The data show that pharmacologic ascorbate concentrations produced Asc•− selectively in extracellular fluid compared with blood and that H2O2 formation occurred when Asc•− concentrations were >100 nM in extracellular fluid.
These data validate the hypothesis that ascorbate is a prodrug for selective delivery of reactive species to the extravascular space
pharmacologic ascorbate as a prooxidant drug for therapeutic use.
Recently we reported that pharmacologic ascorbic acid concentrations produced H2O2 concentrations of ≥25 μM, causing cancer cell death in vitro
We found that H2O2 concentrations generated in vivo were those that caused cancer cell death in vitro
When ascorbate was given parenterally, Asc•−, the product of a loss of one electron from ascorbate, was detected preferentially in extracellular fluid compared with blood
Asc•− generation in extracellular fluid depended on the ascorbate dose and the resulting concentrations
With i.v. administration of ascorbate, Asc•− concentrations were as much as 12-fold greater in extracellular fluid compared to blood and approached 250 nM
In blood, such Asc•− concentrations were never produced and were always <50 nM
These data are all consistent with the hypothesis that pharmacologic ascorbate concentrations in vivo serve as a prodrug for selective delivery of H2O2 to the extracellular space
After oral ingestion, control of intracellular and extracellular ascorbate concentrations is mediated by three mechanisms: intestinal absorption, tissue transport, and renal reabsorption
intestinal absorption, or bioavailability, declines at doses >200 mg
also at ≈60 μM, renal reabsorption approaches saturation, and excess ascorbate is excreted in urine
Parenteral administration bypasses tight control
When tight control is bypassed, H2O2 forms in the extracellular space
in vivo validation of ascorbate as a prodrug for selective H2O2 formation
Temporarily bypassing tight control with parenteral administration of ascorbate allows H2O2 to form in discrete time periods only, decreasing likelihood of harm, and provides a pharmacologic basis for therapeutic use of i.v. ascorbate
H2O2 formation results in selective cytotoxicity
Tumor cells are killed with exposure to H2O2 for ≤30 min
In vitro, killing is mediated by H2O2 rather than Asc•−
In addition to cancer treatment, another potential therapeutic use is for treatment of infections. H2O2 concentrations of 25–50 μM are bacteriostatic
facilitates the transport of intra and extra cellular liquids which helps the organism to eliminate the toxic products
The increased number of insulin receptors on the tumor cell, in comparison to the normal one, allows the before mentioned 2 factors to act predominantly
Increased permeability after the insulin effect on the cellular membrane results in increased intracellular quantity of antitumor agents
have other endocrine effects: directly stimulates suprarenal gland to produce epinephrine and glucocorticoid hormones and stimulates ACTH secretion. These endocrine effects also have a positive influence on the regenerating processes
Insulin influences the intracellular metabolism of the tumor cell, which leads to increase of the number of cells in phase S, where they are with highly sensitive to specific chemotherapeutics.
After the first 6 IPT applications overall (groups A and B) response to treatment on PSA criteria shows partial effect and stabilization in 12 of 16 (75%) patients
After the 10th IPTLD application or 3 months after starting treatment, complete response, partial response, and stabilization were observed in 4 of 9 (66.6%), while in 3 of 9 (33.3%) was registered complete effect
the advanced stage of disease in patients treated
Quality of life after the second IPTLD application is significantly improved
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