Protective activity on radiation-induced mucositis and effect on tumor growth of a dextran-derivative Free

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Background Our purposes were to evaluate effect of an heparan-mimetic dextran-derivative biopolymer called RGTA-OTR4131 and of amifostine-RGTA combination on radiation-induced mucositis in a mouse model and on in vivo and in vitro tumor growth.

Material and methods Radiation-induced mucositis A single 16.5Gy radiation dose was selectively delivered to the oral region of C57/b mice. Several doses and administration timings of OTR4131 and amifostine- OTR4131 combination were evaluated and compared with amifostine alone effect and untreated control mice. Mucosal reaction was evaluated by the Parkins scoring system (Parkins, 1983) and in histological samples. Tumor xenograft HEP-2 and HT-29 cells were grafted subcutaneously into Balb/c nude mice. A 15Gy single dose was delivered selectively to the tumor and mice were treated with several schedules of OTR4131 and amifostine- OTR4131 administration. Clonogenic assays Survival fraction of HEP-2 and HT-29 cells cultured with different doses of RGTA was evaluated using the Puck model.

Results Radiation-induced mucositis Mucositis score was significantly lower with administration of OTR4131 1mg/kg 24h after irradiation, compared to irradiation alone (p=0.001). Various other timings and doses were less effective. Amifostine-OTR4131 combination evidenced a remarkable protective effect (p=0.001) and a mayor and better mucosal control compared to OTR4131 alone (p=0.001) and also to amifostine alone (p=0.005).Histopathological analysis showed an epidermal hypertrophy, a lower deposition of collagen and a significant reduction of inflammatory cell infiltration in OTR4131 treated mice compared to untreated irradiated tissue. Association of amifostine with OTR4131 induced a complete histological recovery of the mucositis. In vivo tumor growth In HEP-2 xenografted we did not observe any tumor protection when OTR4131 and amifostine-OTR4131 combination were administered with or without irradiation. In HT-29 xenografted mice OTR4131 administration did not show effect on tumor growth in presence of irradiation. In absence of irradiation, we observed a significant control on tumor growth with OTR4131 40mg/kg (p<0.0001). The in vitro clonogenic assay on HEP-2 cells did not evidence interference on cell survival of 10µl/ml OTR4131. On HT-29 cells, higher doses of OTR4131 (100-300-500 µl/ml) showed a significant decrease of clonogenic survival in presence and absence of 2Gy irradiation.

Conclusions Our study demonstrates that OTR4131 in mice has a marked protective activity toward radiation-induced mucositis and that the amifostine-OTR4131 association gives an almost total protection. There is not evidence of tumor protection to irradiation induced by OTR4131, rather our observations in vitro et in vivo in the HT-29 tumor cell line suggests that OTR4131 inhibits tumor growth.