Advertisement
No access
Research Article
CANCER

High-Dose Parenteral Ascorbate Enhanced Chemosensitivity of Ovarian Cancer and Reduced Toxicity of Chemotherapy

Science Translational Medicine
5 Feb 2014
Vol 6, Issue 222
p. 222ra18

Not-So-Sour Results for Cancer Patients

Ascorbic acid, or vitamin C, was first proposed as a cancer treatment decades ago. Unfortunately, despite anecdotal evidence for effectiveness of intravenous ascorbate, initial clinical trials used the oral form of the drug. On the basis of the results from these trials, ascorbate was determined to be ineffective, and its use for cancer was largely abandoned outside of alternative medicine. However, accumulating anecdotal evidence once again led scientists to reconsider the therapeutic potential of this compound.
Ma and colleagues investigated the use of intravenous ascorbic acid in conjunction with chemotherapy for ovarian cancer, starting from preclinical models and culminating in a human trial. The preclinical studies provided evidence of anticancer effects of ascorbate and demonstrated synergy with chemotherapeutic agents. The early-phase human trial was too small to statistically confirm efficacy, but it demonstrated a significant reduction in chemotherapy-induced adverse effects in patients receiving ascorbate. Although larger studies will be needed to confirm a direct anticancer effect of ascorbate, its ability to decrease chemotherapy-induced adverse effects should already make it a very valuable addition to chemotherapeutic regimens, because a reduction in toxicity would allow patients to tolerate higher (and potentially more effective) doses of chemotherapy.

Abstract

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 (H2O2) 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.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

Summary

Fig. S1. Effects of PARP inhibitor and catalase on ascorbate-induced cytotoxicity in ovarian cancer cells.
Table S1. Original data (provided as an Excel file).
Table S2. IC50 of ascorbate and carboplatin as single-drug or combination treatment.
Table S3. Number of patient encounters, adverse events, and duration of adverse event record.
Table S4. Number of patients showing adverse events in each category.

Resources

File (6-222ra18_sm.pdf)
File (6-222ra18_table_s1.zip)

REFERENCES AND NOTES

1
González M. J., Miranda-Massari J. R., Mora E. M., Guzmán A., Riordan N. H., Riordan H. D., Casciari J. J., Jackson J. A., Román-Franco A., Orthomolecular oncology review: Ascorbic acid and cancer 25 years later. Integr. Cancer Ther. 4, 32–44 (2005).
2
Padayatty S. J., Sun A. Y., Chen Q., Espey M. G., Drisko J., Levine M., Vitamin C: Intravenous use by complementary and alternative medicine practitioners and adverse effects. PLOS One 5, e11414 (2010).
3
McCormick W. J., Cancer: The preconditioning factor in pathogenesis; a new etiologic approach. Arch. Pediatr. 71, 313–322 (1954).
4
Cameron E., Rotman D., Ascorbic acid, cell proliferation, and cancer. Lancet 1, 542 (1972).
5
Cameron E., Pauling L., Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. U.S.A. 73, 3685–3689 (1976).
6
Cameron E., Pauling L., Supplemental ascorbate in the supportive treatment of cancer: Reevaluation of prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. U.S.A. 75, 4538–4542 (1978).
7
Creagan E. T., Moertel C. G., O’Fallon J. R., Schutt A. J., O’Connell M. J., Rubin J., Frytak S., Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N. Engl. J. Med. 301, 687–690 (1979).
8
Moertel C. G., Fleming T. R., Creagan E. T., Rubin J., O’Connell M. J., Ames M. M., High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N. Engl. J. Med. 312, 137–141 (1985).
9
Levine M., Conry-Cantilena C., Wang Y., Welch R. W., Washko P. W., Dhariwal K. R., Park J. B., Lazarev A., Graumlich J. F., King J., Cantilena L. R., Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance. Proc. Natl. Acad. Sci. U.S.A. 93, 3704–3709 (1996).
10
Padayatty S. J., Sun H., Wang Y., Riordan H. D., Hewitt S. M., Katz A., Wesley R. A., Levine M., Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann. Intern. Med. 140, 533–537 (2004).
11
Chen Q., Espey M. G., Sun A. Y., Pooput C., Kirk K. L., Krishna M. C., Khosh D. B., Drisko J., Levine M., Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. U.S.A. 105, 11105–11109 (2008).
12
Hoffer L. J., Levine M., Assouline S., Melnychuk D., Padayatty S. J., Rosadiuk K., Rousseau C., Robitaille L., Miller W. H., Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann. Oncol. 19, 1969–1974 (2008).
13
Monti D. A., Mitchell E., Bazzan A. J., Littman S., Zabrecky G., Yeo C. J., Pillai M. V., Newberg A. B., Deshmukh S., Levine M., Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLOS One 7, e29794 (2012).
14
Chen Q., Espey M. G., Krishna M. C., Mitchell J. B., Corpe C. P., Buettner G. R., Shacter E., Levine M., Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl. Acad. Sci. U.S.A. 102, 13604–13609 (2005).
15
Chen Q., Espey M. G., Sun A. Y., Lee J. H., Krishna M. C., Shacter E., Choyke P. L., Pooput C., Kirk K. L., Buettner G. R., Levine M., Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. U.S.A. 104, 8749–8754 (2007).
16
Du J., Martin S. M., Levine M., Wagner B. A., Buettner G. R., Wang S. H., Taghiyev A. F., Du C., Knudson C. M., Cullen J. J., Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin. Cancer Res. 16, 509–520 (2010).
17
Verrax J., Calderon P. B., Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic. Biol. Med. 47, 32–40 (2009).
18
Pollard H. B., Levine M. A., Eidelman O., Pollard M., Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo 24, 249–255 (2010).
19
Padayatty S. J., Riordan H. D., Hewitt S. M., Katz A., Hoffer L. J., Levine M., Intravenously administered vitamin C as cancer therapy: Three cases. CMAJ 174, 937–942 (2006).
20
Drisko J. A., Chapman J., Hunter V. J., The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J. Am. Coll. Nutr. 22, 118–123 (2003).
21
Welsh J. L., Wagner B. A., van’t Erve T. J., Zehr P. S., Berg D. J., Halfdanarson T. R., Yee N. S., Bodeker K. L., Du J., Roberts L. J., Drisko J., Levine M., Buettner G. R., Cullen J. J., Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): Results from a phase I clinical trial. Cancer Chemother. Pharmacol. 71, 765–775 (2013).
22
Monk B. J., Coleman R. L., Changing the paradigm in the treatment of platinum-sensitive recurrent ovarian cancer: From platinum doublets to nonplatinum doublets and adding antiangiogenesis compounds. Int. J. Gynecol. Cancer 19 (Suppl. 2), S63–S67 (2009).
23
Singh N. P., McCoy M. T., Tice R. R., Schneider E. L., A simple technique for quantitation of low levels of DNA damage in individual cells. Exp. Cell Res. 175, 184–191 (1988).
24
Lee Y. J., Shacter E., Oxidative stress inhibits apoptosis in human lymphoma cells. J. Biol. Chem. 274, 19792–19798 (1999).
25
Verrax J., Delvaux M., Beghein N., Taper H., Gallez B., Buc Calderon P., Enhancement of quinone redox cycling by ascorbate induces a caspase-3 independent cell death in human leukaemia cells. An in vitro comparative study. Free Radic. Res. 39, 649–657 (2005).
26
Chen P., Yu J., Chalmers B., Drisko J., Yang J., Li B., Chen Q., Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy. Anticancer Drugs 23, 437–444 (2011).
27
Warburg O., Wind F., Negelein E., The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).
28
Alexander A., Cai S. L., Kim J., Nanez A., Sahin M., MacLean K. H., Inoki K., Guan K. L., Shen J., Person M. D., Kusewitt D., Mills G. B., Kastan M. B., Walker C. L., ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc. Natl. Acad. Sci. U.S.A. 107, 4153–4158 (2010).
29
Rothbart S. B., Racanelli A. C., Moran R. G., Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas. Cancer Res. 70, 10299–10309 (2010).
30
Micetich K. C., Barnes D., Erickson L. C., A comparative study of the cytotoxicity and DNA-damaging effects of cis-(diammino)(1,1-cyclobutanedicarboxylato)-platinum(II) and cis-diamminedichloroplatinum(II) on L1210 cells. Cancer Res. 45, 4043–4047 (1985).
31
Chou T. C., Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621–681 (2006).
32
Espey M. G., Chen P., Chalmers B., Drisko J., Sun A. Y., Levine M., Chen Q., Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic. Biol. Med. 50, 1610–1619 (2011).
33
Levine M., Padayatty S., Espey M., Vitamin C: A concentration-function approach yields pharmacology and therapeutic discoveries. Adv. Nutr. 2, 78–88 (2011).
34
Carosio R., Zuccari G., Orienti I., Mangraviti S., Montaldo P. G., Sodium ascorbate induces apoptosis in neuroblastoma cell lines by interfering with iron uptake. Mol. Cancer 6, 55 (2007).
35
Hong S. W., Jin D. H., Hahm E. S., Yim S. H., Lim J. S., Kim K. I., Yang Y., Lee S. S., Kang J. S., Lee W. J., Lee W. K., Lee M. S., Ascorbate (vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells. Oncol. Rep. 18, 811–815 (2007).
36
Lin S. Y., Lai W. W., Chou C. C., Kuo H. M., Li T. M., Chung J. G., Yang J. H., Sodium ascorbate inhibits growth via the induction of cell cycle arrest and apoptosis in human malignant melanoma A375.S2 cells. Melanoma Res. 16, 509–519 (2006).
37
Kang J. S., Cho D., Kim Y. I., Hahm E., Yang Y., Kim D., Hur D., Park H., Bang S., Hwang Y. I., Lee W. J., l-Ascorbic acid (vitamin C) induces the apoptosis of B16 murine melanoma cells via a caspase-8–independent pathway. Cancer Immunol. Immunother. 52, 693–698 (2003).
38
Ohtani S., Iwamaru A., Deng W., Ueda K., Wu G., Jayachandran G., Kondo S., Atkinson E. N., Minna J. D., Roth J. A., Ji L., Tumor suppressor 101F6 and ascorbate synergistically and selectively inhibit non–small cell lung cancer growth by caspase-independent apoptosis and autophagy. Cancer Res. 67, 6293–6303 (2007).
39
Verrax J., Cadrobbi J., Marques C., Taper H., Habraken Y., Piette J., Calderon P. B., Ascorbate potentiates the cytotoxicity of menadione leading to an oxidative stress that kills cancer cells by a non-apoptotic caspase-3 independent form of cell death. Apoptosis 9, 223–233 (2004).
40
Jamison J. M., Gilloteaux J., Taper H. S., Summers J. L., Evaluation of the in vitro and in vivo antitumor activities of vitamin C and K-3 combinations against human prostate cancer. J. Nutr. 131, 158S–160S (2001).
41
Gilloteaux J., Jamison J. M., Arnold D., Ervin E., Eckroat L., Docherty J. J., Neal D., Summers J. L., Cancer cell necrosis by autoschizis: Synergism of antitumor activity of vitamin C: Vitamin K3 on human bladder carcinoma T24 cells. Scanning 20, 564–575 (1998).
42
Gilloteaux J., Jamison J. M., Arnold D., Taper H. S., Summers J. L., Ultrastructural aspects of autoschizis: A new cancer cell death induced by the synergistic action of ascorbate/menadione on human bladder carcinoma cells. Ultrastruct. Pathol. 25, 183–192 (2001).
43
Taper H. S., Jamison J. M., Gilloteaux J., Gwin C. A., Gordon T., Summers J. L., In vivo reactivation of DNases in implanted human prostate tumors after administration of a vitamin C/K3 combination. J. Histochem. Cytochem. 49, 109–120 (2001).
44
Farah I. O., Lewis V. L., Ayensu W. K., Mahmud O., Assessing the survival of MRC-5 and A549 cell lines upon exposure to ascorbic acid and sodium ascorbate. Biomed. Sci. Instrum. 47, 201–206 (2011).
45
Verrax J., Dejeans N., Sid B., Glorieux C., Calderon P. B., Intracellular ATP levels determine cell death fate of cancer cells exposed to both standard and redox chemotherapeutic agents. Biochem. Pharmacol. 82, 1540–1548 (2011).
46
Frömberg A., Gutsch D., Schulze D., Vollbracht C., Weiss G., Czubayko F., Aigner A., Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs. Cancer Chemother. Pharmacol. 67, 1157–1166 (2011).
47
Herst P. M., Broadley K. W., Harper J. L., McConnell M. J., Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic. Biol. Med. 52, 1486–1493 (2012).
48
Cullen J. J., Ascorbate induces autophagy in pancreatic cancer. Autophagy 6, 421–422 (2010).
49
Parrow N., Leshin J., Levine M., Parenteral ascorbate as a cancer therapeutic: A reassessment based on pharmacokinetics. Antioxid. Redox Signal. 19, 2141–2156 (2013).
50
Wendt J., Radetzki S., von Haefen C., Hemmati P. G., Güner D., Schulze-Osthoff K., Dörken B., Daniel P. T., Induction of p21CIP/WAF-1 and G2 arrest by ionizing irradiation impedes caspase-3-mediated apoptosis in human carcinoma cells. Oncogene 25, 972–980 (2006).
51
Surova O., Zhivotovsky B., Various modes of cell death induced by DNA damage. Oncogene 32, 3789–3797 (2013).
52
Vessoni A. T., Filippi-Chiela E. C., Menck C. F., Lenz G., Autophagy and genomic integrity. Cell Death Differ. 20, 1444–1454 (2013).
53
Huang Q., Wu Y. T., Tan H. L., Ong C. N., Shen H. M., A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress. Cell Death Differ. 16, 264–277 (2009).
54
Hayashi M. T., Karlseder J., DNA damage associated with mitosis and cytokinesis failure. Oncogene 32, 4593–4601 (2013).
55
Wojewódzka M., Buraczewska I., Kruszewski M., A modified neutral comet assay: Elimination of lysis at high temperature and validation of the assay with anti-single-stranded DNA antibody. Mutat. Res. 518, 9–20 (2002).
56
Denizot F., Lang R., Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods 89, 271–277 (1986).
57
Crowley J., Breslow N., Statistical analysis of survival data. Annu. Rev. Public Health 5, 385–411 (1984).
Correction: The following items were inadvertently omitted from the authors' competing interests: JD holds an unpaid advisory board position for a grassroots advocacy group, the Alliance for Natural Health-USA. She had previously served as a board member for the American College for Advancement in Medicine. QC holds an unpaid position on an advisory board for the International Society of Integrative Medicine. None of these organizations are connected to the supplement industry. The other authors declare that they have no competing interests. The PDF and Full Text versions of the paper have been corrected.

(0)eLetters

eLetters is a forum for ongoing peer review. eLetters are not edited, proofread, or indexed, but they are screened. eLetters should provide substantive and scholarly commentary on the article. Embedded figures cannot be submitted, and we discourage the use of figures within eLetters in general. If a figure is essential, please include a link to the figure within the text of the eLetter. Please read our Terms of Service before submitting an eLetter.

Log In to Submit a Response

No eLetters have been published for this article yet.

Information & Authors

Information

Published In

Science Translational Medicine
Volume 6 | Issue 222
February 2014

Submission history

Received: 26 July 2013
Accepted: 27 December 2013

Permissions

Request permissions for this article.

Acknowledgments

We thank A. Godwin (University of Kansas Cancer Center) and P. Eck (University of Manitoba, Canada) for providing the cell lines. We thank the Center for Biostatistics and Advanced Informatics at the University of Kansas Medical Center for overseeing randomization and designed data intake databases for the clinical trial. We thank R. Wesley (Biostatistics and Clinical Epidemiology Service, NIH) for advice on statistical analysis. Special thanks are given to clinical trial team members D. Khosh, J. Weed, V. Hunter, and E. Schrick. Funding: This work was financially supported by Gateway for Cancer Research Foundation (formerly Cancer Treatment Research Foundation, Schaumburg, IL), a grant from the University of Kansas Endowment provided by the L. Charles Hilton Family Foundation, a bridging grant from the University of Kansas Research Institute, and the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH. Author contributions: Q.C. and Y.M. designed and performed all the cellular and animal experiments. J.D. and J.C. designed and performed the clinical trial. Q.C., J.D., M.L., and Y.M. analyzed the data and wrote the manuscript. K.P. generated part of the data on Comet assay and combination treatment on cells. All authors participated in the revising of the manuscript. Competing interests: JD holds an unpaid advisory board position for a grassroots advocacy group, the Alliance for Natural Health-USA. She had previously served as a board member for the American College for Advancement in Medicine. QC holds an unpaid position on an advisory board for the International Society of Integrative Medicine. None of these organizations are connected to the supplement industry. The other authors declare that they have no competing interests.

Authors

Affiliations

Yan Ma
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
KU Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Julia Chapman
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Mark Levine
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kishore Polireddy
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
KU Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Jeanne Drisko* [email protected]
KU Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
KU Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.

Notes

*
Corresponding author. E-mail: [email protected] (Q.C.); [email protected] (J.D.).

Metrics & Citations

Metrics

Article Usage

Altmetrics

Citations

Cite as

Export citation

Select the format you want to export the citation of this publication.

Cited by

  1. Nutrients-Rich Food Index Scores and the Overall Survival of Ovarian Cancer Patients: Results from the Ovarian Cancer Follow-Up Study, a Prospective Cohort Study, Nutrients, 15, 3, (717), (2023).https://doi.org/10.3390/nu15030717
    Crossref
  2. High-Dose Ascorbate in Combination with Anti-PD1 Checkpoint Inhibition as Treatment Option for Malignant Melanoma, Cells, 12, 2, (254), (2023).https://doi.org/10.3390/cells12020254
    Crossref
  3. Epigenetic Regulators of DNA Cytosine Modification: Promising Targets for Cancer Therapy, Biomedicines, 11, 3, (654), (2023).https://doi.org/10.3390/biomedicines11030654
    Crossref
  4. Cobalt Single-Atom Nanozyme Co-Administration with Ascorbic Acid Enables Redox Imbalance for Tumor Catalytic Ablation, ACS Biomaterials Science & Engineering, 9, 2, (1066-1076), (2023).https://doi.org/10.1021/acsbiomaterials.2c01301
    Crossref
  5. Fasting and fasting mimicking diets in cancer prevention and therapy, Trends in Cancer, 9, 3, (212-222), (2023).https://doi.org/10.1016/j.trecan.2022.12.006
    Crossref
  6. Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate, Redox Biology, 62, (102651), (2023).https://doi.org/10.1016/j.redox.2023.102651
    Crossref
  7. Molecular mechanism of the unusual biphasic effects of the natural compound hinokitiol on iron-induced cellular DNA damage, Free Radical Biology and Medicine, 194, (163-171), (2023).https://doi.org/10.1016/j.freeradbiomed.2022.11.042
    Crossref
  8. Combined effects of vitamin C and cold atmospheric plasma-conditioned media against glioblastoma via hydrogen peroxide, Free Radical Biology and Medicine, 194, (1-11), (2023).https://doi.org/10.1016/j.freeradbiomed.2022.11.028
    Crossref
  9. Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia, Cell Reports, 42, 1, (112027), (2023).https://doi.org/10.1016/j.celrep.2023.112027
    Crossref
  10. Pharmacological ascorbate potentiates combination nanomedicines and reduces cancer cell stemness to prevent post-surgery recurrence and systemic metastasis, Biomaterials, 295, (122037), (2023).https://doi.org/10.1016/j.biomaterials.2023.122037
    Crossref
  11. See more
Loading...

View Options

Check Access

Log in to view the full text

AAAS ID LOGIN

AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.

Log in via OpenAthens.
Log in via Shibboleth.

More options

Register for free to read this article

As a service to the community, this article is available for free. Login or register for free to read this article.

View options

PDF format

Download this article as a PDF file

Download PDF

Full Text

FULL TEXT

Media

Figures

Multimedia

Tables

Share

Share

Share article link

Share on social media