scholarly journals Decitabine: A Historical Review of the Development Process of an Epigenetic Drug

2020 ◽  
Vol 7 ◽  
Author(s):  
Cihan Zamur ◽  
Uğur Topal
Keyword(s):  
Development Process ◽  
Historical Review ◽  
Low Doses ◽  
Combination Therapies ◽  
Action Mechanism ◽  
Epigenetic Effect ◽  
Epigenetic Drug ◽  
Patient Responses ◽  
High Doses

Decitabine (5-aza-2p-deoxycytidine) is a hypomethylation agent with a double-action mechanism, these are the reactivation of silenced genes; exhibiting differentiation at low doses and showing cytotoxicity at high doses. Decitabine was used as a classic anticancer drug in the original studies in the 1980s, 1500 to 2500 mg/m2 per cycle was the maximum clinically tolerated dose. The dosage was reassessed after a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylation) therapy was obtained, in about 1/20th of the previous doses (i.e., 'optimal biological' doses modulating hypomethylation). It has been found that decitabine (100 to 150 mg / m2 per cycle) can be used in patients with myelodysplastic syndromes (MDS) and other myeloid tumors, with manageable side effects. Combination therapies which amplify the epigenetic effect of decitabine will most likely improve the patient responses and allow it to be used in the treatment of other malignancies.

Oxidants and antioxidative defense

2002 ◽  
Vol 21 (2) ◽  
pp. 61-62 ◽  
Author(s):  
T Grune
Keyword(s):  
Free Radicals ◽  
Oxygen Free Radicals ◽  
Expression Patterns ◽  
Signal Transduction Pathways ◽  
Low Doses ◽  
The Past ◽  
Small Doses ◽  
Long Time ◽  
High Doses

The role of oxygen free radicals and other oxidants in several diseases has been well established over the past decade. Whereas it was long known that high doses of oxidants may damage or kill cells, the effect of low doses or long-time exposure to small flux rates of oxidants have been the focus of the free radical research until now. Here one has to take into account that most physiological and pathophysiological actions of oxidants and free radicals are based on the permanent action of small doses and flux rates. This includes effects of oxidants on signal transduction pathways and gene expression patterns. Therefore, only a few answers can be given today on the relevance of the effects of low doses of oxidants.

Response of rat jejunum to angiotensin II: role of norepinephrine and prostaglandins

1981 ◽  
Vol 240 (1) ◽  
pp. G17-G24 ◽  
Author(s):  
N. R. Levens ◽  
M. J. Peach ◽  
R. M. Carey ◽  
J. A. Poat ◽  
K. A. Munday
Keyword(s):  
Angiotensin Ii ◽  
Water Absorption ◽  
Rapid Onset ◽  
Inhibitory Response ◽  
High Dose ◽  
Low Doses ◽  
Slow Decay ◽  
High Doses ◽  
Stimulation Of

At low doses, angiotensin II (AII) stimulates jejunal sodium and water absorption in the pentobarbital sodium-anesthetized rat. This response to the hormone can be blocked by cycloheximide and has a rapid onset and decay, indicating that any protein involved must have a short half-life and/or fast turnover. At high doses, AII inhibits jejunal absorption by a process that does not involve protein synthesis and has a rapid onset but slow decay. The AII-induced inhibition of water absorption can be abolished, and a net stimulation ensues after pretreatment of the animals with meclofenamate or indomethacin, suggesting that at high doses AII stimulates intestinal prostaglandin biosynthesis. The AII analogue, [Sar1,Leu8]AII, significantly stimulated jejunal water absorption and was devoid of any inhibitory response at any dose administered. Simultaneous infusion of low doses of [Sar1,Leu8]AII and AII resulted in a stimulation of water transport, while simultaneous infusion of high dose [Sar1,Leu8]AII and AII also stimulated water absorption. It is suggested that the AII analogue is a full agonist with regard to stimulation of jejunal transfer but antagonizes the inhibitory response to high doses of AII. A model consistent with these data is discussed.

scholarly journals Pyridoxine and Atherosclerosis: Role of Pyridoxine in the Metabolism of Lipids and Glycosaminoglycans in Rats Fed Normal and High Fat, High Cholesterol Diets Containing 16 % Casein

1978 ◽  
Vol 31 (1) ◽  
pp. 7 ◽  
Author(s):  
PL Vijayammal ◽  
PA Kurup
Keyword(s):  
Body Weight ◽  
Normal Diet ◽  
Low Doses ◽  
High Cholesterol ◽  
High Fat ◽  
High Doses

The effect of administration of low and high doses of pyridoxine on the metabolism of lipids and glycosaminoglycans has been studied in rats fed normal and high fat, high cholesterol diets. Low doses of pyridoxine (0'005 mg/100 g body weight) caused increased concentrations of cholesterol and triglycerides in the serum and aorta in animals fed normal and high fat, high cholesterol diets. Administration of high doses of pyridoxine (5'0 mg/100 g body weight) caused decrease in the concentration of these lipids in these tissues except in the case of the aorta in the animals fed a normal diet.

Escape of Intestinal Resistance Vessels to Angiotensin II

1974 ◽  
Vol 52 (3) ◽  
pp. 458-464 ◽  
Author(s):  
J. Robert McNeill
Keyword(s):  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Intravenous Administration ◽  
Low Doses ◽  
Peak Response ◽  
Resistance Vessel ◽  
Resistance Vessels ◽  
Vessel Response ◽  
High Doses

The escape phase of the intestinal resistance vessel response to infusions of angiotensin II was studied in pentobarbital-anesthetized cats using a technique which did not involve cannulation of the arterial supply to the intestine. During intravenous infusions of angiotensin, the escape was 30% of the peak response. The escape was not related to the increase in arterial pressure. In low doses, the escape during intra-arterial infusions was similar to that observed during intravenous administration. Graded increases in the infusion dose of angiotensin produced increasing vasoconstriction except at high doses. The results indicate that escape of the intestinal resistance vessels to angiotensin is only partial and that a significant vasoconstriction is maintained. The results are consistent with the postulated role of endogenous angiotensin in the mechanism of the intestinal vasoconstriction following hemorrhage.

Collagen-Induced Platelet Aggregation: -Evidence Against the Essential Role of Platelet Adenosine Diphosphate

1979 ◽  
Vol 42 (04) ◽  
pp. 1193-1206 ◽  
Author(s):  
Barbara Nunn
Keyword(s):  
Platelet Aggregation ◽  
Time Course ◽  
Essential Role ◽  
Atp Release ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
High Doses ◽  
Induced Aggregation

SummaryThe hypothesis that platelet ADP is responsible for collagen-induced aggregation has been re-examined. It was found that the concentration of ADP obtaining in human PRP at the onset of aggregation was not sufficient to account for that aggregation. Furthermore, the time-course of collagen-induced release in human PRP was the same as that in sheep PRP where ADP does not cause release. These findings are not consistent with claims that ADP alone perpetuates a collagen-initiated release-aggregation-release sequence. The effects of high doses of collagen, which released 4-5 μM ADP, were not inhibited by 500 pM adenosine, a concentration that greatly reduced the effect of 300 μM ADP. Collagen caused aggregation in ADP-refractory PRP and in platelet suspensions unresponsive to 1 mM ADP. Thus human platelets can aggregate in response to collagen under circumstances in which they cannot respond to ADP. Apyrase inhibited aggregation and ATP release in platelet suspensions but not in human PRP. Evidence is presented that the means currently used to examine the role of ADP in aggregation require investigation.

ANTAGONISTIC ACTION OF NORETHYNODREL ON THE TESTOSTERONE-DEPENDENT PROCESS OF FRUCTOSE FORMATION IN MOUSE SEX ACCESSORY ORGANS

1966 ◽  
Vol 51 (2) ◽  
pp. 224-230 ◽  
Author(s):  
John A. Thomas ◽  
Edward T. Knych
Keyword(s):  
Antagonistic Activity ◽  
Low Doses ◽  
Antagonistic Action ◽  
Dependent Process ◽  
High Doses

ABSTRACT Norethynodrel antagonized the fructose stimulating effects of exogenous testosterone in sex accessory organs of castrate mice. It was antiandrogenic at both low doses (50 μg) and high doses (400 μg) of testosterone. Norethindrone and ethisterone suppressed fructose formation in the testosterone-treated castrate mouse, but not as effectively as norethynodrel. Norethandrolone exerted no antagonistic activity.

scholarly journals Action mechanism of Escherichia coli DNA photolyase. II. Role of the chromophores in catalysis.

1987 ◽  
Vol 262 (1) ◽  
pp. 486-491 ◽  
Author(s):  
M S Jorns ◽  
E T Baldwin ◽  
G B Sancar ◽  
A Sancar
Keyword(s):  
Escherichia Coli ◽  
Action Mechanism ◽  
Dna Photolyase
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