The general activity of AA as an anti-oxidant implies that conditions associated with chronic inflammation and oxidative stress would lead to its depletion. As reviewed by McGregor and Biesalski , numerous inflammatory conditions including gastritis , diabetes [134, 135], pancreatitis , pneumonia , osteoporosis , rheumatoid arthritis , are all associated with marked reduction in plasma AA levels as compared to healthy controls. Within the context of this discussion, profound reduction of AA is observed in cancer patients [140–146], SIRS patients , and ICU patients .
Some studies have demonstrated correlation between plasma AA and survival. Mayland et al.  measured plasma AA in 50 end-stage cancer patients in a hospice setting. A correlation between deficiency in AA, decreased survival, and higher expression of the inflammatory marker CRP was noted. More recently, a correlation between tumor aggressiveness and low AA content has been made . Kuiper et al. found that the proangiogenic transcription factor HIF-1 alpha is negatively correlated with tumor AA content. Correlations where also made between low AA content, high VEGF, and levels of the anti-apoptotic protein bcl-2.
Cancer patients are known to exhibit a general state of chronic inflammation which, as stated above, is related to the tumor itself and the interaction of host factors with the tumor. Elevation in the level o f classical inflammatory markers such as fibrinogen [149–155], CRP [156–160], erythrocyte sedimentation rate , ferritin [162–165], neopterin [166–168], homocysteine [169, 170], IL-6 [161, 171], and free radical stress [172–175] have been well-documented in cancer patients, with numerous studies demonstrating that elevation is associated with poor survival.
The possibility that inflammation itself reduces plasma AA was shown by Fain et al. , who examined 184 hospitalized patients and observed that 47.3% suffered from hypovitaminosis C as defined as either depletion (i.e., serum AA levels < 5 mg/l) or deficiency (i.e., serum AA levels < 2 mg/l). Interestingly, patients with an activated acute phase response, as defined by erythrocyte sedimentation rate above 20 mm and an increase in acute phase reactants (CRP >10 mg/l and/or fibrinogen > 4 g/l) had lower serum AA levels. Also associated with decreased serum AA levels was reduction in hemoglobin and albumin. A Japanese population study of 778 men and 1404 women, aged 40-69 years, demonstrated a negative correlation between plasma AA content and CRP . In an interventional study, Block et al. examined 396 healthy nonsmokers randomized to receive either 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. A statistically significant decrease in plasma CRP levels was found only in the group receiving AA .
While a study by Mayland et al. demonstrated that, in 50 patients with advanced malignancies of various types, a correlation between high CRP levels and AA deficiency existed , to our knowledge no interventional studies in cancer patients have been performed to assess the capacity of AA administered i.v. to inhibit chronic inflammation. In the absence of such studies, we looked at reports of AA inhibition ofs inflammatory markers in the context of other diseases to determine whether a rationale may exist for its use in cancer. Several such supporting studies exist. Administration of IV AA has been shown to decrease CRP levels in smokers . Oral AA supplementation decreased CRP levels in a trial of 44 patients suffering from atrial fibrillation after cardioversion . In a study of 12 healthy volunteers, it was shown that i.v. AA inhibited endothelin-induced IL-6 production . In a study of 1463 coronary artery disease patients, a negative correlation between neopterin (a catabolic product of GTP indicative of immune activation) and AA concentration was noted . Given that there are, at present, numerous trials being conducted using i.v. AA in the treatment of cancer [26–31], it is highly unfortunate that none of them are assessing inflammatory markers or other potential mechanisms of action. This may, to some degree, be detrimental to future study of AA in cancer treatment: if poor tumor regression data is generated, replication of these trials with inclusion of sensitive inflammatory marker endpoints may never occur.