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101.
Ribonuclease A variants with potent cytotoxic activity 总被引:1,自引:0,他引:1
Select members of the bovine pancreatic ribonuclease A (RNase A) superfamily are potent cytotoxins. These cytotoxic ribonucleases enter the cytosol, where they degrade cellular RNA and cause cell death. Ribonuclease inhibitor (RI), a cytosolic protein, binds to members of the RNase A superfamily with inhibition constants that span 10 orders of magnitude. Here, we show that the affinity of a ribonuclease for RI plays an integral role in defining the potency of a cytotoxic ribonuclease. RNase A is not cytotoxic and binds RI with high affinity. Onconase, a cytotoxic RNase A homolog, binds RI with low affinity. To disrupt the RI-RNase A interaction, three RNase A residues (Asp-38, Gly-88, and Ala-109) that form multiple contacts with RI were replaced with arginine. Replacing Asp-38 and Ala-109 with an arginine residue has no effect on the RI-RNase interaction. In addition, these variants are not cytotoxic. In contrast, replacing Gly-88 with an arginine residue yields a ribonuclease (G88R RNase A) that retains catalytic activity in the presence of RI and is cytotoxic to a transformed cell line. Replacing Gly-88 with aspartate also yields a ribonuclease (G88D RNase A) with a decreased affinity for RI and cytotoxic activity. The cytotoxic potency of onconase, G88R RNase A, and G88D RNase A correlate with RI evasion. We conclude that ribonucleases that retain catalytic activity in the presence of RI are cytotoxins. This finding portends the development of a class of chemotherapeutic agents based on pancreatic ribonucleases. 相似文献
102.
In order to ascertain the dynamic relationship between the extracellular glucose in upper skin layers and blood glucose, skin suction blisters were raised in six Type 1 diabetic patients during a three-step glucose clamp. Blister glucose closely paralleled venous glucose (mean of r = 0.998). However, in three patients blister glucose was constantly lower than plasma glucose and this appeared to be related to their slower formation of skin blisters. A substantial difference in skin blister suction time was noted among patients and it was found that suction time was linearly correlated to glycosylated haemoglobin (HbA1C) (n = 6, r = 0.865, p = 0.026). It is concluded that a non-invasive blood glucose monitoring system could be successfully based on measurement of alterations in skin glucose contents. 相似文献
103.
BM Léonard F Hétu L Busque M Gyger R Bélanger C Perreault DC Roy 《Canadian Metallurgical Quarterly》1998,91(1):331-339
The suppressor of Hairy-wing [SU(HW)] binding region disrupts communication between a large number of enhancers and promoters and protects transgenes from chromosomal position effects. These properties classify the SU(HW) binding region as an insulator. While enhancers are blocked in a general manner, protection from repressors appears to be more variable. In these studies, we address whether repression resulting from the Polycomb group genes can be blocked by the SU(HW) binding region. The effects of this binding region on repression established by an Ultrabithorax Polycomb group Response Element were examined. A transposon carrying two reporter genes, the yellow and white genes, was used so that repression and insulation could be assayed simultaneously. We demonstrate that the SU(HW) binding region is effective at preventing Polycomb group repression. These studies suggest that one role of the su(Hw) protein may be to restrict the range of action of repressors, such as the Polycomb group proteins, throughout the euchromatic regions of the genome. 相似文献
104.
105.
BACKGROUND: Nephrolithiasis may be an important consequence of indinavir therapy; however little has been published on the variation in incidence between different populations of patients or the possible mechanisms of calculus formation. OBJECTIVE: To examine variation in the incidence of indinavir-associated nephrolithiasis (IAN) in HIV-positive patients in relation to hemophilia and hepatitis C virus (HCV) infection. METHODS: Clinical data were abstracted retrospectively from the medical records of all adult patients treated with indinavir from September 1995 to September 1997. Occurrence of first IAN, defined as flank pain and hematuria after initiation of therapy, was analyzed in relation to hemophilia status and HCV infection. RESULTS: There were 17 episodes of IAN (22%) among 79 patients treated with indinavir. Of 10 patients with hemophilia, 50% developed IAN as compared with 17% of patients without hemophilia (P = 0.03). Median days to first IAN was 22 (range 7-110 days) for hemophiliacs and 156 (range 5-611 days) for those without hemophilia. Data for HCV status were available for 74 out of 79 patients: 10 out of 27 (37%) patients with HCV developed IAN compared with six out of 42 (14%) without HCV (P = 0.02). CONCLUSION: Overall incidence of IAN was higher than that previously reported and was significantly greater in hemophiliacs than in non-hemophiliacs. HCV may be a contributing factor. 相似文献
106.
BM Meiser P Uberfuhr A Fuchs D Schmidt M Pfeiffer D Paulus C Schulze S Wildhirt WV Scheidt C Angermann V Klauss S Martin H Reichenspurner E Kreuzer B Reichart 《Canadian Metallurgical Quarterly》1998,17(8):782-788
BACKGROUND: To compare the efficacy and safety of tacrolimus and cyclosporine in heart transplantation, this single-center, prospective, randomized, open-label clinical trial was undertaken. METHODS: Seventy-three adult patients were randomly assigned at the time of transplantation to receive either tacrolimus (n=43) or cyclosporine (n=30) as the primary immunosuppressant. Ten of the 43 patients in the tacrolimus group received the drug intravenously in the perioperative period; all other patients received only oral tacrolimus. RESULTS: With a mean follow-up of 27 months, patient survival rates (tacrolimus 83%, cyclosporine 81%) were similar. Fewer patients experienced acute rejection in the tacrolimus group (79%) than in the cyclosporine group (100%), but the difference was not statistically significant. The number of infections and dialysis and insulin requirements were similar for the 2 treatment groups, but the proportion of patients requiring multidrug antihypertensive regimens was lower in the tacrolimus group (12.5% vs 50.0% at month 6; p=.025). The interpatient variance in pharmacokinetic parameters in a subset of 10 patients was much higher after the first oral dose of tacrolimus than at steady-state (eg, first-dose time at which maximal concentration is reached (t(max)): 3.5+/-2.5h, steady-state t(max): 2.0+/-0.7h), and patients treated with intravenous tacrolimus (n=13) rather than oral tacrolimus (n=30) reached target concentrations faster and with less interpatient variability (eg, at day 0: 9.72+/-10.9 ng/mL intravenously vs 3.31+/-8.1 orally). CONCLUSIONS: Tacrolimus was associated with similar efficacy and safety profiles compared with cyclosporine. The higher interpatient variance in absorption associated with oral tacrolimus during the first few days after transplantation would suggest that intravenous tacrolimus should be used during the perioperative period. 相似文献
107.
108.
CS Dolman BM Mueller HN Lode R Xiang SD Gillies RA Reisfeld 《Canadian Metallurgical Quarterly》1998,4(10):2551-2557
Immunocytokines are antibody-cytokine fusion proteins that combine the unique targeting ability of antibodies with the multifunctional activities of cytokines to activate effector cells in the tumor microenvironment. Here, we demonstrate the therapeutic efficacy of a tumor-specific immunocytokine, huKS1/4-IL2, which effectively inhibited growth and dissemination of lung and bone marrow metastases of human prostate carcinoma in severe combined immunodeficient mice. This antitumor effect was specific and highly effective, irrespective of reconstitution of these mice with human lymphokine-activated killer cells. Survival times of mice treated with huKS1/4-IL2 were increased 4-fold as compared with animals treated with a mixture of the corresponding antibody and recombinant human interleukin-2 (rhIL2). A persistent antitumor response after treatment with the huKS1/4-IL2 immunocytokine in B, T, and natural killer cell-deficient severe combined immuodeficient-BEIGE mice, depleted of granulocytes, implies a major role for macrophages in this treatment effect. Our data demonstrate that immunocytokine-directed interleukin-2 therapy to tumor sites is an immunotherapeutic approach with potent effects against disseminated metastases of human prostate carcinoma and suggest that this treatment could be effective in an adjuvant setting for patients with minimal residual disease. 相似文献
109.
OBJECTIVE: A significant proportion of patients who undergo cardiac surgery or carotid endarterectomy appear to develop subtle cognitive deficits, with the occurrence of multiple cerebral microemboli documented by Doppler ultrasound during these procedures. We used an experimental multiple cerebral embolism model to test whether treatment with tirilazad (U74006F), a putative inhibitor of lipid peroxidation, would improve functional outcome after multiple brain emboli. DESIGN: Randomized, controlled trial. SETTING: Animal care facility procedure room. SUBJECTS: A total of 44 New Zealand White rabbits weighing 2 to 3.0 kg. INTERVENTIONS: Variable quantities of 125I-labeled 50-microns microspheres were injected via a carotid catheter to produce multifocal brain ischemia. Rabbits randomly received either: tirilazad (3 mg/kg i.v.) 5 mins before embolization (pretreatment), or 30 mins after embolization (posttreatment) followed by 1.5 mg/kg every 5 hrs x 3 doses. A third group received vehicle only (control) 5 mins before, followed by three doses every 5 hrs. MEASUREMENTS AND MAIN RESULTS: The animals were rated by a blinded observer at 18 hrs after ischemia and scored as either grossly abnormal/dead or normal. The animals were killed and the amount of microspheres in the brain that were required to produce abnormal function at 18 hrs was calculated for each group. To determine if tirilazad also modified leukocyte function during ischemia, neutrophil adhesion to laminin was determined at baseline and 18 hrs after ischemia using a myeloperoxidase assay. In this study, pretreatment, but not posttreatment with tirilazad produced a significant reduction in neurologic deficits. Tirilazad also attenuated postischemic increases in neutrophil adhesion. CONCLUSIONS: Tirilazad pretreatment reduces neurologic deficits from multiple cerebral emboli. This significant protective effect suggests that pretreatment with tirilazad may play a role in clinical situations where the risk of cerebral emboli is high, with changes in leukocyte adherence as a potential mechanism. 相似文献
110.
QY He AB Mason RC Woodworth BM Tam RT MacGillivray JK Grady ND Chasteen 《Canadian Metallurgical Quarterly》1997,36(48):14853-14860
Human serum transferrin N-lobe (hTF/2N) has four iron-binding ligands, including one histidine, one aspartate, and two tyrosines. The present report elucidates the inequivalence of the two tyrosine ligands (Tyr 95 and Tyr 188) on the metal-binding properties of hTF/2N by means of site-directed mutagenesis, metal release kinetics, and absorption and electron paramagnetic resonance (EPR) spectroscopies. When the liganding tyrosines were mutated individually to phenylalanine, the resulting mutant Y95F showed a weak binding affinity for iron and no affinity for copper, whereas, mutant Y188F completely lost the ability to bind iron but formed a stable complex with copper. Since other studies have demonstrated that mutations of the other two ligands, histidine and aspartate, did not completely abolish iron binding, the present findings suggest that the tyrosine ligand at position 188 is essential for binding of iron to occur. Replacement of Tyr 188 with phenylalanine created a favorable chemical environment for copper coordination but a fatal situation for iron binding. The positions of the two liganding tyrosines in the metal-binding cleft suggest a reason for the inequivalence. 相似文献