Targeting hypoxia, a novel treatment for advanced retinoblastoma.

Abstract

PURPOSE:

The purpose of this study was to evaluate the presence and extent of hypoxia in murine retinoblastoma tumors and the feasibility of targeting hypoxic cells as a novel therapeutic strategy.

METHODS:

Hypoxic and vascular areas in LH(BETA)T(AG) mouse retinal tumors were measured using immunohistochemistry. The glycolytic inhibitor 2-deoxy-d-glucose (2-DG) was used to test the efficacy of targeting hypoxic cells in retinoblastoma. Sixteen-week-old LH(BETA)T(AG) mice received injections of saline, carboplatin (31.25 microg/20 microL), 2-DG (500 mg/kg), and carboplatin (31.25 microg/20 microL) + 2-DG (500 mg/kg). Carboplatin was administered through biweekly subconjunctival injections to right eyes only for 3 weeks. 2-DG was administered through intraperitoneal injection three times a week for 5 weeks. Saline was administered using both methods. Eyes were enucleated at 21 weeks of age and examined for residual tumor.

RESULTS:

Hypoxic regions were observed in tumors larger than 3.28 mm(2). When 2-DG was combined with carboplatin, a marked decrease in tumor burden was observed that was significantly more pronounced than when either agent was given alone. The hypoxic tumor cell population as measured by pimonidazole was markedly reduced by carboplatin + 2-DG (P < 0.01) and by 2-DG alone (P < 0.01), but not by carboplatin alone, indicating that 2-DG effectively killed hypoxic retinoblastoma cells in vivo.

CONCLUSIONS:

Treatment with glycolytic inhibitors as adjuvants to chemotherapy has the potential to increase the efficacy of chemotherapy in advanced retinoblastoma. This approach may have benefits for children with this disease and should be further investigated.

• Authors: Hinda Boutrid, Maria-Elena Jockovich, Timothy G Murray, Yolanda Piña, William J Feuer, Theodore J Lampidis, Colleen M Cebulla
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 49 Issue 7 Pg. 2799-805 (Jul 2008) ISSN: 1552-5783 [Electronic] United States
• PMID: 18326690 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites
• Antineoplastic Agents
• Drug Combinations
• Deoxyglucose
• Carboplatin

Topics

• Animals
• Antimetabolites (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Carboplatin (therapeutic use)
• Chemotherapy, Adjuvant
• Deoxyglucose (therapeutic use)
• Disease Progression
• Drug Combinations
• Drug Synergism
• Feasibility Studies
• Glycolysis (drug effects)
• Hypoxia (drug therapy, etiology, pathology)
• Immunohistochemistry
• Mice
• Mice, Transgenic
• Retinal Neoplasms (complications, drug therapy, pathology)
• Retinal Vessels (pathology)
• Retinoblastoma (complications, drug therapy, pathology)