Optimization of the classical oral cancerization protocol in hamster to study oral cancer therapy

Abstract

Objective(s): The hamster carcinogenesis model recapitulates oral oncogenesis.Dimethylbenz [a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal´s welfare and causing tissue loss and pouch shortening. "Short" pouches cannot be everted for local irradiation for Boron Neutron Capture Therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol. Materials and Methods: We studied: Classical cancerization protocol (24 applications); Classical with two interruptions (completed at the end of the cancerization protocol). BNCT mediated by boronophenylalanine (BPA) was performed in both groups. Results: The twice-interrupted group exhibited a significantly lower percentage of animals with severe mucositis vs the non-interrupted group (17% vs 71%) and a significantly higher incidence of long pouches (100% vs 53%). Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis. Conclusion(s): The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favoured the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response.

Boron Neutron Capture Therapy (BNCT) Mediated by Maleimide-Functionalized Closo-Dodecaborate Albumin Conjugates (MID:BSA) for Oral Cancer: Biodistribution Studies and In Vivo BNCT in the Hamster Cheek Pouch Oral Cancer Model

“…None of the remaining animals developed severe mucositis. In addition, BNCT did not exacerbate the pre-BNCT mucositis that the animals exhibited due to the cancerization process [ 36 ].…”

“…For all our experiments, six- to eight-week-old Syrian hamsters were exposed to the optimized classical carcinogenesis protocol [ 36 ]: the topical application of DMBA in mineral oil (0.5%) in the right cheek pouch twice a week for 12 weeks, with 2 interruptions (4 th and 5 th application) completed at the end of the protocol. In previous studies [ 36 ], this optimized protocol reduced the mucositis induced by the cancerization protocol.…”

“…For all our experiments, six- to eight-week-old Syrian hamsters were exposed to the optimized classical carcinogenesis protocol [ 36 ]: the topical application of DMBA in mineral oil (0.5%) in the right cheek pouch twice a week for 12 weeks, with 2 interruptions (4 th and 5 th application) completed at the end of the protocol. In previous studies [ 36 ], this optimized protocol reduced the mucositis induced by the cancerization protocol. The animals were then assigned to different experimental groups for boron biodistribution studies, BNCT radiobiological studies, and to a control group (cancerized sham-irradiated, i.e., matched manipulation, no treatment).…”

“…We evaluated the therapeutic effect of BNCT on those tumors that were present at the time of irradiation (T0) during 28 days. We considered those exophytic tumors that reached a volume of ≥1 mm 3 and ≥0.7 mm in height [ 36 ]. Tumor volume was determined by external caliper measurement of the three largest orthogonal diameters (d) and calculated as d1 × d2 × d3, e.g., [ 40 ].…”

“… The hamster cheek pouch of the animals was cancerized with the optimized classical carcinogenesis protocol [ 36 ]. Once tumors developed, the animals were injected intravenously with MID:BSA (15 mg B/Kg).…”