Differential effect triggered by a heparan mimetic of the RGTA family preventing oral mucositis without tumor protection.
OBJECTIVE
Oral mucositis is a common side effect induced by radio/chemotherapy in patients with head and neck cancer. Although it dramatically impairs patient quality of life, no efficient and safe therapeutic solution is available today. Therefore, we investigated the protective efficacy of a new heparan mimetic biopolymer, RGTA-OTR4131, used alone or in combination with amifostine, for oral mucositis and simultaneously evaluated its effect on tumor growth in vitro and in vivo.


METHODS
A single dose of 16.5 Gy was selectively delivered to the snout of mice, and the effects of OTR4131 or amifostine-OTR4131 were analyzed by macroscopic scoring and histology. The effect of OTR4131 administration on tumor growth was then investigated in vitro and in xenograft models using two cell lines (HEP-2 and HT-29).


RESULTS
Amifostine and OTR4131 significantly decreased the severity and duration of lip mucosal reactions. However, amifostine has to be administered before irradiation, whereas the most impressive protection was obtained when OTR4131 was injected 24 h after irradiation. In addition, OTR4131 was well tolerated, and the combination of amifostine and OTR4131 further enhanced mucosal protection. At the tumor level, OTR4131 did not modify HEP-2 cell line clonogenic survival in vitro or protect xenografted tumor cells from radiotherapy. Of interest, high doses of OTR4131 significantly decreased clonogenic survival of HT-29 cells.


CONCLUSIONS
RGTAs-OTR4131 is a well-tolerated, natural agent that effectively reduces radio-induced mucositis without affecting tumor sensitivity to irradiation. This suggests a possible transfer into the clinic for patients' benefit.
Mangoni
Monica
M
Laboratoire UPRES EA 2710, Institut Gustave Roussy, Villejuif, France.
Yue
Xiaoli
X
Morin
Christophe
C
Violot
Dominique
D
Frascogna
Valerie
V
Tao
Yungan
Y
Opolon
Paule
P
Castaing
Marine
M
Auperin
Anne
A
Biti
Giampaolo
G
Barritault
Denis
D
Vozenin-Brotons
Marie-Catherine
MC
Deutsch
Eric
E
Bourhis
Jean
J
D004999:Amifostine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005936:Glucans / Q000008:administration & dosage / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D008046:Lip / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D013280:Stomatitis / Q000517:prevention & control*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D005936:Glucans; C542264:OTR 4131; D011837:Radiation-Protective Agents; D004999:Amifostine