No effects of chlorophyllin on IQ (2-amino-3-methylimidazo[4,5-f]-quinoline)-genotoxicity and -DNA adduct formation in Drosophila

Previously we demonstrated that chlorophyllin suppressed the genotoxicities of many carcinogens. However, the genotoxicity of IQ (2-amino-3-methylimidazo[4,5-f]quinoline), a carcinogenic heterocyclic amine, was not suppressed in Drosophila. On the contrary, it has been reported that chrolophyllin suppressed the genotoxicity of IQ in rodents, rainbow trout and Salmonella. We demonstrated that the chlorophyllin-induced suppression of MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline)-genotoxicity was associated with a decrease in MeIQx-DNA adduct formation in Drosophila larval DNA. MeIQx represents another type of heterocyclic amine and is similar to IQ in structure. In this study we utilized (32)P-postlabeling to examine whether chlorophyllin reduced IQ-DNA adduct formation in Drosophila DNA in the same way as MeIQx. The results revealed that the formation of IQ-DNA adducts was unaffected by treatment with chlorophyllin. This was consistent with the absence of any inhibitory effect on genotoxicity as observed in the Drosophila repair test. These results suggest that IQ-behavior in Drosophila is not affected by chlorophyllin, indicating that the process of IQ-DNA adduct formation followed by expression of genotoxicity in Drosophila may be different from that in other organisms.     

Transient inhibition of cyp3a in rats by star fruit juice.

Star fruit juice is a potent in vitro inhibitor of CYP3A; however, few reports are available on the inhibition of CYP3A activities by star fruit juice in vivo. Therefore, in this study, we investigated the CYP3A-mediated star fruit-drug interaction in vivo. The effect of star fruit juice on carbamazepine pharmacokinetics was examined in rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.3-fold greater when star fruit juice (2 ml) was orally administered 1 h before the oral administration of carbamazepine (50 mg/kg). In contrast, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the administration of star fruit juice. These results suggest that star fruit juice impairs the function of enteric CYP3A, but not of hepatic CYP3A. In addition, we evaluated the time course of recovery of CYP3A activity that was reduced after the treatment with star fruit juice. The inhibition by star fruit juice was recovered within approximately 24 h. These data suggest that the effect of star fruit juice is mainly reversible and transient. Thus, we discovered that star fruit juice alters the carbamazepine pharmacokinetics in rats.     

Helicobacter pylori-negative / API2-MALT1 translocation-negative low-grade MALT lymphoma

A 71-year-old man with a Helicobacter pylori infection-negative and API2-MALT1 translocation-negative extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type of the stomach has been followed conservatively for over 5 years. The lesion has shown no major morphological changes or malignant progression into a diffuse large-cell type during the time course. The absence of genetic translocation of API2-MALT1 was confirmed with fluorescence in situ hybridization (FISH). The prognosis of H. pylori-negative and API2-MALT1 translocation-negative low-grade MALT lymphoma is unknown, and a standard treatment for such lymphoma has yet to be defined. The case of MALT lymphoma negative for both of the above factors that we report has shown no obvious rapid progression or malignant change over the long-term course. Although curative operation and/or chemoradiotherapy should still be discussed as the treatment of choice, the treatment of this type of lymphoma must be carefully determined on a case-by-case basis, according to its biological status and prognosis.     

Combined chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF), and radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)

We evaluated the recommend dose and efficacy of chemotherapy (CTx) and concurrent chemoradiotherapy (ConcCRTx) with docetaxel (DOC), cisplatin (CDDP) and 5-FU (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients underwent 2 cycles of chemotherapy with TPF. In ConcCRTx, radiation was targeted to begin on Day 1. We compared the efficacy of ConcCRTx and induction chemotherapy followed by radiation (CTx followed by RTx) with TPF. In CTx followed by RTx, radiation was targeted to begin 21 days after the end of CTx. The recommend dose of CTx with TPF was DOC 60 (Day 1), CDDP 70 (Day 4) and 5 FU 750 (Day 1-5) mg/ m2/ day and overall response rate of CTx with TPF was 95%. The recommended dose of ConcCRTx was DOC 50 (Day 1), CDDP 60 (Day 4) and 5-FU 600 (Day 1-5) mg/ m2/ day. Overall response rate of ConcCRTx and CTx followed by RTx with TPF were both 100%, and CR rate of them were 87% and 84% (p > 0.05). One-year survival rate of them were 69% and 95% (p < 0.05). More patients had distant metastasis in CTx followed by RTx than in ConcCRTx. Toxicity, such as mucositis, leukocytopenia and neutropenia, was higher in ConcCRTx than in CTx followed by RTx.     

Clinicopathologic manifestations of early-onset endometrial cancer in Japanese women with a familial predisposition to cancer

AIM: The number of patients under 40 years of age with early-onset endometrial cancer is on the rise in Japan. Preservation of fertility in younger patients is a critical issue. In order to examine the clinical and pathological characteristics of these patients, cases of early-onset endometrial cancer at a single hospital were analyzed. METHODS: Seventy-four patients were diagnosed with endometrial cancer before age 40 and included in this study after obtaining informed consent. RESULTS: The clinical characteristics included a significantly higher prevalence of complications such as nulligravidity and nulliparity (P < 0.001). Pathologically, well-differentiated endometrial carcinoma was significantly more frequent (P = 0.011). The 5-year survival rate was high (98.7%). In regards to the relationship between clinicopathological features and grade of differentiation, the prevalence of G2 and G3 carcinoma was not significantly lower (P = 0.24) in patients with obesity. Although the frequency of G2 and G3 carcinoma was significantly higher in patients with a family history of cancer (P = 0.02), their 5-year survival rate was not significantly lower (100%). CONCLUSION: This study found that these two types of early-onset endometrial cancer are clinicopathologically different. In patients with a family history of cancer, their body mass index was lower, and the frequency of G2 and G3 carcinoma was significantly higher, but their 5-year disease-free survival rate was not significantly lower.     

Leukotriene C(4) enhances the contraction of porcine tracheal smooth muscle through the activation of Y-27632, a rho kinase inhibitor, sensitive pathway

1. An unsaturated fatty acid, leukotriene C(4) (LTC(4)), has a potent contractile effect on human airway smooth muscle, and has been implicated in the pathogenesis of human asthma. Using front-surface fluorometry with fura-PE3, the effect of LTC(4) on the intracellular Ca(2+) concentration ([Ca(2+)](i)) and tension were investigated in porcine tracheal smooth muscle strips. 2. The application of LTC(4) induced little or no contraction despite a small and transient increase in [Ca(2+)](i). In the presence of LTC(4), however, the contractions evoked by high K(+) depolarization or a low concentration of carbachol (CCh) were markedly enhanced without inducing any changes in the [Ca(2+)](i) levels, thus indicating that LTC(4) increases the Ca(2+) responsiveness of the contractile apparatus. This LTC(4)-induced increase in Ca(2+) responsiveness could partly be reproduced in the permeabilized preparation of tracheal smooth muscle strips. 3. The LTC(4)-induced enhancement of contraction was accompanied by an increase in myosin light chain (MLC) phosphorylation and was blocked by a rho kinase inhibitor (Y-27632), but not by either a PKC inhibitor (calphostin C) or a tyrosine kinase inhibitor (genistein). 4. These results indicated that, in porcine tracheal smooth muscle, LTC(4) enhances the contraction by increasing the Ca(2+) responsiveness of the contractile apparatus in a MLC phosphorylation dependent manner, possibly through the activation of the rho-rho kinase pathway.     

Pharmacologic study of intraperitoneal docetaxel in gastric cancer patients with peritoneal dissemination

This study was designed to evaluate the pharmacokinetics and toxicity of docetaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Eleven patients with peritoneal dissemination were entered into this trial. Patients were treated with 45 mg/m2 of i.p. docetaxel administration in 1 l of saline. Peak peritoneal concentration was 40.0 +/- 14.5 micrograms/ml and peritoneal concentration at 24 hours after drug administration was 4.3 +/- 3.9 micrograms/ml. The median pharmacokinetic advantage (AUC peritoneal/AUC plasma) was 515 (range 22-1, 770). Grade 2 and 3 toxicities included 5 episodes of diarrhea; 3 of abdominal pain; 3 of ascites; 2 of alopecia; and 1 of neutropenia. We conclude that intraperitoneal docetaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.