Radiolabeled nucleoside analogs in cancer diagnosis and therapy

Radiolabeled nucleosides, specifically 5-iodo-2'-deoxyuridine (IUdR) radioiodinated with the Auger-electronemitting 123I or 125I, have been shown to produce extensive DNA damage in mammalian cell systems in vitro. Such nucleosides are cycle-dependent agents that are taken up by mitotically dividing cells in the S phase of the cell cycle. The degree of damage that occurs is related to the fact that these nucleosides bind covalently to DNA bringing the decaying Augerelectron-emitting radionuclide in close proximity to the genome. The use of these radiohalogenated nucleosides in vivo is associated with several problems. The first relates to their extremely short biologic half-life in blood (T1/2 of minutes in humans). The second involves achieving therapeutic ratios in tumor cells in the face of efficient hepatic dehalogenation. The third concerns the uptake of these radiopharmaceuticals by actively proliferating normal cell renewal systems, thus potentially causing toxic side effects. The fourth, one shared with other cycle-dependent drugs, relates to the matter of labeling the whole tumor cell population. To facilitate targeting to tumors, investigators have been examining the direct introduction of these agents into the targeted area or into an arterial blood supply that immediately precedes the target. For example, radiopharmaceutical administration could be intracavitary (bladder, spinal fluid, peritoneum), intralesional (brain tumor, breast mass) or intra-arterial (liver, pancreas). In all these situations, the following conditions must be met: (a) once within the vicinity of the tumor the agent can freely diffuse through the tissues and is selectively taken up by cancerous cells; (b) once the agent has left the target area it is converted quickly into a nontoxic form and/or excreted from the body; and finally, (c) the biologic behavior of the agent is not altered by repeated injections. We report herein our experience and that of others with [123I/125I/131I]IUdR in cultured cells, animal tumor-model systems, and patients. In vitro, DNA incorporation of 123I- and 125I-labeled IUdR leads to an exponential decrease in cell survival (no shoulder on the survival curve). However, the total number of decays needed to produce a given lethal effect with [123I]IUdR is approximately twice that required with [125I]IUdR. In vivo, the scintigraphic and antineoplastic capabilities of radioiodinated IUdR have been demonstrated in an intraperitoneal murine ovarian tumor model following intraperitoneal injection; in an intracerebral rat gliosarcoma model after intracranial administration; in an intrathecal rat gliosarcoma model after intrathecal infusion; and in a rat transitional cell bladder cancer model following intravesicular infusion. [123I]IUdR, [125I]IUdR, and/or [131I]IUdR have been administered to patients with brain, breast, colorectal, or gastrointestinal cancers (intratumorally); ovarian cancer (intraperitoneally); bladder cancer (intravesically); liver metastases from colorectal cancer (through the hepatic artery, permanent intra-arterial catheter). These studies have confirmed the observations made in animal models. The data indicate that 5-iodo-2'-deoxyuridine radiolabeled with an Auger electron emitter (123I or 125I) may be a useful agent for the scintigraphic diagnosis and/or therapy of neoplastic diseases that are accessible to direct radiopharmaceutical administration. This radiopharmaceutical should serve as a prototype for, and facilitate the development of, other radiolabeled nucleoside analogs. Further investigations are certainly warranted.     

The influence of advanced age on the outcome of assisted reproduction

This study investigates within-subject variations and associations of salivary viscosities and flow rates in a test panel of healthy adults. After several practice sessions, unstimulated and stimulated whole saliva samples were collected 5 times daily (at 0800, 1100, 1400, 1700, and 2000 h) from 30 university students. There was a significant within-subject variation in viscosity and flow rate of unstimulated saliva (P<0.001). Intra-item correlations were significantly different for salivary flow rates (r= 0.82 for unstimulated, r= 0.88 for stimulated, P< 0.001) and viscosity of unstimulated saliva (r= 0.54, P< 0.05), but viscosity of stimulated saliva was different in this respect. Our results indicate that there is a significant within-subject variation in viscosity of unstimulated saliva.     

Chronic hepatitis in children after liver transplantation: role of hepatitis C virus and hepatitis G virus infections

BACKGROUND/AIMS: Chronic graft hepatitis occurs in 20-30% adults after liver transplantation but the prevalence and causes in children are not known. In adults, hepatitis C virus infection is prevalent prior to transplantation and recurrent infection is a frequent cause of graft dysfunction. The significance of the recently described hepatitis G virus infection remains unproven. The aim of this study was to examine the role of hepatitis C virus and hepatitis G virus infection in chronic graft hepatitis after paediatric liver transplantation. METHODS: The prevalence of graft hepatitis and the role of hepatitis C virus and hepatitis G virus infections in 80 children after liver transplantation have been studied, with a median follow up of 4.4 years (range 0.4 to 10.7), and the persistence of hepatitis G infection in the presence of immunosuppression has been determined. RESULTS: Chronic graft hepatitis was diagnosed in 19/80 (24%) children and was most frequently seen in children transplanted for cryptogenic cirrhosis (71%). There was no significant difference in the prevalence of chronic hepatitis in those transplanted before or after donor anti-HCV screening. Hepatitis C infection occurred in three children transplanted prior to donor screening but in only one was associated with chronic hepatitis. Hepatitis G infection was found in 22/79 (28%) transplant recipients but was not associated with graft hepatitis. In 17/21 children hepatitis G infection persisted for a median of 5.2 years after transplantation. CONCLUSION: Chronic hepatitis occurred in 24% of children after liver transplantation, a similar prevalence to that in adults. Cryptogenic liver disease predisposed to graft hepatitis, but neither hepatitis C nor hepatitis G infection was associated. Hepatitis G virus caused a frequent and usually persistent infection after transplantation.     

Percutaneous transjejunal biliary intervention: 10-year experience with access via Roux-en-Y loops

Ancylostoma duodenale is still the dominant hookworm species in the Mediterranean area, India, China and Japan. In the present study, biopsied materials were taken from the small intestine of 30 patients infected only with A. duodenale and 12 cross matched controls. The results showed some pathological changes in severely infected cases. However, normal or insignificant changes were seen in the enzymatic activity of the intestinal mucosa.     

Uterine relaxation responses to calcitonin gene-related peptide and calcitonin gene-related peptide receptors decreased during labor in rats

OBJECTIVES: Our purpose was to investigate (1) whether uterine relaxation responses to calcitonin gene-related peptide are differentially regulated during pregnancy and labor, (2) the involvement of nitric oxide in smooth muscle relaxant action of calcitonin gene-related peptide in the rat uterus, (3) whether receptors for calcitonin gene-related peptide are expressed in rat uterus, and if so (4) whether the concentrations of these receptors are differently regulated during pregnancy and labor. STUDY DESIGN: Rats were killed on day 18 of gestation, at the time of spontaneous labor, or postpartum day 2. The uteri were removed for in vitro contractility measurements, nitric oxide production, and calcitonin gene-related peptide receptor binding assay. RESULTS: (1) Calcitonin gene-related peptide induced a dose-dependent relaxation in spontaneously contracting uterine strips from pregnant rats on day 18 of gestation; (2) the relaxation effects of calcitonin gene-related peptide on the uterus were decreased during spontaneous delivery at term and post partum compared with that during pregnancy; (3) calcitonin gene-related peptide-induced relaxation was inhibited by pretreatment of the uterine tissue with a calcitonin gene-related peptide receptor antagonist, calcitonin gene-related peptide(8-37); (4) nitric oxide synthesis inhibitor (N(G)-nitro-L-arginine methyl ester) and soluble guanylate cyclase inhibitor (LY83583) significantly decreased calcitonin gene-related peptide-induced relaxation of the rat uterus during pregnancy; (5) calcitonin gene-related peptide increased the uterine nitric oxide production in pregnant rats, and this increase was obliterated in the presence of calcitonin gene-related peptide(8-37); and (6) calcitonin gene-related peptide receptors are present in rat uterus, and the concentration of these receptors dramatically increases during pregnancy and decreases during labor at term. CONCLUSIONS: Calcitonin gene-related peptide inhibits uterine spontaneous contractions in rats during pregnancy but not during labor and post partum. The inhibitory effects of calcitonin gene-related peptide on uterine contractility appear to be modulated, at least in part, by the activation of nitric oxide generation in the rat uterus. Changes in calcitonin gene-related peptide receptors could contribute to the changes in calcitonin gene-related peptide-mediated uterine relaxation during pregnancy and labor.     

Isolation of translactone-containing triterpenes with thrombin inhibitory activities from the leaves of Lantana camara

Methanolic extracts prepared from the leaves of Lantana camara have been found to inhibit human thrombin. An assay, in which thrombin activity is measured as a function of clot formation from fibrinogen, was used to guide the fractionation and purification of five principal active constituents (1-5), which were all characterized as 5,5-trans-fused cyclic lactone-containing euphane triterpenes.     

Influence of receptor number on the stimulation by salmeterol of gene transcription in CHO-K1 cells transfected with the human beta2-adrenoceptor

We investigated the behavior of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APx), in potato tubers during storage at low temperature. SOD activity increased temporarily within 3 weeks and was higher at 1 degree C than at 20 degrees C. APx activity also increased more at low (1 degree C) than at higher temperatures (5 and 20 degrees C). The contents of ascorbic acid (AsA), which is the substrate of APx, decreased immediately within 3 weeks and then gradually decreased until 15 weeks. The activity of CAT, the other enzyme which can scavenge hydrogen peroxide, decreased once in the first six weeks and thereafter increased to 15 weeks. Thus, the enhancement of the active oxygen-scavenging system that was induced by low temperature in potato tubers could result not only in a decrease of AsA but also in combined increases in APx and CAT activity whose manners were different.