Hidenori Mori

Control of cell proliferation in cancer prevention

Control of cell proliferation is important for cancer prevention since cell proliferation has essential roles in carcinogenesis including the process of initiation and promotion. In rodent models for carcinogenesis, especially those for the carcinogenesis in digestive organs such as colon, liver or oral cavity, chemopreventive agents suppress carcinogen-induced hyperproliferation of cells in the target organs during the initiation as well as the postinitiation phases. Therefore, effective agents usually suppress cell proliferation and inhibit the occurrence of malignant lesions. Availability of new biomarkers for cell proliferation, apoptosis or telomerase activity could be promising. By combining the use of intermediate biomarkers including premalignant lesions such as aberrant crypt foci in the colon or enzyme-altered foci in the liver and cell proliferation, short-term screening of effective chemopreventive agents will be possible.

Use of multidetector row CT to evaluate the need for bronchial arterial embolization in hemoptysis patients.

Background: Bronchial artery (BA) embolization (BAE) is recommended as a minimally invasive therapy for hemoptysis, though some patients recover after only conservative treatment. Objectives: The purpose of our study was to assess the characteristics of BAs using multidetector row computed tomography (MDCT) and identify BAs requiring BAE without BA angiography (BAG). Methods: We retrospectively studied 41 patients and classified the visualized BAs into groups based on their BAE and bleeding statuses. Patients presenting with massive hemoptysis requiring emergency BAE were excluded. Patients presenting with persistent hemoptysis that was resistant to conservative treatment received BAE. Radiologists measured BA diameters at the ostium, bronchial bifurcation and pulmonary hilum, and also evaluated the degree of vascularization. Results: MDCT enabled visualization of 102 ostia and 96 traceable BAs. Among the participating patients, 13 had at least one ectopic origin. We obtained a good correlation between BAG and MDCT diameters (r = 0.709, p < 0.001). The diameters of BAs responsible for bleeding and receiving BAE were apparently larger in each measured segment than those that were not (p < 0.05). Moreover, the diameters of arteries receiving BAE remained largely unchanged from the origin to the hilum and through the mediastinum. BAs with low MDCT scores were significantly less likely to required BAE than those with high scores (p = 0.004), and in multiple logistic regression analysis, ostium diameter and bleeding status were independent predictive factors for BAE. Conclusions: Evaluation of BAs on MDCT could be useful for identifying the anatomical characteristics of bleeding-related BAs and determining whether BAE is indicated or whether conservative treatment is sufficient.

Genotoxicity of a variety of nitroarenes and other nitro compounds in DNA-repair tests with rat and mouse hepatocytes

Genotoxicity of a variety of nitroarenes and other compounds was examined in DNA-repair tests with rat or mouse hepatocytes. Out of 15 nitroarenes tested, 9 compounds, i.e., 1-nitropyrene, 1,3-dinitropyrene, 1,6-dinitropyrene, 1,8-dinitropyrene, 1-nitro-3-acetoxypyrene, 3-nitrofluoranthene, 2-nitrofluorene, 2,7-di-nitrofluorene and 5-nitroacenaphthene elicited positive response of DNA repair in the tests with rat and mouse hepatocytes. Among the positive chemicals, the DNA-repair level of the 3 dinitropyrene isomers was much higher than other nitroarenes. The results indicate that a number of nitroarenes are metabolically activated in the primary culture of rodent hepatocytes, and suggest potential carcinogenicity of 1-nitropyrene and 1-nitro-3-acetoxypyrene the carcinogenicity of which is either not clear or unknown. Of the other nitro compounds, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide as well as 4-nitroquinoline 1-oxide were clearly genotoxic in the assays with hepatocytes of both species. However, 5-nitro-2-furaldehyde semicarbazone was negative in both assays with hepatocytes of 2 species.

Effects of Fas-mediated liver cell apoptosis on diethylnitrosamine-induced hepatocarcinogenesis in mice

The present study was designed to investigate the effect of Fas-mediated liver cell apoptosis, induced by a hamster monoclonal antibody against mouse Fas antigen, on diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. DEN (10 μg g–1, intraperitoneally (i.p.)) was given to 15-day-old male C3H/HeJ mice. Three weeks after DEN treatment, Fas-mediated liver cell apoptosis induced by anti-Fas antibody resulted in a biphasic effect on induction of liver cell tumours, depending on dosage and time of antibody administration. Single or multiple treatment with high dose anti-Fas antibody (5 μg animal–1), induced gross liver cell damage and decreased the incidence of liver cell tumours in DEN-treated mice. In contrast, five treatments with low dose anti-Fas antibody (2 μg animal–1), induced dispersed localized liver cell damage and promoted the number of large-sized liver cell adenomas and hepatocellular carcinomas. These findings suggest that high dose anti-Fas antibody has a marked effect on the clearance of DEN-initiated liver cells, whereas repeated administration of low dose anti-Fas antibody promotes hepatocarcinogenesis. It is concluded that Fas-mediated liver cell apoptosis has a biphasic effect on hepatocarcinogenesis.

Polymerase Chain Reaction Positivity of Pneumocystis jirovecii During Primary Lung Cancer Treatment

OBJECTIVE When treating lung cancer, pneumocystic pneumonia is a life-threatening complication seen during chemotherapy. Polymerase chain reaction is used to detect its cause, Pneumocystis jirovecii, but polymerase chain reaction positives without pneumocystic pneumonia are sometimes seen. The purpose of this study was to assess the frequency of pneumocystic pneumonia during cancer treatment. METHODS Fifty induced sputum specimens and 4 bronchoalveolar lavage specimens collected from 50 patients with acute respiratory symptoms during anticancer therapy were retrospectively studied after classifying the patients into lung cancer (n = 29) and solid tumor (n = 21) groups. All of the patients in both groups had an interstitial shadow suspected of being pneumocystic pneumonia, and all had polymerase chain reaction tests. RESULTS Eleven of the 54 specimens were polymerase chain reaction positive, and 1 patient was clinically diagnosed with pneumocystic pneumonia. The incidence of polymerase chain reaction positivity in the lung cancer group was significantly higher than in the solid tumor group (31 vs. 5%; P = 0.03), and the incidence of subclinical pneumocystic pneumonia (29 vs. 5%; P = 0.059) also tended to be higher in that group. There were no significant biochemical differences between the two groups, irrespective of the polymerase chain reaction results. Among polymerase chain reaction-positive patients in the lung cancer group, the cumulative dose of corticosteroid administration tended to be higher than among the polymerase chain reaction-negative patients (P = 0.09). Following the polymerase chain reaction tests, nearly all polymerase chain reaction-positive patients without pneumocystic pneumonia received antipneumocystic agents, and none developed pneumocystic pneumonia. CONCLUSIONS Our findings suggest polymerase chain reaction positivity for P. jirovecii will be detected in a fraction of lung cancer patients. Although it is difficult to predict the need for administration of pneumocystic pneumonia treatment to subclinical pneumocystic pneumonia based on polymerase chain reaction and biochemical results, polymerase chain reaction-positive patients should be followed-up with antipneumocystic agents to ensure they are not at an early stage of pneumocystic pneumonia.

Effect of Intermittent Systemic Corticosteroid on Bone Metabolism in Bronchial Asthma Patients

The purpose of this study was to assess the effect on bone mineral density (BMD) of systemic corticosteroid (SCS) intermittently administered for rescue from asthmatic exacerbation. Through digital image processing and calculation of four other indices, BMD was compared in groups of asthmatic patients receiving inhaled corticosteroid (ICS) alone or ICS plus intermittent SCS. We defined SCS as intermittent administration of the equivalent of 1 mg/day prednisolone in the management of asthma exacerbations during the previous 1 year. Serum NTX, a bone resorption marker, was significantly higher (p = 0.02) in the SCS group than the ICS group. SCS had no effect on BMD, although the frequency of patients at “high-risk” for osteoporosis according to the Female Osteoporosis Self-assessment Tool for Asia (FOSTA) tended to be higher in the SCS group (35%) than in the ICS (28%) or control (10%) group. Because patients in the ICS group already had impaired respiratory function due to repeated asthma exacerbations, it was difficult to determine whether it was asthma itself or SCS that is the risk factor for osteoporosis. In addition, the response of biochemical markers of bone turnover to intermittent SCS remains unclear and likely differs from that elicited by high-dose, short-term, or continuous SCS. That said, relatively low-dose intermittent administration of SCS raised levels of bone resorption markers, which likely reflects altered bone metabolism. Taken together, these findings suggest that, without consideration of its effects on bone, SCS administration should be avoided.

The telomerase activities in several organs and strains of rats with ageing

Telomerase activity is known to be implicated both in cell immortalization and carcinogenesis. Telomerase activity has not been detected in most human somatic tissues. However, we previously confirmed that the activity is present both in methylazoxymethanol acetate-induced rat colonic adenocarcinoma and non-treated colonic mucosa, presumably indicating the tissue-specific activity of the enzyme in rats. To determine the standard activity of rat telomerase in various organs in relation to differences in sex, age and strain, we examined the activity by using the telomeric repeat amplification protocol (TRAP) assay. The testis, liver, and colon mucosa showed the activity. The brain had very low or negative activity in 5-week-old male rats of the F344, SD, Wistar, Donryu or ACI strains. Age (5-week-old and 9-month-old) or sex difference for the activity was not apparent in rats of these strains. In general, telomerase activity in the fetal brain, liver and kidney was stronger than in the adult organ. The telomerase activity of each organ was different from that of human. This difference may indicate that the rat has a specific mechanism for maintaining the telomeric repeats of the chromosome even in somatic tissues. The basic information resulting from this study may be useful for the study of the role of telomerase in tumorigenesis in animal experiment models.

Pharmacokinetics of consecutive oral moxifloxacin (400 mg/day) in patients with respiratory tract infection

A population pharmacokinetic analysis was performed to investigate the pharmacokinetics of moxifloxacin (400 mg) following a once-daily oral administration in 28 patients with respiratory tract infection disease. The maximum plasma concentration and the area under the plasma concentration–time curve were 3.97 µg/ml and 51.74 µg·h/ml, respectively; these values were nearly equivalent to those of healthy adult men. Two adverse drug reactions (nausea, vomiting) occurred, but both reactions were mild and nonserious and the patients recovered without treatment. The pharmacokinetic profile of moxifloxacin in Japanese patients with respiratory tract infection and an underlying disease should thus be considered safe and comparable with that in healthy adult men, and adjustment of dose may do not need for age, sex, body weight, or renal function.

Massive Hematuria from the Bilateral Upper Urinary Tract in a Patient Treated for Advanced Lung Cancer with Gefitinib

We report a case of gefitinib-induced bilateral upper urinary tract bleeding in an 82-year-old woman administered the drug daily for advanced non-small cell adenocarcinoma of the lung (T4N3M0). Hematuria is an uncommon adverse effect of gefitinib, and in most cases, the bleeding site is unknown. On the 44th day of oral gefitinib administration, the patient noted asymptomatic macroscopic bloody urine. Cystoscopy revealed bleeding from the bilateral ureteric orifices without hemorrhagic inflammation of the bladder. One week later, she was admitted complaining of severe abdominal pain, and her condition was found to be complicated by liver damage and renal dysfunction. We stopped gefitinib administration and started hydration and diuresis. Renal function and urine output soon recovered, and at the request of the patient, we restarted gefitinib, administering it every other day, which was sufficient to maintain antitumor activity and stabilize the disease. On the 41st day after restarting gefitinib, hematuria and proteinuria reappeared. We therefore stopped the gefitinib, and the patient was followed with supportive care. The patients autopsy findings denied organic urologic diseases. Instead, the reproducibility of the hematuria from the upper urinary system strongly suggests an unexpected gefitinib-related adverse effect.