Insulin-like growth factor-1 preserves salivary gland function after fractionated radiation.
OBJECTIVE
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
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.


CONCLUSIONS
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.
Limesand
Kirsten H
KH
Department of Physiological Sciences, University of Arizona, Tucson, USA. limesank@u.arizona.edu
Avila
Jennifer L
JL
Victory
Kerton
K
Chang
Hui-Hua
HH
Shin
Yoon Joo
YJ
Grundmann
Oliver
O
Klein
Rob R
RR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019583:Dose Fractionation, Radiation; D005240:Feasibility Studies; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D014987:Xerostomia / Q000209:etiology / Q000517:prevention & control*
D018809:Proliferating Cell Nuclear Antigen; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt