To the Editor:

On the basis of cell and animal experiments with dehydroascorbic acid, Heaney and colleagues state, “These results suggest that supplementary vitamin C may have adverse consequences in patients receiving cancer therapy” (1). Selectively referring to dehydroascorbic acid as vitamin C throughout the majority of this work may send a clouded message to patients and their caregivers. All known actions of vitamin C are mediated by the reduced molecule ascorbate, not the oxidized molecule dehydroascorbic acid. Mice lacking the tissue transport protein specific for ascorbate (Slc23a2) do not survive because of severe vitamin C deficiency, despite having no impairments in dehydroascorbic acid transport (2).

The suggestion that “…study conditions were relevant to clinical conditions” (1) should be viewed cautiously. Compared with cells devoid of any ascorbate, researchers attenuated cytotoxicity to antineoplastic agents in vitro (11-27%) by prior treatment with 500 μmol/L dehydroascorbic acid, which rapidly elevated intracellular ascorbate concentrations up to 18 mmol/L within 1 hour (1). In vivo, numerous reductive systems ensure plasma concentrations of dehydroascorbic acid do not exceed 1 μmol/L (3, 4). Although alluded to, the actual level of dehydroascorbic acid formed endogenously within the oxidative environments of tumors was not measured in either this (1) or the previous studies cited by this group (5, 6). Most cells in vivo, including cancer cells, maintain a constant intracellular ascorbate concentration of 1 to 5 mmol/L, which never decreases to zero. Data collected in vitro by comparing two extremes, 0 and 18 mmol/L ascorbate for instance, are implausible with regard to tumors and other tissues in general. The investigators conclude that “This finding could have important clinical relevance given the wide use of vitamin C as a nutritional supplement” (1). However, to produce an effect in xenografted mice, a course of 8 × 250 mg/kg dehydroascorbic acid was administered intravenously (1). This regimen does not simulate oral ingestion of vitamin C supplements. In fact, irreversible diabetes can be induced in rats after intravenous injection of 700 mg/kg dehydroascorbic acid (7).

Because meaningful differences exist in regard to chemistry, bioavailability, and metabolism, it may be imprudent to connect data gathered with dehydroascorbic acid to vitamin C (ascorbate) and oral supplements. Numerous randomized human clinical trials have not shown decreased chemotherapeutic efficacy with dietary supplement usage, including vitamin C (8). Scientific dialogue on the subject may benefit from further preclinical testing of oral vitamin C (ascorbate) supplementation and cancer treatment in addition to experiments deigned solely with dehydroascorbic acid.

No potential conflicts of interest were disclosed.

1
Heaney
ML
,
Gardner
JR
,
Karasavvas
N
, et al
. 
Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs
.
Cancer Res
2008
;
68
:
8031
8
.
2
Sotiriou
S
,
Gispert
S
,
Cheng
J
, et al
. 
Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival
.
Nat Med
2002
;
8
:
514
7
.
3
Lykkesfeldt
J
. 
Ascorbate and dehydroascorbic acid as reliable biomarkers of oxidative stress: analytical reproducibility and long-term stability of plasma samples subjected to acidic deproteinization
.
Cancer Epidemiol Biomarkers Prev
2007
;
16
:
2513
6
.
4
Wilson
JX
. 
The physiological role of dehydroascorbic acid
.
FEBS Lett
2002
;
527
:
5
9
.
5
Agus
DB
,
Vera
JC
,
Golde
DW
. 
Stromal cell oxidation: a mechanism by which tumors obtain vitamin C
.
Cancer Res
1999
;
59
:
4555
8
.
6
Langemann
H
,
Torhorst
J
,
Kabiersch
A
,
Krenger
W
,
Honegger
CG
. 
Quantitative determination of water- and lipid-soluble antioxidants in neoplastic and nonneoplastic human breast tissue
.
Int J Cancer
1989
;
43
:
1169
73
.
7
Patterson
JW
. 
Course of diabetes and development of cataracts after injecting dehydroascorbic acid and related substances
.
Am J Physiol
1951
;
165
:
61
5
.
8
Block
KI
,
Koch
AC
,
Mead
MN
,
Tothy
PK
,
Newman
RA
,
Gyllenhaal
C
. 
Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials
.
Cancer Treat Rev
2007
;
33
:
407
18
.