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Anemia has also been identified as an adverse prognostic factor

mild (10 g/dl—normal), moderate (8–10 g/dl), severe (6.5–8 g/dl) and life threatening (<6.5 g/dl or unstable patient) anemia

anemia in cancer patients is often multifactorial.

Cancer itself can directly cause or exacerbate anemia either by suppressing hematopoiesis through bone marrow infiltration or production of cytokines that lead to iron sequestration, or by reduced red blood cell production

in inflammatory anemia, iron deficiency should be defined by a low transferrin saturation of <20%, ferritin levels of <100 ng/ml and a low reticulocyte hemoglobin concentration of <32 pg

anemia to thrombocytosis, as commonly seen in cancer patients

TNF-α inhibits hemoglobin production

treatment itself may be a major cause of anemia

Other cytokines, such as interleukin-6 (IL-6), IL-1 and interferon-γ, have also been shown to inhibit erythroid precursors in vitro [9], albeit to a lesser extent

In inflammation, from whatever cause, IL-6 induces the liver to produce hepcidin. Hepcidin decreases iron absorption from the bowel and blocks iron utilization in the bone marrow

Numerous in vitro studies have illustrated the central role of TNF-α in the pathogenesis of anemia

nephrotoxic effects of particular cytotoxic agents such as platinum salts can also lead to the persistence of anemia through reduced Epo production by the kidney

Currently two options are at the disposal of the clinician for the treatment of anemia in cancer patients: transfusion of packed red blood cells and the use of erythropoiesis-stimulating agents (ESAs)

The goal of the treatment is to relieve the symptoms of anemia such as fatigue and dyspnea.

Transfusion of 1 unit of packed red blood cells has been estimated to result in an increase in the hemoglobin level of 1 g/dl in a normal-sized adult

a higher mortality rate in patients receiving ESA treatment

Recent concerns regarding the risk of thromboembolism in patients treated with ESA have been corroborated by the meta-analyses conducted by Tonnelli and Bennett

Under steady-state conditions, intracellular GSH is maintained at millimolar concentrations, which keeps cells in a reduced environment and serves as the principal intracellular redox buffer when cells are subjected to an oxidative stressor including H2O2 (26). Glutathione peroxidase (GPx) activity catalyzes the reduction of H2O2 to water with the conversion of GSH to glutathione disulfide (GSSG). Under steady-state conditions, GSSG is recycled back to GSH by glutathione disulfide reductase using reducing equivalents from NADPH. However, under conditions of increased H2O2 flux, this recycling mechanism may become overwhelmed leading to a depletion of intracellular GSH (27, 28).

ascorbate radiosensitization can create an overwhelming oxidative stress to pancreatic cancer cells resulting in oxidation/depletion of the GSH intracellular redox buffer, resulting in cell death.

Treatment with the combination of ascorbate + IR significantly delayed tumor growth compared to controls or ascorbate alone

Ascorbate + IR also significantly increased overall survival compared to controls, IR alone or ascorbate alone

54% of mice treated with the combination of IR + ascorbate had no measurable tumors

Glutathione is a measurable marker indicative of the oxidation state of the thiol redox buffer in cells. In severe systemic oxidative stress, the GSSG/2GSH couple may become oxidized, i.e. the concentration of GSH decreases and GSSG may increase because the capacity to recycle GSSG to GSH becomes rate-limiting

This suggests that the very high levels of pharmacological ascorbate in these experiments may have a pro-oxidant toward red blood cells as seen by a decrease in the capacity of the intracellular redox buffer

These data support the hypothesis that ascorbate radiosensitization does not cause an increase in oxidative damage from lipid-derived aldehydes to other organs.

Our current study demonstrates the potential for pharmacological ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

pharmacological ascorbate enhances IR-induced cell killing and DNA fragmentation leading to induction of apoptosis in HL60 leukemia cells

pharmacological ascorbate significantly decreases clonogenic survival and inhibits the growth of all pancreatic cancer cell lines as a single agent, as well as sensitizes cancer cells to IR

Hurst et al. demonstrated that pharmacological ascorbate combined with IR leads to increased numbers of double-strand DNA breaks and cell cycle arrest when compared to either treatment alone

pharmacological ascorbate could serve as a “pro-drug” for the delivery of H2O2 to tumors

the double-strand breaks induced by H2O2 were more slowly repaired

The combination of ascorbate and IR provide two distinct mechanisms of action: ascorbate-induced toxicity due to extracellular production of H2O2 that then diffuses into cells and causes damage to DNA, protein, and lipids; and radiation-induced toxicity as a result of ROS-induced damage to DNA. In addition, redox metal metals like Fe2+ may play an important role in ascorbate-induced cytotoxicity. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of H2O2; labile iron can also react with H2O2. Recently our group has demonstrated that pharmacological ascorbate and IR increase the labile iron in tumor homogenates from this murine model of pancreatic cancer

we demonstrated that ascorbate or IR alone decreased tumor growth, but the combination treatment further inhibited tumor growth, indicating that pharmacological ascorbate is an effective radiosensitizer in vivo

data suggest that pharmacological ascorbate may protect the gut locally by decreasing IR-induced damage to the crypt cells, and systemically, by ameliorating increases in TNF-α

“Intrinsic processes” include those that result in mutations due to random errors in DNA replication whereas “extrinsic factors” are environmental factors that affect mutagenesis rates (such as UV radiation, ionizing radiation, and carcinogens

intrinsic factors do not play a major causal role.

intrinsic cancer risk should be determined by the cancer incidence for those cancers with the least risk in the entire group controlling for total stem cell divisions

if one or more cancers would feature a much higher cancer incidence, for example, lung cancer among smokers vs. non-smokers, then this most likely reflects additional (and probably extrinsic) risk factors (smoking in this case)

Particularly, for breast and prostate cancers, it has long been observed that large international geographical variations exist in their incidences (5-fold for breast cancer, 25-fold for prostate cancer)14, and immigrants moving from countries with lower cancer incidence to countries with higher cancer rates soon acquire the higher risk of their new country

Colorectal cancer is another high-incidence cancer that is widely considered to be an environmental disease17, with an estimated 75% or more colorectal cancer risk attributable to diet

melanoma, its risk ascribed to sun exposure is around 65–86%

non-melanoma basal and squamous skin cancers, ~90% is attributable to UV

75% of esophageal cancer, or head and neck cancer are caused by tobacco and alcohol

HPV may cause ~90% cases in cervical cancer23, ~90% cases in anal cancer24, and ~70% in oropharyngeal cancer

HBV and HCV may account for ~80% cases of hepatocellular carcinoma

H pylori may be responsible for 65–80% of gastric cancer

While a few cancers have relatively large proportions of intrinsic mutations (>50%), the majority of cancers have large proportions of extrinsic mutations, for example, ~100% for Myeloma, Lung and Thyroid cancers and ~80–90% for Bladder, Colorectal and Uterine cancers, indicating substantial contributions of carcinogen exposures in the development of most cancers

onsistent estimate of contribution of extrinsic factors of >70–90% in most common cancer types. This concordance lends significant credibility to the overall conclusion on the role of extrinsic factors in cancer development