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

• Published in: Clinical cancer research Vol. 13; no. 6; pp. 1903 - 1910
• Main Authors: DEARLING, Jason L. J, QURESHI, Uzma, BEGENT, Richard H. J, PEDLEY, R. Barbara
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-03-2007
• Subjects: 2DG; Adenocarcinoma - drug therapy; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adenocarcinoma - radiotherapy; Animals; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; ATP-depleting therapy; Biological and medical sciences; Cell Hypoxia; Colonic Neoplasms - drug therapy; Colonic Neoplasms - mortality; Colonic Neoplasms - pathology; Colonic Neoplasms - radiotherapy; combination therapies; Combined Modality Therapy - adverse effects; Deoxyglucose - adverse effects; Deoxyglucose - therapeutic use; Female; Humans; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; radioimmunotherapy; Radioimmunotherapy - adverse effects; Radioimmunotherapy - methods; Survival Analysis; Tumor Burden - drug effects; Tumor Burden - radiation effects; Xenograft Model Antitumor Assays; Immunoradiotherapy; Treatment; Glucose; Radiotherapy; Treatment efficiency
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-2094

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 colony-forming 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 μCi 131 I alone mean survival time, 48.33 ± 16.83 days; combined with 2DG, 30.67 ± 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.