Source: clincancerres.aacrjournals.org
Authors: Changyu Zheng et al.

Purpose:
Salivary glands are significantly affected when head and neck cancer patients are treated by radiation. We evaluated the effect of human keratinocyte growth factor (hKGF) gene transfer to murine salivary glands on the prevention of radiation-induced salivary hypofunction.

Experimental Design:
A hybrid serotype 5 adenoviral vector encoding hKGF (AdLTR2EF1alpha-hKGF) was constructed. Female C3H mice, 8 weeks old, were irradiated by single (15 Gy) or fractionated (6 Gy for 5 days) doses to induce salivary hypofunction. AdLTR2EF1alpha-hKGF or Adcontrol was administered (108 – 1010 particles/gland) to both submandibular glands (SGs) by retrograde ductal instillation before irradiation. Salivary flow was measured following pilocarpine stimulation. Human KGF levels were measured by ELISA. SG cell proliferation was measured with bromodeoxyuridine labeling. Endothelial and progenitor or stem cells in SGs were measured by flow cytometry. The effect on SG hKGF production on SCC VII tumor growth was assessed.

Results:
In 3 separate single dose irradiation experiments salivary flow rates of mice administered the AdLTR2EF1alpha-hKGF vector were not significantly different from non-irradiated control mice (P greater than 0.05). Similarly, in 3 separate fractionated irradiation experiments the hKGF-expressing vector prevented salivary hypofunction dramatically. Transgenic hKGF protein was found at high levels in serum and SG extracts. AdLTR2EF1alpha-hKGF-treated mice showed increased cell proliferation, and numbers of endothelial cells, compared to mice treated with AdControl. hKGF gene transfer had no effect on SCC VII tumor growth plus/minus radiation.

Conclusions:
hKGF gene transfer prevents salivary hypofunction caused by either single or fractionated radiation dosing in mice. The findings suggest a potential clinical application. α≥±α

Authors:
1. Changyu Zheng1,
2. Ana Cotrim2,
3. Anne Rowzee3,
4. William Swaim1,
5. Anastasia Sowers4,
6. James B Mitchell5, and
7. Bruce J Baum1

Authors’ affilaitions:
1 MPTB/NIDCR, NIH
2 MPTB, NIDCR, NIH
3 Neurology and Neurosciences, University of Medicine and Dentistry of NJ
4 Radiation Biology Branch, NCI, NIH
5 Radiation Biology Branch, National Cancer Institute, NIH