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Non-recombinant urate oxidase (Uricozyme®)

recombinant urate oxidase (Rasburicase®)

urine alkalisation may induce calcium phosphate deposition

renal replacement therapy should be started on an emergency basis when hydration fails to produce a prompt metabolic improvement or when ARF develops

Up to 50% of patients with newly diagnosed multiple myeloma have renal failure and up to 10% require dialysis

renal ultrasonography remains the method of choice for investigating extra-renal obstruction

The relief of the obstruction, either by percutaneous nephrostomy or through a ureteral stent, is the cornerstone of treatment

TMA may be associated with the cancer itself, with cancer chemotherapy, or with allogeneic BMT

thrombotic microangiopathy (TMA)

it may be as high as 5%

Most of the cases occur in patients with solid tumours, the most common type being adenocarcinoma (stomach, breast and lung)

The pathophysiology of the TMA-malignancy association remains controversial, although many studies suggest an insult to the vascular endothelium

mitomycin C. Subsequently, TMA has been reported with many anti-cancer agents, including gemcita-bine, bleomycin, cisplatin, CCNU, cytosine arabinoside, daunorubicin, deoxycoformycin, 5-FU, azathioprine and interferon α

Plasma exchanges have been shown to improve prognosis in the general population of patients with TMA

Causative factors should be looked for and antihypertensive treatment given. Lastly, in the absence of guidelines, we believe that plasma exchange should be proposed in patients with severe cancer treatment-associated TMA

The most widely used protective measure is saline infusion to induce solute diuresis

During methotrexate infusion and elimination, fluids should be given to maintain a high urinary output and urinary alkalisation should be performed to keep the urinary pH above 7.5. Rescue with folinic acid (50 mg four times a day) should be started 24 hours after each high-dose metho-trexate infusion and serum methotrexate concentrations should be measured every day

cyclophosphamide and ifosfamide

pharmacokinetic data indicate that intravenous administration of ascorbate can bypass this tight control resulting in highly elevated plasma levels

ascorbate readily oxidizes to produce H2O2, pharmacological ascorbate has been proposed as a prodrug for the delivery of H2O2 to tumors

Ascorbate is an excellent reducing agent and readily undergoes two consecutive, one-electron oxidations to form ascorbate radical (Asc•−) and dehydroascorbic acid (DHA)

Ascorbate oxidizes readily. The rate of oxidation is dependent on pH and is accelerated by catalytic metals

In near-neutral buffers with contaminating metals, the oxidation and subsequent loss of ascorbate can be very rapid

Ascorbate is required for maintaining iron in the ferrous state

In the presence of catalytic metal ions, ascorbate can also exert pro-oxidant effects

Ascorbate is an excellent one-electron reducing agent that can reduce ferric (Fe3+) to ferrous (Fe2+) iron, while being oxidized to ascorbate radical

In a classic Fenton reaction, Fe2+ reacts with H2O2 to generate Fe3+ and the very oxidizing hydroxyl radical

e presence of ascorbate can allow the recycling of Fe3+ back to Fe2+, which in turn will catalyze the formation of highly reactive oxidants from H2O2

Depending on concentrations, the effects of ascorbate on models of lipid peroxidation can be pro- or antioxidant

metabolic activity, oxygen transport, and DNA synthesis

Iron is found in the human body in the form of haemoglobin in red blood cells and growing erythroid cells.

macrophages contain considerable quantities of iron

iron is taken up by the majority of cells in the form of a transferrin (Tf)-Fe(III) complex that binds to the cell surface receptor transferrin receptor 1 (TfR1)

excess iron is retained in the liver cells

the endosomal six transmembrane epithelial antigen of the prostate 3 (STEAP3) reduces Fe(III) (ferric ion) to Fe(II) (ferrous ion), which is subsequently transferred across the endosomal membrane by divalent metal transporter 1 (DMT1)

labile iron pool (LIP)

LIP is toxic to the cells owing to the production of massive amounts of ROS.

DHA is quickly converted to Vit-C within the cell, by interacting with reduced glutathione (GSH) [45,46,47]. NADPH then recycles the oxidized glutathione (glutathione disulfide (GSSG)) and converts it back into GSH

Fe(II) catalyzes the formation of OH• and OH− during the interaction between H2O2 and O2•− (Haber–Weiss reaction)

Ascorbate can efficiently reduce free iron, thus recycling the cellular Fe(II)/Fe(III) to produce more OH• from H2O2 than can be generated during the Fenton reaction, which ultimately leads to lipid, protein, and DNA oxidation

Vit-C-stimulated iron absorption

reduce cellular iron efflux

high-dose Vit-C may elevate cellular LIP concentrations

ascorbate enhanced cancer cell LIP specifically by generating H2O2

Vit-C produces H2O2 extracellularly, which in turn inhibits tumor cells immediately

tumor cells have a need for readily available Fe(II) to survive and proliferate.

Tf has been recognized to sequester most labile Fe(II) in vivo

Asc•− and H2O2 were generated in vivo upon i.v Vit-C administration of around 0.5 g/kg of body weight and that the generation was Vit-C-dose reliant

free irons, especially Fe(II), increase Vit-C autoxidation, leading to H2O2 production

iron metabolism is altered in malignancies

increase in the expression of various iron-intake pathways or the downregulation of iron exporter proteins and storage pathways

Fe(II) ion in breast cancer cells is almost double that in normal breast tissues

macrophages in the cancer microenvironment have been revealed to increase iron shedding

Advanced breast tumor patients had substantially greater Fe(II) levels in their blood than the control groups without the disease

increased the amount of LIP inside the cells through transferrin receptor (TfR)

Warburg effect, or metabolic reprogramming,

Warburg effect is aided by KRAS or BRAF mutations

Vit-C is supplied, it oxidizes to DHA, and then is readily transported by GLUT-1 in mutant cells of KRAS or BRAF competing with glucose [46]. DHA is quickly converted into ascorbate inside the cell by NADPH and GSH [46,107]. This decrease reduces the concentration of cytosolic antioxidants and raises the intracellular ROS amounts

increased ROS inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH)

ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+ (a critical co-factor of GAPDH); thus, further reducing the GAPDH associated with a multifaceted metabolic rewiring

Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production

high-dose Vit-C recruited metabolites and increased the enzymatic activity in the pentose phosphate pathway (PPP), blocked the tri-carboxylic acid (TCA) cycle, and increased oxygen uptake, disrupting the intracellular metabolic balance and resulting in irreversible cell death, due to an energy crisis

mega-dose Vit-C influences energy metabolism by producing tremendous amounts of H2O2

Due to its great volatility at neutral pH [76], bolus therapy with mega-dose DHA has only transitory effects on tumor cells, both in vitro and in vivo.