Toll-like Receptor 5 Agonist Protects Mice From Dermatitis and Oral Mucositis Caused by Local Radiation: Implications for Head-and-Neck Cancer Radiotherapy

Abstract

Purpose Development of mucositis is a frequent side effect of radiotherapy of patients with head and neck cancer. We have recently reported that bacterial flagellin, an agonist of Toll-like receptor 5 (TLR5), can protect rodents and primates from acute radiation syndrome caused by total body irradiation (Burdelya et al., 2008, Science 320: 226-30). Here we analyzed the radioprotective efficacy of TLR5 agonist under conditions of local, single dose or fractionated radiation treatment. Methods and Materials Mice received either single-dose (10, 15, 20 or 25 Gy) or fractioned irradiation (cumulative dose up to 30 Gy) of the head and neck area with or without subcutaneous injection of pharmacologically optimized flagellin, CBLB502, 30 minutes prior to irradiation. Results CBLB502 significantly reduced the severity of dermatitis and mucositis, accelerated tissue recovery and reduced the extent of radiation induced weight loss in mice after a single dose of 15 or 20 Gy but not from 25 Gy of radiation. CBLB502 was also protective from cumulative doses of 25 and 30 Gy delivered in two (10+15 Gy) or three (3 × 10 Gy) fractions, respectively. While providing protection to normal epithelia, CBLB502 did not affect the radiosensitivity of syngeneic squamous carcinoma SCCVII grown orthotopically in mice. Use of CBLB502 also elicited a radiation independent growth inhibitory effect upon TLR5-expressing tumors demonstrated in the mouse xenograft model of human lung adenocarcinoma A549. Conclusion CBLB502 combines properties of supportive care (radiotherapy adjuvant) and anticancer agent, both mediated via activation of TLR5 signaling in the normal tissues or the tumor, respectively.

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis

“…Although many studies have generated RIOM [39,50,53,194] animal models, most of them were artificial models and the tight duration of OM resulted in limitation of the experimental procedures. The main objective of our experimentations this time was to generate a RIOM mouse model having the longest possible ulcer duration using the maximally tolerated RT dose, signifying the need to develop a self-resolving lesion.…”

“…RIOM mouse models have been developed in earlier studies for both fractionated [15,39,48,49] and single dose RT [1, [50][51][52][53]. Both models did not have a long enough inflammatory and ulceration phase of RIOM as needed.…”

“…The fear of MSCs-mediated radioprotection of tumor tissues has been a raised concern after the availability of in-vitro data suggesting that breast cancer cells grow and proliferate more with MSCs-therapy owing to high insulin-like factor production [53]. Also, MSCs have some agiogenic properties evident by increased secretion of (platelets derived growth factor) PDGF, VEGF and TGF-β at the tumor perivascular area and parenchyma in low dose irradiated mice owing to MSCs infiltration at the tumor site [53].…”

“…Also, MSCs have some agiogenic properties evident by increased secretion of (platelets derived growth factor) PDGF, VEGF and TGF-β at the tumor perivascular area and parenchyma in low dose irradiated mice owing to MSCs infiltration at the tumor site [53]. MSCs angiogenic properties might counteract the anti-angiogenic cancer therapies, a question that needs to be answered with solid in-vitro and in-vivo studies [71,104].…”

“…MSCs have been found to have heterogeneous radiation resistant populations, both in human and mouse MSCs [53]. A finding that might interfere with the overall radio-protective and tissue regenerative properties of MSCs.…”