Hyperthermia and radiation in vivo: Effect of 2-deoxy-D-glucose

Gridley, Daila S.; Nutter, Robert L.; Mantik, David W.; Slater, James M.

doi:10.1016/0360-3016(85)90189-0

Cited by 9 publications

(12 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests an increased response by the cell under a more aggressive therapeutic regimen, possibly leading to increased repair and survival. Furthermore, data extracted from a previous publication seem to agree with our findings (22). Here, tumors given external beam therapy (V2Gy) alone were smaller than when the same irradiation regime was combined with 1 g/kg 2DG.…”

Section: Discussionsupporting

confidence: 91%

“…In vivo studies of 2DG alone have reported either no effect (22,24) or slight tumor growth delay (22,23). These differences may be explained in part in the light of our in vitro results, which suggest that only the very hypoxic regions of solid tumor are susceptible to 2DG toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Previous in vivo studies have reported that the LD 50 of 2DG is in the range 3.85 to 4.5 g/kg (22,37). Preliminary studies were undertaken to investigate the effect of 2DG in our model system.…”

Section: Therapy Studiesmentioning

confidence: 97%

“…The depletion of tumor ATP by 2DG in vivo has been shown (21). 2DG has been shown to be cytotoxic in vitro; given alone, it can affect the growth of some tumors in vivo (22,23). However, this effect has not been reported in all cases (22,24).…”

mentioning

confidence: 99%

“…2DG has been shown to be cytotoxic in vitro; given alone, it can affect the growth of some tumors in vivo (22,23). However, this effect has not been reported in all cases (22,24). When included in the diet, it can also reduce tumor incidence and growth (25).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Combining Radioimmunotherapy with Antihypoxia Therapy 2-Deoxy-d-Glucose Results in Reduction of Therapeutic Efficacy

Dearling

Qureshi

Begent

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The efficacy of solid tumor radioimmunotherapy is reduced by heterogeneous tumor distribution of the radionuclide, with dose mainly deposited in the normoxic region and by the relative radioresistance of hypoxic tumor cells. In an attempt to overcome these challenges, radioimmunotherapy was combined with 2-deoxy-D-glucose (2DG), a hypoxia-selective cytotoxic inhibitor of glucose metabolism. Experimental Design: In vitro toxicity of 2DG in LS174T cultures was tested using a colonyforming assay. The effect of combining 2DG with radioimmunotherapy in vivo was tested by administering radiolabeled anti^carcinoembryonic antigen antibody ([ 131 I]A5B7 IgG1 whole monoclonal) to nude mice bearing s.c. LS174T tumors, followed by 10 daily injections of 2DG (2.0 g/kg). Tumors were measured to assess therapeutic efficacy. Results: Data from in vitro studies confirmed 2DG cytotoxicity in this cell line. Greater toxicity was observed under standard laboratory conditions and in hypoxic cultures than at intermediate, physiologically relevant levels of glucose and oxygen. Alone, 2DG had no effect on in vivo tumor growth (P = 0.377 compared with saline-treated controls). Combination of radioimmunotherapy with 2DG reduced the therapeutic effect of radioimmunotherapy (e.g., 150 ACi 131 I alone mean survival time, 48.33 F 16.83 days; combined with 2DG, 30.67 F 5.62 days, P = 0.038). Conclusions: The combination investigated had a detrimental effect on survival. It is suggested that a cellular metabolic response to more aggressive therapy, previously reported in vitro, caused this. The results of this study have implications for the clinical application of combined cancer therapies with an antimetabolic modality component.Radioimmunotherapy is a cancer treatment that uses a tumorspecific antibody to deliver a cytotoxic radionuclide. Delivered systemically, this therapy can access and treat tumor sites throughout the body, which might evade other therapies, such as surgery or locoregional external beam radiotherapy. Radioimmunotherapy has shown efficacy in model systems (1), lymphomas (2), and some common carcinomas (3), but has yet to achieve its clinical potential in solid tumors in which its effect has been suboptimal (4, 5).Despite advances in antibody formats and radionuclide availability, use, and selection, radioimmunotherapy of common epithelial tumors is yet to achieve the success seen in the treatment of hematologic malignancies. Reasons for this include difficulty in delivering sufficient radiation dose to kill the tumor. Common epithelial tumors often have an abnormal vascular system leading to poor delivery of systemically delivered therapeutic molecules. Moreover, once the radionuclide has been delivered, its effect is hindered by heterogeneous resistance of tumor cells to therapy. Addressing these mechanisms of therapeutic resistance is critical to successful treatment in the clinic.Oxygen is a potent radiosensitizer. Hypoxic cells require up to a 3-fold higher radiation dose than their aerobic cou...

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Therapy Studiesmentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Combining Radioimmunotherapy with Antihypoxia Therapy 2-Deoxy-d-Glucose Results in Reduction of Therapeutic Efficacy

Dearling

Qureshi

Begent

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo

et al. 2015

View full text Add to dashboard Cite

Efficient Elimination of Cancer Cells by Deoxyglucose-ABT-263/737 Combination Therapy

et al. 2011

View full text Add to dashboard Cite

As single agents, ABT-263 and ABT-737 (ABT), molecular antagonists of the Bcl-2 family, bind tightly to Bcl-2, Bcl-xL and Bcl-w, but not to Mcl-1, and induce apoptosis only in limited cell types. The compound 2-deoxyglucose (2DG), in contrast, partially blocks glycolysis, slowing cell growth but rarely causing cell death. Injected into an animal, 2DG accumulates predominantly in tumors but does not harm other tissues. However, when cells that were highly resistant to ABT were pre-treated with 2DG for 3 hours, ABT became a potent inducer of apoptosis, rapidly releasing cytochrome c from the mitochondria and activating caspases at submicromolar concentrations in a Bak/Bax-dependent manner. Bak is normally sequestered in complexes with Mcl-1 and Bcl-xL. 2DG primes cells by interfering with Bak-Mcl-1 association, making it easier for ABT to dissociate Bak from Bcl-xL, freeing Bak to induce apoptosis. A highly active glucose transporter and Bid, as an agent of the mitochondrial apoptotic signal amplification loop, are necessary for efficient apoptosis induction in this system. This combination treatment of cancer-bearing mice was very effective against tumor xenograft from hormone-independent highly metastasized chemo-resistant human prostate cancer cells, suggesting that the combination treatment may provide a safe and effective alternative to genotoxin-based cancer therapies.

show abstract

Hyperthermia and radiation in vivo: Effect of 2-deoxy-D-glucose

Cited by 9 publications

References 21 publications

Combining Radioimmunotherapy with Antihypoxia Therapy 2-Deoxy-d-Glucose Results in Reduction of Therapeutic Efficacy

Combining Radioimmunotherapy with Antihypoxia Therapy 2-Deoxy-d-Glucose Results in Reduction of Therapeutic Efficacy

Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo

Efficient Elimination of Cancer Cells by Deoxyglucose-ABT-263/737 Combination Therapy

Contact Info

Product

Resources

About