Summary Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2•− and H2O2 are capable of disrupting intracellular iron metabolism thereby selectively sensitizing non-small cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

SUMMARY Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2.− and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

Erythropoietin elimination via EpoR in the bone marrow was non-linear and increased following phlebotomy-induced anemia. This is consistent with an up-regulation of the erythropoietic EpoR pool in BM. Assuming that the elimination of Epo after BM ablation was via non-hematopoietic EpoR, then this post-ablation EpoR population was not significantly up-regulated by the phlebotomy.

Pre-clinical studies have demonstrated that bone marrow ablation has a profound effect in decreasing erythropoietin (EPO) elimination. The study's objective was to determine in humans if EPO pharmacokinetics (PKs) are perturbed following bone marrow ablation. EPO PK studies were performed in eight subjects, aged 4 to 61 years, undergoing fully myeloablative hematopoietic stem cell transplantation. Serial PK studies using intravenous injection of recombinant human EPO (92 ±2.0 U/kg) (mean±SEM) were carried out during four periods of altered marrow integrity: baseline pre-ablation, post-ablation pre-transplant, early post-transplant pre-engraftment, and late posttransplant full engraftment. Compared with baseline, post-ablation pre-transplant and early posttransplant EPO PKs demonstrated declines in clearance increases in terminal elimination half-life of 36 and 95%, respectively. Clearance and half-life returned to baseline following full engraftment. The association of EPO elimination with decreased bone marrow activity in patients undergoing transplantation conclusively establishes the bone marrow as a key determinant of EPO elimination in humans.Erythropoietin (EPO), a 34-kDa glycoprotein hormone, has a dominant action in the regulation of erythrocyte production. 1 EPO exerts its biological effect in stimulating the proliferation and differentiation of erythroid progenitors by binding to specific cell-surface receptors (EPO-Rs) that are in greatest abundance on erythroid progenitors located primarily in the bone marrow. 2 EPO-Rs are also located on virtually all non-hematopoietic tissues and have diverse additional biologic effects. 3 There is a paucity of information regarding which organ(s) and tissue(s) are important in EPO metabolism and elimination. Previous in vivo studies demonstrated that the kidney and liver exert no measurable effect on EPO in vivo elimination. [4][5][6] Erythropoietic tissues in rats, e.g., bone marrow and spleen, have also been shown to rapidly metabolize EPO with tissue uptake and clearance directly correlated with the number of erythroid colony-forming units. 7 These pre-clinical in vivo studies are supported by in vitro studies demonstrating that EPO is rapidly degraded by ligand-specific EPO-R erythroid progenitors, 8,9 and by clinical studies in anemic patients with hypoplastic marrows manifesting high serum EPO levels relative to their hemoglobin (Hb) levels. [10][11][12] Correspondence: JA Widness (john-widness@uiowa.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. In adults, EPO has demonstrated nonlinear pharmacokinetic (PK) behavior, with EPO clearance decreasing as the administered EPO dose increases. [12][13][14] The half-life of EPO ranges from 4 to 8 h in healthy adults given therapeutic doses of EPO. 13 In very-low-birth-weight premature infants, EPO also manifests nonlinear PK behavior, with clearances approximately threefold greater than adults. 15 Notably premature and term infants also manifest proportionally greater red marrow spac...

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