Insulin-Like Growth Factor–1 Preserves Salivary Gland Function After Fractionated Radiation

• Published in: International journal of radiation oncology, biology, physics Vol. 78; no. 2; pp. 579 - 586
• Main Authors: Limesand, Kirsten H., Ph.D, Avila, Jennifer L., M.S, Victory, Kerton, Chang, Hui-Hua, Shin, Yoon Joo, Grundmann, Oliver, Ph.D, Klein, Rob R., M.D
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2010; Elsevier
• Subjects: Akt; ANIMALS; APOPTOSIS; Apoptosis - drug effects; Biological and medical sciences; BODY; CELL PROLIFERATION; Cell Proliferation - drug effects; DISEASES; Dose Fractionation; Ent and stomatology; Feasibility Studies; FRACTIONATED IRRADIATION; GLANDS; GROWTH FACTORS; HEAD; Hematology, Oncology and Palliative Medicine; HOMEOSTASIS; HORMONES; IGF-1; INSULIN; Insulin-Like Growth Factor I - therapeutic use; IRRADIATION; MAMMALS; Medical sciences; MEDICINE; MICE; Mice, Transgenic; MITOGENS; NECK; NEOPLASMS; NUCLEAR MEDICINE; ORGANIC COMPOUNDS; ORGANS; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; PEPTIDE HORMONES; Proliferating Cell Nuclear Antigen - metabolism; PROTEINS; Proto-Oncogene Proteins c-akt - metabolism; Radiation Injuries, Experimental - pathology; Radiation Injuries, Experimental - prevention & control; Radiation therapy and radiosensitizing agent; Radiation-Protective Agents - therapeutic use; RADIOLOGY; RADIOLOGY AND NUCLEAR MEDICINE; RADIOTHERAPY; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Recombinant Proteins - metabolism; RODENTS; salivary gland dysfunction; SALIVARY GLANDS; Salivary Glands - drug effects; Salivary Glands - pathology; Salivary Glands - radiation effects; THERAPY; TRANSGENIC ANIMALS; TRANSGENIC MICE; Treatment with physical agents; Treatment. General aspects; Tumors; VERTEBRATES; xerostomia; Xerostomia - etiology; Xerostomia - prevention & control; apoptosis; IGF-1; Akt; xerostomia; salivary gland dysfunction; Biological properties; Radioprotector; Toxicity; Transgenic animal; Xerostomia; ENT disease; Complication; Aptyalism; Rodentia; Akt protein kinase; Salivary gland; Malignant tumor; Insulin like growth factor 1; Radiotherapy; Fractionated dose; Vertebrata; Mammalia; Salivary gland disease; Treatment; Mouse; Dysfunction; Radiation injury; Head and neck cancer; Cancer; Apoptosis
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2010.03.035

Purpose Radiotherapy for head-and-neck cancer consists of fractionated radiation treatments that cause significant damage to salivary glands leading to chronic salivary gland dysfunction with only limited prevention and treatment options currently available. This study examines the feasibility of IGF-1 in preserving salivary gland function following a fractionated radiation treatment regimen in a pre-clinical model. Methods and Materials Mice were exposed to fractionated radiation, and salivary gland function and histological analyses of structure, apoptosis, and proliferation were evaluated. Results In this study, we report that treatment with fractionated doses of radiation results in a significant level of apoptotic cells in FVB mice after each fraction, which is significantly decreased in transgenic mice expressing a constitutively active mutant of Akt1 (myr-Akt1). Salivary gland function is significantly reduced in FVB mice exposed to fractionated radiation; however, myr-Akt1 transgenic mice maintain salivary function under the same treatment conditions. Injection into FVB mice of recombinant insulin-like growth factor–1 (IGF-1), which activates endogenous Akt, suppressed acute apoptosis and preserved salivary gland function after fractionated doses of radiation 30 to 90 days after treatment. FVB mice exposed to fractionated radiation had significantly lower levels of proliferating cell nuclear antigen–positive salivary acinar cells 90 days after treatment, which correlated with a chronic loss of function. In contrast, FVB mice injected with IGF-1 before each radiation treatment exhibited acinar cell proliferation rates similar to those of untreated controls. Conclusion These studies suggest that activation of IGF-1–mediated pathways before head-and-neck radiation could modulate radiation-induced salivary gland dysfunction and maintain glandular homeostasis.