Response of quiescent and total tumor cells in solid tumors to neutrons with various cadmium ratios

Purpose: Response of quiescent (Q) and total tumor cells in solid tumors to neutron irradiation with three different cadmium (Cd) ratios was examined. The role of Q cells in tumor control was also discussed.Methods and Materials: C3H/He mice bearing SCC VII tumors received continuous administration of 5-bromo-2′-deoxyuridine (BrdU) for 5 days using implanted mini-osmotic pumps to label all proliferating (P) cells. Thirty minutes after intraperitoneal injection of sodium borocaptate-¹⁰B (BSH), or 3 h after oral administration of dl-p-boronophenylalanine-¹⁰B (BPA), the tumors were irradiated with neutrons, or those without ¹⁰B-compounds were irradiated with gamma rays. This neutron irradiation was performed using neutrons with three different cadmium (Cd) ratios. The tumors were then excised, minced, and trypsinized. The tumor cell suspensions were incubated with cytochalasin-B (a cytokinesis-blocker), and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. The MN frequency in total (P + Q) tumor cells was determined from tumors that were not pretreated with BrdU. The sensitivity to neutrons was evaluated in terms of the frequency of induced micronuclei in binuclear tumor cells (MN frequency).Results: Without ¹⁰B-compounds, the MN frequency in Q cells was lower than that in the total cell population. The sensitivity difference between total and Q cells was reduced by neutron irradiation. Relative biological effectiveness (RBE) of neutrons compared with gamma rays was larger in Q cells than in total cells, and the RBE values for low-Cd-ratio neutrons tended to be larger than those for high-Cd-ratio neutrons. With ¹⁰B-compounds, MN frequency for each cell population was increased, especially for total cells. This increase in MN frequency was marked when high-Cd-ratio neutrons were used. BPA increased the MN frequency for total tumor cells more than BSH. Nevertheless, the sensitivity of Q cells treated with BPA was lower than that in BSH-treated Q cells. This tendency was clearly observed in high-Cd-ratio neutrons.Conclusion: From the viewpoint of enhancing the Q-cell sensitivity, tumors should be irradiated with high-Cd-ratio neutrons after BSH administration. However, normal tissue reaction remains to be examined because of its low tumor-to-normal tissue and tumor-to-blood biodistribution ratios.     

The local spread of lower bile duct cancer: evaluation by thin-section helical CT

This study illustrates the local spread of lower bile duct cancer with thin-section helical CT in correlation with the surgical and pathological findings. Pathologically, 16 patients had pancreatic invasion, 4 had small bowel mesentery invasion, 7 had extrapancreatic nerve plexus invasion, and 3 patients had vascular invasion. On thin-section helical CT, pancreatic invasion was correlated to the clarity or non-clarity of the bile duct mass-pancreas border and the presence of an intrapancreatic mass. Cases with small bowel mesentery and extrapancreatic nerve plexus invasion showed mass or stranding around the superior mesenteric artery and/or inferior pancreatoduodenal artery. Vascular invasion was seen as tumor contiguity to these vessels. Received: 28 September 1998; Revised: 30 December 1998; Accepted: 2 April 1999     

Spontaneous closure of ventricular septal defects followed up from <3 months of age

BACKGROUND: This study evaluates the incidence and timing of spontaneous closure (SC) of ventricular septal defect (VSD) using Doppler color flow mapping. METHODS: A total of 225 infants (mean age 30 days) were diagnosed with uncomplicated VSD: 31 (14%) subpulmonary VSD, 159 (70%) perimembranous, and 35 (16%) muscular. The patients were divided into two groups according to the presence or absence of congestive heart failure (CHF). SC was confirmed with color Doppler. RESULTS: Surgical closure was performed in 59 patients (26%). SC occurred in 107 patients (48%); three (10%) of 31 with subpulmonary VSD, 75 (47%) of 159 with perimembranous VSD, and 29 (83%) of 35 with a muscular VSD. Average age at SC was 19 months. In three SC patients with a subpulmonary VSD, there was no aortic valve prolapse and no aortic regurgitation. SC occurred in 96% of SC patients with a perimembranous VSD by the age of 6 years, and in 93% of those with a muscular VSD by the age of 3 years. In patients without CHF, the rate of SC was 72%; 23% in subpulmonary VSD, 74% in perimembranous, and 85% in muscular. SC occurred in only 23% of patients with a perimembranous VSD with CHF. Mean age at the final examination was 6.9 years in 59 patients with a VSD remaining open, and 63% of patients with a perimembranous VSD remaining open had an aneurysm of the ventricular membranous septum. CONCLUSIONS: The SC rate of VSD by mean age of 6.9 years was 48%, but it was 72% in patients without CHF. In patients with CHF, SC was seen only in patients with a perimembranous VSD. The rate of SC was 10% in subpulmonary VSD. The authors contend that SC probably occurred by growth of muscular septum surrounding VSD. Muscular VSD spontaneously closed earlier than perimembranous VSD.     

In vitro metabolism of the calmodulin antagonist DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) by human liver microsomes: involvement of cytochromes p450 in atypical kinetics and potential drug interactions.

Human cytochrome P450 (P450) isozyme(s) responsible for metabolism of the calmodulin antagonist 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e) and kinetic profiles for formation of its six primary metabolites [M3, M5, M6, M7, M8, and DY-9836 (3-[2-[4-(3-chloro-2-methylphenyl)piperazinyl]ethyl]-5,6-dimethoxyindazole)] were identified using human liver microsomes and recombinant P450 enzymes. In vitro experiments, including an immunoinhibition study, correlation analysis, and reactions with recombinant P450 enzymes, revealed that CYP3A4 is the primary P450 isozyme responsible for the formation of the DY-9760e metabolites, except for M5, which is metabolized by CYP2C9. Additionally, at clinically relevant concentrations, CYP2C8 and 2C19 make some contribution to the formation of M3 and M5, respectively. The formation rates of DY-9760e metabolites except for M8 by human liver microsomes are not consistent with a Michaelis-Menten kinetics model, but are better described by a substrate inhibition model. In contrast, the enzyme kinetics for all metabolites formed by recombinant CYP3A4 can be described by an autoactivation model or a mixed model of autoactivation and biphasic kinetics. Inhibition of human P450 enzymes by DY-9760e in human liver microsomes was also investigated. DY-9760e is a very potent competitive inhibitor of CYP2C8, 2C9 and 2D6 (Ki 0.25-1.7 microM), a mixed competitive and noncompetitive inhibitor of CYP2C19 (Ki 2.4 microM) and a moderate inhibitor of CYP1A2 and 3A4 (Ki 11.4-20.1 microM), suggesting a high possibility for human drug-drug interaction.