In Vitro and In Vivo Studies of Drug-Releasing Poly(amino acids)

1985 ◽  
Vol 446 (1 Macromolecule) ◽  
pp. 67-75 ◽  
Author(s):  
JAMES M. ANDERSON
Keyword(s):  
Blood ◽  
2010 ◽  
Vol 116 (4) ◽  
pp. 603-613 ◽  
Author(s):  
Christian Wichmann ◽  
Yvonne Becker ◽  
Linping Chen-Wichmann ◽  
Vitali Vogel ◽  
Anna Vojtkova ◽  
...  

Abstract RUNX1/ETO, the fusion protein resulting from the chromosomal translocation t(8;21), is one of the most frequent translocation products in acute myeloid leukemia. Several in vitro and in vivo studies have shown that the homo-tetramerization domain of ETO, the nervy homology region 2 (NHR2), is essential for RUNX1/ETO oncogenic activity. We analyzed the energetic contribution of individual amino acids within the NHR2 to RUNX1/ETO dimer-tetramer transition and found a clustered area of 5 distinct amino acids with strong contribution to the stability of tetramers. Substitution of these amino acids abolishes tetramer formation without affecting dimer formation. Similar to RUNX1/ETO monomers, dimers failed to bind efficiently to DNA and to alter expression of RUNX1-dependent genes. RUNX1/ETO dimers do not block myeloid differentiation, are unable to enhance the self-renewal capacity of hematopoietic progenitors, and fail to induce leukemia in a murine transplantation model. Our data reveal the existence of an essential structural motif (hot spot) at the NHR2 dimer-tetramer interface, suitable for a molecular intervention in t(8;21) leukemias.


1994 ◽  
Vol 266 (1) ◽  
pp. R158-R163 ◽  
Author(s):  
Q. F. Huang ◽  
A. Gebrewold ◽  
A. Zhang ◽  
B. T. Altura ◽  
B. M. Altura

Recently, attention has been drawn to the possibility that excitatory amino acids (EAAs) may play an important role in the pathogenesis of hypoxic-ischemic neuronal injury. Exaggerated release of EAAs and excessive stimulation of N-methyl-D-aspartate (NMDA) receptors and other EAA receptors have been suggested to contribute to neuronal death in ischemia and anoxia. A number of in vitro and in vivo experimental studies have shown that EAA-receptor antagonists exert a protective effect on the brain after cerebral ischemia. Because neurons are in close apposition to small intracerebral vessels, synaptically released EAAs might also regulate small blood vessel function. With the use of quantitative television microscopic observations, in vivo studies were undertaken on pial arterioles of rats. Perivascular administration of cumulative doses (10(-7)-10(-2) M) of L-glycine, L-glutamate, L-aspartate, and NMDA on the pial microvessels resulted in concentration-dependent constriction of pial arterioles (5-30% decreases in diameter) and cerebrovasospasm; the relative order of potency was aspartate > NMDA > glycine > glutamate. High concentrations of EAAs often resulted in rupture of postcapillary venules. No amine or opiate antagonist or cyclooxygenase inhibitor prevented or attenuated the effects of these putative EAAs. EAA-induced constriction and spasm of pial arterioles as well as rupture of venules could, however, be blocked by the noncompetitive NMDA-receptor antagonist MK-801 and by Mg2+. MK-801 also produced a concentration-dependent relaxation on normal pial arterioles. These results are compatible with the idea that a specific NMDA-receptor complex (RC) exists in rat cortical microvessels, which subserves vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)


2019 ◽  
Vol 26 (3) ◽  
pp. 446-464 ◽  
Author(s):  
Vadim S. Pokrovsky ◽  
Olga E. Chepikova ◽  
Denis Zh. Davydov ◽  
Andrey A. Zamyatnin Jr ◽  
Alexander N. Lukashev ◽  
...  

Background:Amino acids are essential components in various biochemical pathways. The deprivation of certain amino acids is an antimetabolite strategy for the treatment of amino acid-dependent cancers which exploits the compromised metabolism of malignant cells. Several studies have focused on the development and preclinical and clinical evaluation of amino acid degrading enzymes, namely L-asparaginase, L-methionine γ-lyase, L-arginine deiminase, L-lysine α-oxidase. Further research into cancer cell metabolism may therefore define possible targets for controlling tumor growth.Objective:The purpose of this review was to summarize recent progress in the relationship between amino acids metabolism and cancer therapy, with a particular focus on Lasparagine, L-methionine, L-arginine and L-lysine degrading enzymes and their formulations, which have been successfully used in the treatment of several types of cancer.Methods:We carried out a structured search among literature regarding to amino acid degrading enzymes. The main aspects of search were in vitro and in vivo studies, clinical trials concerning application of these enzymes in oncology.Results:Most published research are on the subject of L-asparaginase properties and it’s use for cancer treatment. L-arginine deiminase has shown promising results in a phase II trial in advanced melanoma and hepatocellular carcinoma. Other enzymes, in particular Lmethionine γ-lyase and L-lysine α-oxidase, were effective in vitro and in vivo.Conclusion:The findings of this review revealed that therapy based on amino acid depletion may have the potential application for cancer treatment but further clinical investigations are required to provide the efficacy and safety of these agents.


2001 ◽  
Vol 5 (8) ◽  
pp. 645-651
Author(s):  
M. Peeva ◽  
M. Shopova ◽  
U. Michelsen ◽  
D. Wöhrle ◽  
G. Petrov ◽  
...  
Keyword(s):  

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S198-S198
Author(s):  
Joseph R Meno ◽  
Thien-son K Nguyen ◽  
Elise M Jensen ◽  
G Alexander West ◽  
Leonid Groysman ◽  
...  

1994 ◽  
Vol 72 (06) ◽  
pp. 942-946 ◽  
Author(s):  
Raffaele Landolfi ◽  
Erica De Candia ◽  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Armando Antinori ◽  
...  

SummarySeveral “in vitro” and “in vivo” studies indicate that heparin administration may affect platelet function. In this study we investigated the effects of prophylactic heparin on thromboxane (Tx)A2 biosynthesis “in vivo”, as assessed by the urinary excretion of major enzymatic metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2. Twenty-four patients who were candidates for cholecystectomy because of uncomplicated lithiasis were randomly assigned to receive placebo, unfractionated heparin, low molecular weight heparin or unfractionaed heparin plus 100 mg aspirin. Measurements of daily excretion of Tx metabolites were performed before and during the treatment. In the groups assigned to placebo and to low molecular weight heparin there was no statistically significant modification of Tx metabolite excretion while patients receiving unfractionated heparin had a significant increase of both metabolites (11-dehydro-TxB2: 3844 ± 1388 vs 2092 ±777, p <0.05; 2,3-dinor-TxB2: 2737 ± 808 vs 1535 ± 771 pg/mg creatinine, p <0.05). In patients randomized to receive low-dose aspirin plus unfractionated heparin the excretion of the two metabolites was largely suppressed thus suggesting that platelets are the primary source of enhanced thromboxane biosynthesis associated with heparin administration. These data indicate that unfractionated heparin causes platelet activation “in vivo” and suggest that the use of low molecular weight heparin may avoid this complication.


2020 ◽  
Vol 72 (5) ◽  
Author(s):  
Mario Fadin ◽  
Maria C. Nicoletti ◽  
Marzia Pellizzato ◽  
Manuela Accardi ◽  
Maria G. Baietti ◽  
...  
Keyword(s):  

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