of capecitabine in Japanese patients with metastatic colorectal cancer.

BACKGROUND: Although the standard 3-week capecitabine regimen (1250 mg/m(2) twice daily for 2 weeks followed by a 1-week rest) has shown superior activity and improved safety over bolus 5-fluorouracil/leucovorin in two large randomized phase III trials in Europe and in the United States, only a 4-week regimen of capecitabine (828 mg/m(2) twice daily for 3 weeks) has been studied in Japan. Therefore, we performed a phase II study to investigate the 3-week regimen of capecitabine in Japanese patients with metastatic colorectal cancer (MCRC). METHODS: Previously untreated patients with MCRC received oral capecitabine 1250 mg/m(2) twice daily for 2 weeks. Treatment was repeated every 3 weeks. Blood and urine samples were collected for pharmacokinetic analysis. RESULTS: Sixty patients were enrolled. The overall response rate was 35% [95% confidence interval (CI), 23-48%], and 52% of patients had stable disease. The median time to progression was 5.5 months (95% CI, 4.2-6.7 months). The median overall survival was 20.2 months (95% CI, 16.6-27.8 months). The most frequently occurring adverse drug reaction was hand-foot syndrome (all-grade 73%; grade 3 13%). Diarrhea, anorexia, nausea and stomatitis were each seen in 37% of patients. The pharmacokinetic profiles of capecitabine and its metabolites were similar to those reported in Caucasian patients. CONCLUSIONS: The 3-week regimen of capecitabine was effective and well tolerated in Japanese patients with MCRC as well, and could be used as the basic regimen for future combination therapies.

Administration, Oral↗

PubMed2006

Phase I study of single-dose oxaliplatin in Japanese patients with malignant tumors.

BACKGROUND: Oxaliplatin, a platinum compound, has been commonly used around the world for treating advanced colorectal cancer. The generally recommended dose and schedule of oxaliplatin monotherapy is 130 mg/m(2) every 3 weeks. This trial was conducted to evaluate the safety and pharmacokinetics of oxaliplatin monotherapy in Japanese patients with solid tumors. METHODS: Oxaliplatin was administered as a 2-h intravenous infusion every 3 weeks at a dose of 90 and 130 mg/m(2). Blood was collected to determine the total platinum and the ultrafiltrate platinum concentrations in plasma in all cycles. RESULTS: Nine patients were enrolled; three were given oxaliplatin monotherapy at 90 mg/m(2) and six received 130 mg/m(2). All tumors were colorectal cancer. The major adverse reactions included myelosuppressive, neurological and gastrointestinal toxicities, although most were grades 1 and 2 at both dose levels. Peripheral sensory neuropathy of without movement disturbance (grade 1 or 2) was observed in all patients at both dose levels. The 130 mg/m(2) dose level was not found to be the maximum tolerated dose, but was judged to be the recommended dose. No objective responses were seen and five cases of no change were observed. A bi-exponential open model best described the disappearance of platinum in the plasma, and a tri-exponential open model best described the disappearance of ultrafilterable platinum in the plasma at both dose levels. No racial difference was suggested in the pharmacokinetics of oxaliplatin. CONCLUSIONS: The oxaliplatin monotherapy dose schedule of 130 mg/m(2) every 3 weeks, recommended worldwide, is acceptable for Japanese patients.

Adult↗

PubMed2006

Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trial.

BACKGROUND: Although adjuvant radiotherapy was proved to be effective for local control of rectal cancer even after standardized mesorectal excision, the role of adjuvant chemotherapy after such standardized surgery remains to be clarified. We aimed to assess the efficacy of a combination of uracil and tegafur for pathological stage III rectal cancer treated by standardized mesorectal excision with selective lateral pelvic lymphadenectomy. METHODS: We randomly assigned patients with completely resected stage III rectal cancer, who underwent standardized mesorectal excision with selective lateral pelvic lymphadenectomy, to receive either oral uracil-tegafur (400 mg/m2 tegafur per day) for one year or no treatment. Standardization and quality control of the surgery and pathological techniques were ensured by use of the guidelines of the Japanese Society for Cancer of the Colon and Rectum. The primary endpoint was relapse-free survival. The secondary endpoint was overall survival. RESULTS: We enrolled and randomized 276 patients. Excluding two ineligible patients, 274 were included in the analysis. Planned interim analysis 2 years after accrual termination revealed significant prolongation of relapse-free survival (P = 0.001) and overall survival (P = 0.005) in the uracil-tegafur group. The 3-year relapse-free survival and overall survival rates were 78 and 91% in the chemotherapy group and 60 and 81% in the surgery-alone group, respectively. Local recurrence rates were low in both groups. Grade 3 events occurred in 17% of the chemotherapy patients, but no grade 4 or more events occurred. CONCLUSION: Adjuvant chemotherapy with uracil-tegafur improves survival of patients with stage III rectal cancer after standardized mesorectal excision with selective lateral pelvic lymphadenectomy.

Adult↗

PubMed2006

Phase I/II study of oxaliplatin with weekly bolus fluorouracil and high-dose leucovorin (ROX) as first-line therapy for patients with colorectal cancer.

BACKGROUND: Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for the treatment of patients with metastatic colorectal cancer. Weekly bolus 5-FU with high-dose LV (Roswell Park Memorial Institute Regimen: RPMI) is the most commonly used regimen in Japan. The objectives of this study were to determine the recommended dose (RD) of RPMI combined with oxaliplatin and to evaluate the toxicity and efficacy at the RD. METHODS: The subjects were 18 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m2) was given intravenously over 2 h on days 1 and 15 with l-LV (250 mg/m2) given intravenously over 2 h and 5-FU as an intravenous bolus on days 1, 8, and 15. This treatment was repeated every 4 weeks. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2). RESULTS: A total of 14 patients received level 1, and 4 received level 2. Three of the patients had dose-limiting toxicity (DLT) in cycle 1 of level 2 (grade 3 thrombocytopenia, grade 4 neutropenia and grade 2 neutropenia in one patient each), requiring that treatment was delayed for longer than 7 days. None of the 14 patients given level 1 had DLT or grade 3 or 4 gastrointestinal toxicity. Sensory neuropathy occurred in all patients. Objective response rates were 61% in the 18 patients studied and 64% at level 1. The median time to progression was 171 days, and the median overall survival time was 603 days in the 18 patients studied. CONCLUSIONS: Oxaliplatin (85 mg/m2) with weekly bolus 5-FU (400 mg/m2) and high-dose l-LV (250 mg/m2) is recommended for further phase III studies in patients with metastatic colorectal cancer.

Adult↗

PubMed2006

Genetic variation and haplotype structure of the ABC transporter gene ABCG2 in a Japanese population.

The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCG2, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of ABCG2 from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5'-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in ABCG2 and pharmacokinetic/pharmacodynamic parameters.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Fourteen novel genetic variations and haplotype structures of the TYMS gene encoding human thymidylate synthase (TS).

Forty genetic variations including 14 novel ones were found in the human TYMS gene, which encodes thymidylate synthase, in 263 Japanese cancer patients who received 5-fluorouracil (FU)-based chemotherapy. Three novel variations were located within the 28-bp tandem repeat sequence in the 5'-untranslated region (UTR) and were designated 5Rc, 3Rc-ins and 4Rc. Allele frequencies were 0.021 for 5Rc, 0.006 for 3Rc-ins and 0.002 for 4Rc. Other novel variations included -133G>C and -125G>C in the 5'-UTR; IVS1-278G>A, IVS2-68C>T, IVS2-23T>C, IVS4+122_+123insATTG, IVS4-141G>A, IVS5-100A>T and IVS6-111G>A in the introns; and 1244(*302)A>G and 1264(*322)G>A in the 3'-UTR. The allele frequencies were 0.34 for IVS4+122_+123insATTG, 0.042 for -133G>C, 0.011 for IVS4-141G>A, 0.006 for -125G>C, 0.004 for IVS1-278G>A, IVS2-68C>T, 1244(*302)A>G and 1264(*322)G>A, and 0.002 for IVS2-23T>C, IVS5-100A>T and IVS6-111G>A. Using the detected polymorphisms, linkage disequilibrium (LD) analysis was performed, which divided the TYMS gene into three LD blocks. The 28-bp tandem repeat sequence in the 5'-UTR was assigned as Block 2 with a total of 7 alleles. In Blocks 1 and 3, 7 and 19 haplotypes were determined/inferred, respectively. Our findings provide fundamental and useful information for genotyping TYMS in the Japanese and probably other Asian populations.

3' Untranslated Regions↗

PubMed2006

[S-1 as a single agent for colorectal cancer].

Chemotherapy for colorectal cancer is now improving rapidly due to new drugs like oxaliplatin and molecular targeting drugs. The key drug, however, is still 5-fluorouracil (5-FU). S-1 is an oral 5-FU anti-tumor drug that combines three pharmacological agents: tegafur, 5-chloro-2,4-dihydroxypyridine, which inhibits dihydropyrimidine dehydrogenase activity, and potassium oxonate, which reduces gastrointestinal toxicity. The results of the phase II study suggested that S-1 as a single agent was active against metastatic colorectal cancer: CR rate was 36-40% and MST was about one-year. Toxicity was all tolerable. Clinical trials of S-1 with oxaliplatin or CPT-11 combination chemotherapy are ongoing in Japan. S-1 with molecular targeting drugs will also be studied. Therefore, S-1 is expected to play an important part in chemotherapy for colorectal cancer.

Administration, Oral↗

PubMed2005

Functional characterization of three naturally occurring single nucleotide polymorphisms in the CES2 gene encoding carboxylesterase 2 (HCE-2).

Twelve single nucleotide polymorphisms (SNPs) in the human CES2 gene, which encodes a carboxylesterase, hCE-2 [human carboxylesterase 2 (EC 3.1.1.1)], have been reported in the Japanese. In this report, we have examined functional alterations of three SNPs, a nonsynonymous SNP (100C>T, R34W), an SNP at the splice acceptor site in intron 8 (IVS8-2A>G), and one newly discovered nonsynonymous SNP (424G>A, V142M). For the two nonsynonymous SNPs, the corresponding variant cDNAs were expressed in COS-1 cells. Both the R34W and V142M variants showed little esterase activities toward the anticancer agent irinotecan and two typical carboxylesterase substrates, p-nitrophenol acetate and 4-methylumbelliferyl acetate, although increased levels of cDNA-mediated protein expression were observed by Western blotting as compared with the wild type. To investigate a possible splicing aberration in IVS8-2A>G, an in vitro splicing assay was utilized and transcripts derived from CES2 gene fragments of the wild type and IVS8-2A>G were compared. Sequence analysis of the cloned transcripts revealed that IVS8-2A>G yielded mostly aberrantly spliced transcripts, including a deleted exon or a 32-bp deletion proximal to the 5' end of exon 9, which resulted in truncated hCE-2 proteins. These results suggested that 100C>T (R34W), 424G>A (V142M), and IVS8-2A>G are functionally deficient SNPs.

Animals↗

PubMed2005

Functional analysis of four naturally occurring variants of human constitutive androstane receptor.

The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.

Animals↗

PubMed2005

Functional analysis of six human aryl hydrocarbon receptor variants in a Japanese population.

Aryl hydrocarbon receptor (AhR) is an important transcriptional regulator involved in the induction of CYP1A1, CYP1A2, CYP1B1, UGT1A1, and UGT1A6. In this study, functional properties of four novel naturally occurring human AhR variants (K401R, N487D, I514T, and K17T/R554K) were examined along with the single variants K17T and R554K. The luciferase reporter assay using the CYP1A1 promoter reporter in HeLa cells treated with beta-naphthoflavone or 3-methylcholanthrene, which are known as typical agonists for AhR, showed that reporter activities of the K401R and N487D variants were reduced to 40 to 58% of those of wild-type (WT) but not of the other variants. Similarly, the K401R and N487D variants also reduced the omeprazole-induced reporter activities to approximately 56 and 74% of those of the WT, respectively. The reduced activities of the two variants were probably caused by the reduced protein expression levels, since the protein levels of the K401R and N487D variants were approximately 52 and 47% of the WT, respectively, without any changes in their mRNA levels. The reduced protein levels were recovered by treatment with a proteasome inhibitor MG132 [N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal], suggesting that the reduced protein levels were caused by the accelerated proteasomal degradation by a proteasome. Together, the current data demonstrate that the K401R and N487D variants reduce their apparent transcriptional activities, both ligand-induced and omeprazole-induced activation, probably through reduced protein expression. Thus, these two variants may influence drug metabolism through reduced induction of CYP1A1 and other target enzymes.

Genes, Reporter↗

PubMed2005

Genetic variations and haplotypes of UGT1A4 in a Japanese population.

Nineteen genetic variations, including 11 novel ones, were found in exon 1 and its flanking region of the UDP-glucuronosyltransferase (UGT) 1A4 gene from 256 Japanese subjects, consisting of 60 healthy volunteers, 88 cancer patients and 108 arrhythmic patients. These variations include -217T>G and -36G>A in the 5'-flanking region, 30G>A (P10P), 127delA (43fsX22; frame-shift from codon 43 resulting in the termination at the 22nd codon, codon 65), 175delG (59fsX6), 271C>T (R91C), 325A>G (R109G), and 357T>C (N119N) in exon 1, and IVS1+1G>T, IVS1+98A>G and IVS1+101G>T in the following intron. Among them, 127delA and 175delG can confer early termination of translation, resulting in an immature protein that probably lacks enzymatic activity. Variation IVS1+1G>T is located at a splice donor site and thus may lead to aberrant splicing. Since we did not find any significant differences in the frequencies of all the variations among the three subject groups, the data were analyzed as one group. The allele frequencies of the novel variations were 0.006 for IVS1+101G>T, 0.004 for 30G>A (P10P) and 357T>C (N119N), and 0.002 for the 8 other variations. In addition, the two known nonsynonymous single nucleotide polymorphisms (SNPs), 31C>T (R11W) and 142T>G (L48V), were found at 0.012 and 0.129 frequencies, respectively. The SNP 70C>A (P24T), mostly linked with 142T>G (L48V) in German Caucasians, was not detected in this study. Sixteen haplotypes were identified or inferred, and some haplotypes were confirmed by cloning and sequencing. It was shown that most of 142T>G (L48V) was linked with -219C>T, -163G>A, 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T, comprising haplotype *3a; haplotype *4a harbors 31C>T (R11W); 127delA (43fsX22) and 142T>G (L48V) were linked (haplotype *5a); 175delG (59fsX6) was linked with 325A>G (R109G) (*6a haplotype); and -219C>T, -163G>A, 142T>G (L48V), 271C>T (R91C), 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T comprised haplotype *7a. Our results provide fundamental and useful information for genotyping UGT1A4 in the Japanese and probably Asian populations.

Arrhythmias, Cardiac↗

PubMed2005

Novel genetic polymorphisms in the NR3C1 (glucocorticoid receptor) gene in a Japanese population.

Glucocorticoid receptor, encoded by NR3C1, is a transcriptional regulator of many drug metabolizing enzymes and anti-inflammatory molecules. In order to identify genetic variations of the NR3C1 gene, genomic DNA from 265 Japanese individuals was sequenced. Fifty genetic polymorphisms were identified, including 32 novel ones [3 were in coding exons, 17 in the introns, 4 in the 5'-untranslated region (UTR), and 8 in the 5'-flanking region]. The novel nonsynonymous variation was 420G>T (Lys140Asn), and the allele frequency was 0.004. We did not detect any nonsynonymous polymorphism reported previously in other races, including a relatively frequent SNP Asn363Ser found in Caucasians and African-Americans. Thus, ethnic differences between Japanese and other races are suggested to exist in NR3C1.

Amino Acid Substitution↗

PubMed2005

Genetic polymorphisms of UGT1A6 in a Japanese population.

Thirteen single nucleotide polymorphisms (SNPs), including 6 novel ones, were found in exon 1 and its flanking region of UDP-glucuronosyltransferase (UGT) 1A6 from 195 Japanese subjects. Several novel SNPs were identified, including 269G>A (R90H), 279A>G (S93S), and 308C>A (S103X) in exon 1, and IVS1+109C>T, IVS1+120A>G, and IVS1+142C>T in the intron downstream of exon 1. Among these SNPs, 308C>A confers termination of translation at codon 103, resulting in the production of an immature protein that probably lacks enzymatic activity. The allele frequencies were 0.003 for all the 6 SNPs. In addition, the 3 known nonsynonymous SNPs were detected: 19T>G (S7A), 541A>G (T181A), and 552A>C (R184S) with frequencies of 0.226, 0.218, and 0.226, respectively. High linkage disequilibrium was observed among 19T>G (S7A), 315A>G (L105L), 541A>G (T181A), 552A>C (R184S), and IVS1+130G>T, as reported in Caucasian and African-American populations. Then, 11 haplotypes in UGT1A6 were estimated. The novel nonsynonymous variant, 269A or 308A, was shown to be located on the same DNA strand together with 19G, 315G, 541G, 552C, and IVS1+130T. Our results provide fundamental and useful information for genotyping UGT1A6 in the Japanese, and probably Asian populations.

Asian People↗

PubMed2004

Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma.

BACKGROUND: The goal of the current study was to evaluate the objective response rate and toxicity associated with the oral fluoropyrimidine S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) in patients with previously untreated metastatic colorectal carcinoma. METHODS: Thirty-eight patients were enrolled in the study. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14-day rest period. Treatment was repeated every 6 weeks unless disease progression was observed. RESULTS: A combined total of 173 courses of S-1 were administered to the 38 enrolled patients. The median number of courses administered to a given patient was 3.5 (range, 1-18). Although no patient exhibited a complete response to treatment, 15 had partial responses (response rate, 39.5%; 95% confidence interval, 24.0-56.6%). In addition, 5 patients had minor responses, and 14 had stable disease. Four patients were found to have progressive disease after two courses of treatment. The median survival time was 358 days (95% confidence interval, 305-490 days), and the 1-year survival rate was 47.4%. The most common adverse reactions included myelosuppression and gastrointestinal toxicity; most cases involved Grade 1 or 2 toxicity, but Grade 3 toxicities (anemia [7.9% of patients], neutropenia [5.3% of patients], diarrhea [2.6% of patients], and abnormal bilirubin levels [7.9% of patients]) also were noted. Neither Grade 4 toxicity nor treatment-related death was observed during the study. CONCLUSIONS: Orally administered S-1 is active against metastatic colorectal carcinoma and has an acceptable toxicity profile. This promising agent has the potential to become a valuable chemotherapeutic option.

Adenocarcinoma↗

PubMed2004

Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population.

In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A4 in a Japanese population, the distal enhancer and proximal promoter regions, all exons, and the surrounding introns were sequenced from genomic DNA of 416 Japanese subjects. We found 24 SNPs, including 17 novel ones: two in the distal enhancer, four in the proximal promoter, one in the 5'-untranslated region (UTR), seven in the introns, and three in the 3'-UTR. The most common SNP was c.1026+12G>A (IVS10+12G>A), with a 0.249 frequency. Four non-synonymous SNPs, c.554C>G (p.T185S, CYP3A4(*)16), c.830_831insA (p.E277fsX8, (*)6), c.878T>C (p.L293P, (*)18), and c.1088 C>T (p.T363M, (*)11) were found with frequencies of 0.014, 0.001, 0.028, and 0.002, respectively. No SNP was found in the known nuclear transcriptional factor-binding sites in the enhancer and promoter regions. Using these 24 SNPs, 16 haplotypes were unambiguously identified, and nine haplotypes were inferred by aid of an expectation-maximization-based program. In addition, using data from 186 subjects enabled a close linkage to be found between CYP3A4 and CYP3A5 SNPs, especially among the SNPs at c.1026+12 in CYP3A4 and c.219-237 (IVS3-237, a key SNP site for CYP3A5(*)3), c.865+77 (IVS9+77) and c.1523 in CYP3A5. This result suggested that CYP3A4 and CYP3A5 are within the same gene block. Haplotype analysis between CYP3A4 and CYP3A5 revealed several major haplotype combinations in the CYP3A4-CYP3A5 block. Our findings provide fundamental and useful information for genotyping CYP3A4 (and CYP3A5) in the Japanese, and probably Asian populations.

Cytochrome P-450 CYP3A↗

PubMed2004

Retrospective analysis of clinical results and predictors of response in chemo-naive patients with advanced gastric cancer treated with S-1, an oral fluoropyrimidine derivative, as single-agent chemotherapy.

BACKGROUND: Despite the fact that there are only a few reports of phase II studies, S-1 is widely used in single-agent or combination therapies for patients with advanced gastric cancer in Japan. We retrospectively analyzed the effectiveness of S-1 as single-agent chemotherapy for patients with advanced gastric cancer. METHODS: A total of 119 patients with advanced or recurrent gastric cancer were treated with S-1 as first-line monochemotherapy from September 1999 to March 2003 at the National Cancer Center Hospital. S-1 was administered orally twice daily, at a standard dose of 80 mg/m2 per day for 28 days, followed by a 14-day rest. RESULTS: One hundred and eleven patients were analyzed retrospectively. The overall response rate was 26.1% (29/111; 95% confidence interval [CI], 17.8% to 34.1%). Median time to progression and median overall survival were 141 days (95% CI, 108 to 175 days) and 378 days (95% CI, 310 to 447 days), respectively. The response rate of ascites, according to the Japanese classification of gastric carcinoma, was 36.8% (14/38; 95% CI, 25.4% to 56.6%). Among all of the pretreatment variables examined, hemoglobin level and the presence of lymph node metastasis were related to the response. CONCLUSION: Single-agent chemotherapy of S-1 for chemo-naive patients with advanced gastric cancer was modestly effective and well-tolerated in the outpatient setting.

Administration, Oral↗

PubMed2004

Phase I/II study of irinotecan, 5-fluorouracil, and l-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer.

BACKGROUND: A combination of irinotecan 125 mg/m2, 5-fluorouracil (5-FU) 500 mg/m2, and leucovorin (LV) 20 mg/m2 (Saltz regimen; treatment on days 1, 8, 15, and 22 every 6 weeks) is widely used for the treatment of metastatic colorectal cancer. A modified schedule with chemotherapy on days 1 and 8 of a 21-day cycle was recommended in 2001 because of early treatment-related mortality. We conducted a phase I/II study of this modified Saltz regimen as first-line therapy in Japanese patients with metastatic colorectal cancer to assess the maximum tolerated dose (MTD) and the recommended dose of 5-FU when given with fixed doses of l-LV and irinotecan, and to evaluate the efficacy and the feasibility of this regimen. METHODS: Irinotecan, 5-FU, and l-LV were administered on days 1 and 8 of a 21-day cycle. Irinotecan 100 mg/m2 was given intravenously over the course of 90 min on day 1, followed by l-LV 10 mg/m2, and then 5-FU. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2). If neither level met the criteria for the MTD, the recommended dose was defined as level 2, and dose escalation was discontinued, because the maximum approved weekly dose of irinotecan alone in Japan is 100 mg/m2 and the dose of 5-FU in the original Saltz regimen was 500 mg/m2. RESULTS: One patient had grade 4 neutropenia with fever at level 1, and four patients had grade 3 neutropenia at level 2. There was no treatment-related death. Level 2 did not meet the criteria for the MTD. The relative dose intensities of the first five cycles were 91% for both 5-FU and irinotecan at level 1 and 86% for 5-FU and 93% for irinotecan at level 2. The response rates were 58% for all patients, and 69% for patients at level 2. CONCLUSION. Our results confirm that the modified Saltz regimen is safe and efficacious for Japanese patients. The recommended doses for phase II studies are irinotecan 100 mg/m2, 5-FU 500 mg/m2, and l-LV 10 mg/m2.

Adenocarcinoma↗