-
Indian Journal of Cancer Mar 2022Human epidermal growth factor receptor 2 (HER2)-negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor... (Review)
Review
Human epidermal growth factor receptor 2 (HER2)-negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)-positive and HR-negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR-positive HER2-negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin-dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged for HER2-negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA-mutated (gBRCAm) HER2-negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2-negative breast cancer.
Topics: Adenosine Diphosphate; Adenosine Diphosphate Ribose; Breast Neoplasms; Female; Humans; Receptor, ErbB-2; Ribose
PubMed: 35343197
DOI: 10.4103/ijc.IJC_30_21 -
Current Medicinal Chemistry 2009The current adenosine diphosphate inhibitors, ticlopidine and clopidogrel, are thienopyridine compounds that inhibit adenosine diphosphate mediated platelet aggregation.... (Review)
Review
The current adenosine diphosphate inhibitors, ticlopidine and clopidogrel, are thienopyridine compounds that inhibit adenosine diphosphate mediated platelet aggregation. They interfere with platelet activation by selectively and irreversibly blocking P2Y12 sub-unit of the adenosine diphosphate receptor on the surface of platelets. This provides an antiplatelet effect that is additive to the inhibition of the thromboxane A2 pathway by aspirin. Dual antiplatelet therapy is extensively used in cardiovascular medicine. Randomized controlled trials have substantiated the fact that thrombotic complications after percutaneous coronary intervention procedures can be decreased by using dual antiplatelet therapy. However, there is a concern of bleeding due to enhanced and irreversible platelet inhibition in patients who will require any operation including coronary artery bypass grafting while on adenosine diphosphate inhibitors. This applies to a large population of patients requiring either coronary artery bypass grafting after angiographic definition of their coronary anatomy, or patients requiring semi-elective or urgent operation while under dual antiplatelet therapy. This concern is more present in era of drug-eluting stents, where long-term use of dual antiplatelet therapy is encouraged, and the incidence of late thrombosis after late cessation of adenosine diphosphate inhibitors is increasingly surfacing in the literature. The goal this review is to provide the medical chemistry of most commonly used adenosine diphosphate inhibitors, examine the literature on the effect of adenosine diphosphate inhibitors in hemorrhagic-related complications after surgical intervention, and provide the ramifications and alternatives in modern clinical practice.
Topics: Adenosine Diphosphate; Drug Delivery Systems; Humans; Perioperative Care; Stents
PubMed: 19199924
DOI: 10.2174/092986709787458443 -
Drugs Aug 1999Adenosine 5'-triphosphate (ATP) is a purine nucleotide found in every cell of the human body. In addition to its well established role in cellular metabolism,... (Review)
Review
Adenosine 5'-triphosphate (ATP) is a purine nucleotide found in every cell of the human body. In addition to its well established role in cellular metabolism, extracellular ATP and its breakdown product adenosine, exert pronounced effects in a variety of biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation and liver glycogen metabolism. These effects are mediated by both P1 and P2 receptors. A cascade of ectonucleotidases plays a role in the effective regulation of these processes and may also have a protective function by keeping extracellular ATP and adenosine levels within physiological limits. In recent years several clinical applications of ATP and adenosine have been reported. In anaesthesia, low dose adenosine reduced neuropathic pain, hyperalgesia and ischaemic pain to a similar degree as morphine or ketamine. Postoperative opioid use was reduced. During surgery, ATP and adenosine have been used to induce hypotension. In patients with haemorrhagic shock, increased survival was observed after ATP treatment. In cardiology, ATP has been shown to be a well tolerated and effective pulmonary vasodilator in patients with pulmonary hypertension. Bolus injections of ATP and adenosine are useful in the diagnosis and treatment of paroxysmal supraventricular tachycardias. Adenosine also allowed highly accurate diagnosis of coronary artery disease. In pulmonology, nucleotides in combination with a sodium channel blocker improved mucociliary clearance from the airways to near normal in patients with cystic fibrosis. In oncology, there are indications that ATP may inhibit weight loss and tumour growth in patients with advanced lung cancer. There are also indications of potentiating effects of cytostatics and protective effects against radiation tissue damage. Further controlled clinical trials are warranted to determine the full beneficial potential of ATP, adenosine and uridine 5'-triphosphate.
Topics: Adenosine Diphosphate; Anesthesia; Animals; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Lung Diseases; Neoplasms
PubMed: 10473017
DOI: 10.2165/00003495-199958020-00002 -
Circulation Jan 2010
Review
Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Humans; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis
PubMed: 20048234
DOI: 10.1161/CIRCULATIONAHA.109.853069 -
Journal of Separation Science Oct 2020Adenosine triphosphate is a universal energy currency that can directly provide energy required for a multitude of biochemical reactions and biophysical actions through...
Adenosine triphosphate is a universal energy currency that can directly provide energy required for a multitude of biochemical reactions and biophysical actions through adenosine triphosphatase catalyzed hydrolysis. Adenosine triphosphatase activity is thus one important feature for the characterization of protein function and cell activity. Herein, we optimized ion-pair reversed-phase high-performance liquid chromatography technique for highly efficient separation of adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate, and the method demonstrated good linearity. Moreover, by coupling a protein-removable ultrafiltration, we developed a sensitive and robust approach for quantification of adenosine triphosphatase hydrolytic activity. By this assay, we demonstrated that RecA filaments-catalyzed adenosine triphosphate hydrolysis approached a second-order reaction, and its rate constant was estimated as 0.057 mM min . In addition, we explored the effects of DNA length on this reaction and revealed that the increase of the length of single-stranded DNA can promote the adenosine triphosphatase hydrolytic activity of RecA filaments. All these results confirm the feasibility of this new method in quantification of adenosine triphosphatase hydrolytic activity assays. Compared with previous complicated enzyme-coupled or homogeneous colorimetric measurements, the developed approach with high resolution separation allows a simple reaction system for adenosine triphosphatase assay and a sensitive detection free of interference from background noise.
Topics: Adenosine Diphosphate; Adenosine Triphosphatases; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Hydrolysis
PubMed: 32776712
DOI: 10.1002/jssc.202000561 -
Journal of Medicinal Chemistry Sep 2003Polyadenosine diphosphoribose glycohydrolase (PARG) catalyzes the intracellular hydrolysis of adenosine diphosphoribose polymers. Because structure-activity data are...
Polyadenosine diphosphoribose glycohydrolase (PARG) catalyzes the intracellular hydrolysis of adenosine diphosphoribose polymers. Because structure-activity data are lacking for PARG, the specific inhibitor adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) was utilized to determine the effects of structure on inhibitor potency using PARG isolated from bovine thymus (bPARG) and recombinant bovine PARG catalytic fragment (rPARG-CF). Both enzymes were strongly inhibited by submicromolar levels of ADP-HPD, but ADP and the phosphorylated pyrrolidine displayed no activity. Utilizing ADP-HPD analogues containing 2-, N(6), or 8-adenosyl substituents or guanine instead of adenine, the importance of adenine ring recognition as well as a correlation between loss of PARG inhibition and the length and bulkiness of 8-adenosyl substituents was shown. Utilization of ADP-HPD analogues lacking one or both pyrrolidine cis-hydroxyls demonstrated their importance for inhibitor binding. Last, the similarity between naturally occurring bPARG and heterologously expressed rPARG-CF was demonstrated. Therefore, readily available rPARG-CF is suitable for use in future studies to determine the structural aspects of PARG.
Topics: Adenosine Diphosphate; Animals; Binding Sites; Cattle; Enzyme Inhibitors; Glycoside Hydrolases; Inhibitory Concentration 50; Peptide Fragments; Poly Adenosine Diphosphate Ribose; Pyrrolidines; Recombinant Proteins; Structure-Activity Relationship
PubMed: 13678410
DOI: 10.1021/jm020541u -
The Biochemical Journal Jan 1978An analogue of ADP was made in which the terminal phosphono-oxy group, -O-PO(OH)2, has been replaced by the arsonomethyl group, -CH2-AsO(OH)2. This compound cannot form...
An analogue of ADP was made in which the terminal phosphono-oxy group, -O-PO(OH)2, has been replaced by the arsonomethyl group, -CH2-AsO(OH)2. This compound cannot form a stable analogue of ATP because anhydrides of arsonic acids are rapidly hydrolysed, so that any enzyme that phosphorylates ADP and accepts this analogue as a substrate should release orthophosphate in its presence. The analogue proves to be a poor substrate for 3-phosphoglycerate kinase (V/Km is diminished by a factor of 10(2)-10(3)) and a very poor substrate for pyruvate kinase (V/Km is diminished by a factor of 10(5)-10(6)). No substrate action was detected with adenyl kinase and creatine kinase.
Topics: Adenosine Diphosphate; Arsenic; Electrophoresis, Paper; Phosphotransferases
PubMed: 204292
DOI: 10.1042/bj1690239 -
The Journal of Biological Chemistry Feb 1985Equilibrium binding and activity studies indicate that adenosine 5'-diphosphate binds to phosphorylase kinase with high affinity at a site, or sites, distinct from the...
Equilibrium binding and activity studies indicate that adenosine 5'-diphosphate binds to phosphorylase kinase with high affinity at a site, or sites, distinct from the catalytic site. Equilibrium dialysis at pH 6.8 and 8.2, with and without Mg2+, and with phosphorylated and nonphosphorylated enzyme preparations revealed approximately 8 ADP binding sites per alpha 4 beta 4 gamma 4 delta 4 hexadecamer, with Kd values ranging from 0.26 to 17 microM. Decreasing the pH from 8.2 to 6.8 or removing the Mg2+ enhanced the affinity for ADP. At pH 6.8, ADP stimulated the phosphorylase conversion and autophosphorylation activities of the nonactivated enzyme. Analogs of ADP with modifications at the 2'-, 3'-, and 5'-positions allowed determination of structural requirements for the stimulation of activity. ADP seems to alter the conformation of the beta subunit because addition of the nucleotide inhibits its dephosphorylation by phosphoprotein phosphatase and its chemical cross-linking by 1,5-difluoro-2,4-dinitrobenzene. The binding affinities and effects of ADP suggest that it may function physiologically as an allosteric effector of phosphorylase kinase.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Allosteric Regulation; Allosteric Site; Animals; Cross-Linking Reagents; Dinitrofluorobenzene; Macromolecular Substances; Muscles; Phosphorylase Kinase; Phosphorylation; Rabbits; Structure-Activity Relationship
PubMed: 3972796
DOI: No ID Found -
Thrombosis and Haemostasis May 1979An improved measuring system based on the Coulter principle and developed in our laboratory is used to size human blood platelets. The mean volume of platelets in 24...
An improved measuring system based on the Coulter principle and developed in our laboratory is used to size human blood platelets. The mean volume of platelets in 24 healthy subjects is found to be 8.45 micron 3 with a standard deviation of 1.07 micron 3; the typical size-distribution curve is unimodal and asymmetrical, with a marked skew to the right. The effects of different reagents on platelet size (shape factor x volume) are evaluated. Platelets increase in size by 23% following suspension in isotonic, phosphate-buffered saline and incubation with 10 microM adenosine diphosphate; no change is observed when the suspending medium is autologous plasma. Cooling the platelets to 0-4 degrees C results in a size increase of 25%; rewarming to 37 degrees C restores them to their initial size within 2 hr. A similar increase occurs when the platelets are incubated with 1-10 mM colchicine. It is proposed that these reagents, which are known to produce changes in the orientation of the marginal bundle of microtubules, cause platelets to undergo disc-sphere transformations. Calculations are made which show that such transformations increase platelet size by 27% as measured electrically, and we conclude that the so-called volume changes reported in the literature reflect shape changes only and that no true volume increase actually takes place.
Topics: Adenosine Diphosphate; Blood Platelets; Colchicine; Humans; Particle Size; Temperature
PubMed: 462416
DOI: No ID Found -
Nucleosides, Nucleotides & Nucleic Acids 2018CD73 inhibitors are considered to be used in the therapies of melanomas, gliomas or breast cancer. However, little is known about their pharmacology and kinetics in...
CD73 inhibitors are considered to be used in the therapies of melanomas, gliomas or breast cancer. However, little is known about their pharmacology and kinetics in mouse experimental models. Thus, this study is aimed to define a metabolic stability and elimination of the adenosine diphosphate (ADP) analog - α,β-Methylene-ADP also known as AOPCP in BALB/c mice. The process starts with an intravenous injection of AOPCP, next blood and serum samples are collected. Urine samples are possessed by a bladder puncture. Mice aortas are dissected for the e5NT activity evaluation. In order to assess the AOPCP degradation, the incubation of AOPCP in mice blood and plasma is performed. The AOPCP concentration as well as the activity of e5NT were analyzed with the reverse phase-high pressure liquid chromatography (RP-HPLC). The study shows that after 60 minutes of the 20 mg/kg intravenous injection of AOPCP (body weight dose), the concentration of AOPCP in blood diminished rapidly from 38.6 ± 5.0 µM (measured 5 minutes after the injection) to 6.4 ± 1.4 µM. Interestingly, it is also noted that 60 minutes after the incubation of mice blood samples the AOPCP concentration decreases from 50 µM to 30.0 ± 0.3 µM. This study demonstrates a significant and quick decrease of AOPCP concentration in BALB/c mice blood after the intravenous injection and in isolated blood sample incubation. These findings emphasize the quick elimination of AOPCP as well as its instability and suggest that the AOPCP concentration have to be accurately and frequently monitored in all the studies that address its clinical application.
Topics: 5'-Nucleotidase; Adenosine Diphosphate; Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Injections, Intravenous; Mice, Inbred BALB C
PubMed: 30623751
DOI: 10.1080/15257770.2018.1489052