Inefficient double-strand DNA break repair is associated with increased fasciation in Arabidopsis BRCA2 mutants

BRCA2 is a breast tumour susceptibility factor with functions in maintaining genome stability through ensuring efficient double-strand DNA break (DSB) repair via homologous recombination. Although best known in vertebrates, fungi, and higher plants also possess BRCA2-like genes. To investigate the role of Arabidopsis BRCA2 genes in DNA repair in somatic cells, transposon insertion mutants of the AtBRCA2a and AtBRCA2b genes were identified and characterized. atbrca2a-1 and atbrca2b-1 mutant plants showed hypersensitivity to genotoxic stresses compared to wild-type plants. An atbrca2a-1/atbrca2b-1 double mutant showed an additive increase in sensitivity to genotoxic stresses compared to each single mutant. In addition, it was found that atbrca2 mutant plants displayed fasciation and abnormal phyllotaxy phenotypes with low incidence, and that the ratio of plants exhibiting these phenotypes is increased by γ-irradiation. Interestingly, these phenotypes were also induced by γ-irradiation in wild-type plants. Moreover, it was found that shoot apical meristems of the atbrca2a-1/atbrca2b-1 double mutant show altered cell cycle progression. These data suggest that inefficient DSB repair in the atbrca2a-1/atbrca2b-1 mutant leads to disorganization of the programmed cell cycle of apical meristems

Correlation of plasma concentration and adverse effects of bosutinib: standard dose or dose-escalation regimens of bosutinib treatment for patients with chronic myeloid leukemia

Abstract Purpose To investigate the exposure-toxicity relationship of bosutinib and to identify the target trough plasma concentration (C0). Methods The toxicity and C0 of bosutinib in Japanese chronic myeloid leukemia (CML) patients were monitored every 2 weeks for the first 3 months of treatment, and subsequently once a month during the 6 months after beginning 500 mg/day of standard dose (SD group, n = 10) or beginning 100 mg/day and increased by 100 mg every 2 weeks of dose escalation (DE group, n = 15). Results Nine of 10 patients (90%) in the SD group were not able to continue bosutinib therapy without interruption due to adverse events, compared to 2 patients (13.5%) in the DE group. The total duration of treatment interruption was 35 and 14 days in the SD and DE groups, respectively. The median time until liver dysfunction or diarrhea was day 28 and day 1 in the SD group, and day 53.5 and day 19 in the DE group, respectively. The cumulative dose of bosutinib was comparable between the SD and DE groups (51,700 vs. 53,550 mg, respectively). At 6 months, the median C0 was 63.7 ng/mL and 63.0 ng/mL in the SD and DE groups, respectively. Liver dysfunction (all grades) and diarrhea (> grade 2) were prevalent in quartile 4 of C0 (> 91.0 ng/mL), as calculated by the total C0 distribution. Conclusions The DE regimen was better suited to avoid treatment interruption. The daily dose of bosutinib might be adjusted based on target C0 to avoid adverse events by therapeutic drug monitoring in general practice

Synthesis and Evaluation of Topoisomerase I Inhibitors Possessing the 5,13-Dihydro-6H-benzo[6,7]indolo[3,2-c]quinolin-6-one Scaffold

Novel topoisomerase I inhibitors possessing the 5,13-dihydro- 6H-benzo[6,7]indolo[3,2-c]quinolin-6-one (BIQ) scaffold were designed and synthesized. This scaffold was constructed using sequential and regioselective functionalization of the pyrrole core through palladium-catalyzed cross-coupling, conventional electrophilic substitution, directed lithiation, and subsequent diphenylphosphoryl azide (DPPA)-mediated lactam ring construction. The obtained BIQs were evaluated for their topoisomerase I inhibitory activities and their antiproliferative activities in the panel of 39 human cancer cell lines established by the Japanese Foundation for Cancer Research (JFCR39)