PMID- 24500406
OWN - NLM
STAT- MEDLINE
DCOM- 20140928
LR  - 20151119
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 6
IP  - 222
DP  - 2014 Feb 5
TI  - High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and 
      reduced toxicity of chemotherapy.
PG  - 222ra18
LID - 10.1126/scitranslmed.3007154 [doi]
AB  - Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an 
      outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate 
      was ineffective in two cancer clinical trials, ascorbate was abandoned by 
      conventional oncology but continued to be used in complementary and alternative 
      medicine. Recent studies provide rationale for reexamining ascorbate treatment. 
      Because of marked pharmacokinetic differences, intravenous, but not oral, 
      ascorbate produces millimolar concentrations both in blood and in tissues, 
      killing cancer cells without harming normal tissues. In the interstitial fluid 
      surrounding tumor cells, millimolar concentrations of ascorbate exert local 
      pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which 
      kills cancer cells. We investigated downstream mechanisms of ascorbate-induced 
      cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced 
      DNA damage and depleted cellular adenosine triphosphate (ATP), activated the 
      ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein 
      kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) 
      inhibition and death in ovarian cancer cells. The combination of parenteral 
      ascorbate with the conventional chemotherapeutic agents carboplatin and 
      paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced 
      chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of 
      its potential benefit and minimal toxicity, examination of intravenous ascorbate 
      in combination with standard chemotherapy is justified in larger clinical trials.
FAU - Ma, Yan
AU  - Ma Y
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, KS 66160, USA.
FAU - Chapman, Julia
AU  - Chapman J
FAU - Levine, Mark
AU  - Levine M
FAU - Polireddy, Kishore
AU  - Polireddy K
FAU - Drisko, Jeanne
AU  - Drisko J
FAU - Chen, Qi
AU  - Chen Q
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antineoplastic Agents)
RN  - BG3F62OND5 (Carboplatin)
RN  - P88XT4IS4D (Paclitaxel)
RN  - PQ6CK8PD0R (Ascorbic Acid)
SB  - IM
CIN - Nat Rev Clin Oncol. 2014 Apr;11(4):180. PMID: 24569447
MH  - Animals
MH  - Antineoplastic Agents/*adverse effects/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use
MH  - Ascorbic Acid/*administration & dosage/adverse effects/*therapeutic use
MH  - Carboplatin/pharmacology/therapeutic use
MH  - Cell Death/drug effects
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Female
MH  - *Infusions, Parenteral
MH  - Mice
MH  - Ovarian Neoplasms/*drug therapy/pathology
MH  - Paclitaxel/pharmacology/therapeutic use
MH  - Xenograft Model Antitumor Assays
EDAT- 2014/02/07 06:00
MHDA- 2014/10/01 06:00
CRDT- 2014/02/07 06:00
PHST- 2014/02/07 06:00 [entrez]
PHST- 2014/02/07 06:00 [pubmed]
PHST- 2014/10/01 06:00 [medline]
AID - 6/222/222ra18 [pii]
AID - 10.1126/scitranslmed.3007154 [doi]
PST - ppublish
SO  - Sci Transl Med. 2014 Feb 5;6(222):222ra18. doi: 10.1126/scitranslmed.3007154.