-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study is to investigate associations between allelic variations of ABCG2 and ABCB1 with skin toxicity, diarrhea, liver injury and interstitial lung disease (ILD) in gefitinib-treated patients. A prospective clinical study of 83 Japanese patients with non-small-cell lung cancer was performed. Polymorphic loci in ABCG2 and ABCB1 were genotyped, and their effects on gefitinib toxicities were evaluated. ABCG2 34G>A was statistically associated with occurrence of skin rash; 13 (42%) of the 32 patients with at least one variant ABCG2 34G>A allele (G/A and A/A) developed grade 2 or worse skin rash, whereas only 10 (19%) of 51 patients homozygous for the reference allele (G/G) for the wild-type sequence for both alleles did so (P=0.046). There was no significant association between severe toxicities and polymorphisms of ABCG2 421C>A nor ABCB1 3435C>T. The results suggested that ABCG2 34G>A would be useful for predicting grade 2 or worse skin rash.
Nagoya journal of medical science 02/2012; 74(1-2):133-40.
-
[show abstract]
[hide abstract]
ABSTRACT: This article focuses on pharmacogenetic associations between genetic polymorphism of uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene and irinotecan toxicity. Accumulating evidence provides support to the idea that determination of UGT1A1 polymorphisms before irinotecan treatment is clinically useful and important for predicting and avoiding related toxicities. On the basis of these backgrounds, the irinotecan label was updated in 2005 in the United States to provide pharmacogenetic information, and a dose reduction of irinotecan should be considered for patients known to be homozygous for the UGT1A1*28 allele when administered in combination with other agents or a single agent. The irinotecan/UGT1A1 issue and the development of molecular diagnostic testing are now to be translated into clinical practice.
Annals of the New York Academy of Sciences 12/2006; 1086:223-32. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This review focuses on a pharmacogenetic association between genetic polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan. Although many studies used pharmacokinetic parameters as surrogate measures for predicting clinical outcomes of irinotecan chemotherapy, they have not produced consistent evidence. On the other hand, genotyping results of UGT1A1 gene appear to predict severe adverse reactions more straightforward than the pharmacokinetic parameters or the phenotypes of the enzymatic activity. A case-control study of Japanese cancer patients revealed that those with the variant UGT1A1 alleles were at significantly higher risk of severe adverse reactions to irinotecan, suggesting that the genotyping strategy would be clinically useful. Nevertheless, clinical importance of the pharmacogenetic testing should differ for different patient groups and for different clinical situations. We need to keep this issue in mind in applying the pharmacogenetic evidence in clinical practice.
Investigational New Drugs 01/2006; 23(6):539-45. · 3.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate sequence effects on toxicity, tumor response and pharmacokinetics of docetaxel and carboplatin, together with a determination of the maximum-tolerated dose (MTD) and recommended dose for each schedule.
A total of 46 chemotherapy-naive patients with advanced non-small-cell lung cancer were randomized to receive docetaxel before (schedule A) or after (schedule B) carboplatin. The dose levels studied were [docetaxel (mg/m(2))/carboplatin (mg x min/ml)] 50/5, 60/5, 60/6, 60/7, and 70/6. Treatment cycles were repeated every 3 or 4 weeks unless disease progression or undue toxicity occurred.
Of the 46 patients, 44 were assessable for toxicity and received a total of 84 cycles. The major dose-limiting toxicity was neutropenia. When the docetaxel dose was 60 mg/m(2), the carboplatin MTD was deemed to be AUC 7 in both schedules. When the docetaxel dose was escalated to 70 mg/m(2), the carboplatin MTD was reached in schedule A, and the dose-limiting toxicity was not observed in schedule B. Tumor response was observed in 4 of 22 patients (18%) with schedule A and 8 of 19 (42%) with schedule B. Clearances of both drugs were not affected by sequence: 111.2+/-26.8 ml/min and 107.8+/-29.0 ml/min for carboplatin (P=0.69), and 26.7+/-8.3 l/h and 22.8+/-7.0 l/h for docetaxel (P=0.19) in schedules A and B, respectively.
Carboplatin AUC 6 followed by docetaxel 70 mg/m(2) was a favorable regimen for phase II study because of likely lower toxicity and a potentially higher response rate than the reverse sequence schedule. The mechanism of the sequence effects on toxicity and tumor response could not be explained by the pharmacokinetic interactions.
Cancer Chemotherapy and Pharmacology 07/2005; 55(6):552-8. · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Genetic polymorphism of the UDP-glucuronosyltransferase (UGT) 1A1 gene is associated with the decreased glucuronidation activity of an active metabolite of irinotecan, SN-38, and UGT1A1*28 has been shown as a predictive factor for irinotecan toxicity. The phenobarbital-responsive enhancer module (PBREM) of the UGT1A1 promoter region has been reportedly associated with the transcriptional activity of the gene. We investigated whether the polymorphism of PBREM (T-3279G) would affect inter-patient variations in sensitivity to irinotecan toxicity. The study population comprised 119 cancer patients who had received irinotecan. We reviewed their clinical records, including patient characteristics, and observed their toxicity levels following irinotecan infusion. Genotyping was performed by sequencing analyses. Logistic regression analyses were performed to assess the relationship between genotypes and irinotecan toxicity. We identified the homozygotes of the reference allele for T-3279G in 68 patients, the heterozygotes in 37, and the homozygotes for the variant in 14. Logistic regression analysis indicated a significant association between the homozygotes for T-3279G and the severe toxicity (odds ratio 5.80; 95% confidence interval 1.67-20.1). However, multivariate analysis, including the data of UGT1A1*28 polymorphism, revealed a diminution of the association due to a highly significant linkage disequilibrium between these polymorphisms. Our results suggest that a highly significant linkage disequilibrium exists between T-3279G and UGT1A1*28 polymorphisms, and that the variants of T-3279G and UGT1A1*28 cooperatively decrease transcriptional activity of the UGT1A1 promoter. The determination of T-3279G and UGT1A1*28 genotypes might be clinically useful in predicting severe irinotecan toxicity in cancer patients.
Pharmacogenetics and Genomics 02/2005; 15(1):35-41. · 3.48 Impact Factor
-
Clinical Chemistry 09/2004; 50(8):1479-80. · 7.91 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Irinotecan often causes unpredictably severe, occasionally fatal, toxicity involving leukopenia or diarrhea. It is converted by carboxyesterase to an active metabolite, SN-38, which is further conjugated and detoxified to SN-38-glucuronide by UDP-glucuronosyltransferase (UGT). We genotyped the UGT1A7 gene by direct sequencing analysis and polymerase chain reaction-restriction fragment length polymorphism in 118 cancer patients and 108 healthy subjects. All the patients had received irinotecan-containing chemotherapy and were evaluated to see whether the variant UGT1A7 genotype would increase the likelihood of severe toxicity of irinotecan consisting of grade 4 leukopenia and/or grade 3 or more diarrhea. Among the 26 patients with severe toxicity, the allele frequencies were 61.5% for UGT1A7 (*)1, 15.4% for UGT1A7 (*)2, and 23.1% for UGT1A7 (*)3. On the other hand, the frequencies were 63.6% for UGT1A7 (*)1, 15.8% for UGT1A7 (*)2, and 20.7% for UGT1A7 (*)3 among the 92 patients without severe toxicity. None of the 118 patients had UGT1A7 (*)4. Neither univariate analysis (odds ratio, 1.13; 95% confidential interval, 0.46 - 2.75) nor multivariate logistic regression analysis (odds ratio, 0.74; 95% confidential interval, 0.26 - 2.07) found any significant association between carrying at least one of the variant alleles and the occurrence of severe toxicity. The distribution of UGT1A7 genotypes in 108 healthy subjects was not significantly different from that in the patients (P = 0.99 and 0.86 for those with and without severe toxicity, respectively), but significantly less than that in Caucasians reported previously (P < 0.001). The results suggested that determination of UGT1A7 genotypes would not be useful for predicting severe toxicity of irinotecan.
Japanese journal of cancer research: Gann 06/2002; 93(5):591-7.
-
Mitsuo Sato,
Masahiko Ando,
Hironobu Minami,
Yuichi Ando, Maki Ando,
Masashi Yamamoto,
Shuzo Sakai,
Atsushi Watanabe,
Takuya Ikeda,
Yoshitaka Sekido,
Hideo Saka,
Kaoru Shimokata,
Yoshinori Hasegawa
[show abstract]
[hide abstract]
ABSTRACT: Purpose: To determine the maximum tolerated dose (MTD) of irinotecan combined with carboplatin, to evaluate its efficacy and toxicity for patients with lung cancer, and to examine its pharmacokinetics and pharmacodynamics. Methods: The dose of irinotecan was escalated from 40 mg/m2 per week in increments of 10 mg/m2. Carboplatin was fixed at 300 mg/m2. Multivariate regression models with an interaction term were used to evaluate synergistic pharmacodynamic interactions. Results: The MTD and recommended dose of irinotecan were 60 and 50 mg/m2, respectively. Dose-limiting toxicities were grade 4 neutropenia and grade 3 or 4 diarrhea. In phase II studies, response rates were 81.3% (95% confidence interval 61.8-100%) in 16 patients with small-cell lung cancer and 22.2% (2.7-41.8%) in 18 patients with non-small-cell lung cancer. Two patients (6%) experienced grade 4 neutropenia, thrombocytopenia, and grade 3 diarrhea. The area under the plasma concentration versus time curve (AUC) of carboplatin ranged from 2.87 to 9.31 mgmin/ml, with a median of 4.66 mgmin/ml. In pharmacodynamic analyses, the log-transformed surviving fraction in platelet count (SFp) showed a significant association with the AUC of carboplatin (P=0.010), while that in neutrophil count (SFn) was not significantly correlated with any pharmacokinetic parameter. The interaction term was not significant in either case. Conclusions: These results indicate that AUC-based dosing of carboplatin is still rational in combination chemotherapy. A more sensitive method for predicting life-threatening toxicities is needed, however, because traditional pharmacokinetic parameters were not adequate tools for identifying patients at high risk of severe neutropenia and diarrhea. This combination regimen has only modest activity, and further studies are necessary to evaluate a different dose schedule.
Cancer Chemotherapy and Pharmacology 11/2001; 48(6):481-487. · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Transbronchial needle aspiration (TBNA) is used most frequently to assess subcarinal nodes because of its technical ease.
We conducted a prospective observational clinical study to define the indications for TBNA use for subcarinal nodes (transcarinal needle aspiration, TCNA) related to the nodal size by computed tomography (CT) of the chest.
One hundred and eight consecutive patients with lung cancer underwent TCNA at the time of initial diagnostic bronchoscopy within a 22-month period.
TCNA was positive in 21 of the patients. Only 1 of 75 patients (1%) with subcarinal nodes less than 10 mm in short-axis diameter by CT had a positive result. TCNA for enlarged nodes, 10 mm or greater, had a high positive yield of 61% (20/33). The procedure provided the only evidence of unresectable non-small cell lung cancer (stage IIIA-N2 disease) in 3 patients and the sole pathological evidence for malignancy in 5 patients.
The high yield of positive TCNA results for enlarged subcarinal nodes contributes to the improvement of the overall diagnostic yield of bronchoscopy. We recommend that TCNA for enlarged subcarinal nodes on CT in patients with presumptive lung cancer should be performed routinely at the time of initial diagnostic bronchoscopy.
Respiration 71(5):523-7. · 2.26 Impact Factor
