A previous phase I ascorbic acid trial [20
] stopped dose escalation at 1.5 g/kg (approximately 56 g/m2
) when peak blood levels approached 26 mM, the level that inhibited tumor growth in mice [3
]. However, 30–40 mM ascorbic acid in mouse blood only partially inhibited the rate of tumor growth and did not produce tumor regression. Our study achieved higher blood levels, longer drug exposures, and higher dose intensity to better assess both toxicity and the potential for antitumor efficacy. These parameters are compared for the two studies in Table . Our protocol produced approximately a twofold higher Cmax
and AUC values for ascorbic acid in patient’s blood, reaching values of 49 mM and 246 h mM, respectively. Dose levels of 70, 90, and 110 g/m2
also maintained ascorbic acid blood levels at or above 10–20 mM for about 5–6 h. These high concentrations of ascorbic acid (both peak and sustained) were generally well tolerated.
Although the Cmax and AUC values for ascorbic acid increased proportionately with ascorbic acid doses between 0 and 70 g/m2, the values of these parameters did not increase much further at the higher doses of 90 and 110 g/m2. Therefore, a dose of 70–80 g/m2 appears to be optimal for future studies since higher doses provide no additional drug-exposure benefits and subject the patient to unnecessarily longer infusions.
The 2008 report of Heaney et al. [32
] advised caution concerning combining ascorbic acid with other chemotherapeutic agents. Using hematopoietic cell cultures and hematopoietic xenogenic tumors in mice, they studied the effects of ‘vitamin C’ on the antitumor activity of several common chemotherapeutic agents (doxorubicin, cisplatin, vincristine, methotrexate, and imatinib), including some agents that do not have reactive oxygen mechanisms of action. They found that ascorbate at higher concentrations antagonized the cytotoxicity of some chemotherapeutic agents, and they concluded that ‘vitamin C’ might interfere with the treatment for hematopoietic tumors (and other tumor types) in cancer patients. Unfortunately, they used dehydroascorbic acid (not ascorbic acid) and claimed that it was converted to ascorbic acid intracellularly. A particular concern with this study is that one of the more likely potential antitumor mechanisms of action of ascorbic acid depends on the extracellular conversion of ascorbic acid to dehydroascorbic acid, which generates extracellular H2
, an active cytotoxic antitumor agent [3
]. Thus, dosing with dehydroascorbic acid may circumvent this particular antitumor activity of ascorbic acid. This probability is supported by their findings that 8.5–18 mM dehydroascorbic acid alone produced no antitumor activity against their two cell lines and that 250 mg/kg dehydroascorbic acid produced only minimal antitumor activity against the xenographic tumors in mice. Similar criticism of the conclusions of this report has been voiced by others [34
Further support for a potential role of i.v. ascorbic acid is provided by the work of Verrax and Calderon [33
] who demonstrated that ascorbic acid completely kills a variety of tumor cells, T24 (bladder), DU145 (prostate), HepG2 (liver), MCF7 (breast), and Ishikawa (cervix), with EC50
values of 3–7 mM. They also showed that 1 g/kg/d i.p. ascorbic acid significantly inhibited TLT tumor growth in mice without any obvious toxicity. Notably, orally dosed ascorbic acid had no effect on tumor growth. In addition, this group demonstrated that ascorbic acid significantly potentiated the antitumor activity of several chemotherapeutic agents including etoposide, cisplatin, 5-fluorouracil, doxorubicin, and paclitaxel and in all three tumor lines tested (MCF7, DU145, and T24).
The use of i.v. ascorbic acid in combination with cytotoxic chemotherapy is further encouraged by a recent report showing that ascorbic acid potentiated the antitumor activity of gemcitabine against seven human and one murine pancreatic cancer cell lines [35
]. The observation is of particular interest as two of the human lines were resistant to gemcitabine. Synergistic antitumor activity occurred in tissue culture and in vivo studies with implanted tumors in mice. This and other reported preclinical investigations provide encouragement for additional exploration of i.v. ascorbic acid to improve therapeutic outcomes [36
]. A recently published phase I clinical trial by Monti et al. evaluated i.v. ascorbate combined with gemcitabine and erlotinib in nine patients with stage IV metastatic pancreatic cancer. Potentially biologically and clinically active ascorbic acid concentrations were achievable in all treated individuals, and primary tumor size decreased in eight out of nine patients [21
]. The findings of the current study coupled with the collective evidence from the available literature suggest that the combination of i.v. ascorbic acid with gemcitabine to treat pancreatic cancer is an attractive approach that deserves further evaluation.