AdLTR2EF1α-FGF2-mediated prevention of fractionated irradiation-induced salivary hypofunction in swine

Abstract

Patients frequently experience a loss of salivary function following irradiation (IR) for the treatment of an oral cavity and oropharyngeal cancer. Herein, we tested if transfer of fibroblast growth factor-2 (FGF2) cDNA could limit salivary dysfunction after fractionated IR (7.5 or 9 Gy for 5 consecutive days to one parotid gland) in the miniature pig (minipig). Parotid salivary flow rates steadily decreased by 16 weeks post-IR, whereas blood flow in the targeted parotid gland began to decrease ~3 days after beginning IR. By 2 weeks, post-IR salivary blood flow was reduced by 50%, at which point it remained stable for the remainder of the study. The single preadministration of a hybrid serotype 5 adenoviral vector encoding FGF2 (AdLTR2EF1a-FGF2) resulted in the protection of parotid microvascular endothelial cells from IR damage and significantly limited the decline of parotid salivary flow. Our results suggest that a local treatment directed at protecting salivary gland endothelial cells may be beneficial for patients undergoing IR for oral cavity and oropharyngeal cancer.

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

“…Current thinking points to radiation-induced loss of primitive mesenchymal stem-like progenitor cells as well as the loss of acinar cells, both of which may potentially contribute to repopulate the salivary gland, together with decreased parasympathetic innervation and loss of endothelial cells and microvessels as the main causes of irreversible salivary hypofunction (12,15,16,27,(47)(48)(49). Previous studies indicate that progenitor populations that are capable of repopulating and restoring salivary gland function following irradiation reside in the ductal cell compartment (10,27,50).…”

“…The fundamental cellular and molecular mechanisms underlying the loss of salivary gland function are not clearly understood (4). Evidence derived largely from animal models supports the notion that radiation-induced salivary hypofunction is a multifactorial process initiated by DNA damage to various tissue components within the gland, including the parenchymal acinar cells, endothelium, stem/progenitor cells and also parasympathetic innervation (10)(11)(12)(13)(14)(15)(16). Apoptosis, occurring within the first few days following irradiation, has also been proposed as a fundamental mechanism underlying loss of both acinar cells and glandular innervation (15,17,18).…”

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

“…8,17,29 However, after IR KGF treatment did not significantly rescue IR-induced hyposalivation, whereas mobilizing bone marrow-derived cells including endothelial progenitors ameliorated vascular damage and facilitated functional restoration of salivary glands. 30,31 Hh signaling promotes homeostatic angiogenesis during tissue repair and/or regeneration via multiple pathways.…”

Advances in salivary gland gene therapy – oral and systemic implications

“…We developed two potentially useful gene therapy approaches to prevent gland radiation damage, using cDNAs encoding either human fibroblast growth factor-2 (hFGF2) or human keratinocyte growth factor [28,29]. Both of those studies were conducted in mice, but recently we have shown that the hFGF2 strategy can be scaled and be effective in miniature pigs, an important consideration for eventual clinical application [30]. These studies provided proof of concept that the salivary glands can be protected from radiation-induced damage.…”

“…However, both must now be tested in a large animal model, e.g., as noted above [24,30], as well as shown to be safe in toxicological and biodistribution studies, e.g., [25,26] before any clinical trial can be initiated.…”