Tumor Blood Vessel “Normalization” Improves the Therapeutic Efficacy of Boron Neutron Capture Therapy (BNCT) in Experimental Oral Cancer

Abstract

We previously demonstrated the efficacy of BNCT mediated by boronophenylalanine (BPA) to treat tumors in a hamster cheek pouch model of oral cancer with no normal tissue radiotoxicity and moderate, albeit reversible, mucositis in precancerous tissue around treated tumors. It is known that boron targeting of the largest possible proportion of tumor cells contributes to the success of BNCT and that tumor blood vessel normalization improves drug delivery to the tumor. Within this context, the aim of the present study was to evaluate the effect of blood vessel normalization on the therapeutic efficacy and potential radiotoxicity of BNCT in the hamster cheek pouch model of oral cancer. Blood vessel normalization was induced by two doses of thalidomide in tumor-bearing hamsters on 2 consecutive days. All studies in thalidomide-treated animals were performed 48 h after the first dose of thalidomide, previously established as the window of normalization. Biodistribution studies were performed with BPA at a dose of 15.5 mg (10)B/kg in thalidomide-treated (Th+) and untreated (Th-) tumor-bearing hamsters. The effect of blood vessel normalization prior to BPA administration on the efficacy of BNCT was assessed in in vivo BNCT studies at the RA-3 Nuclear Reactor in tumor-bearing hamsters. Group I was treated with BPA-BNCT after treatment with thalidomide (Th+ BPA-BNCT). Group II was treated with BPA-BNCT alone (Th- BPA-BNCT). Group III was treated with the beam only after treatment with thalidomide (Th+ BO), and Group IV was treated with the beam only (Th- BO). Groups I and II were given the same dose of BPA (15.5 mg (10)B/kg), and all groups (I-IV) were exposed to the same neutron fluence. Two additional groups were treated with the beam only at a higher dose to exacerbate mucositis in precancerous tissue and to explore the potential direct protective effect of thalidomide on radiation-induced mucositis in a scenario of more severe toxicity, i.e. Group V (Th+ hdBO) and Group VI (Th- hdBO). The animals were followed for 28 days. Biodistribution studies revealed no statistically significant differences in gross boron content between Th+ and Th- animals. Overall tumor control (complete response + partial response) at 28 days post-treatment was significantly higher for Group I (Th+ BPA-BNCT) than for Group II (Th- BPA-BNCT): 84 ± 3% compared to 67 ± 5%. Pretreatment with thalidomide did not induce statistically significant changes in overall tumor control induced by the beam only, i.e. 15 ± 5% in Group III (Th+ BO) and 18 ± 5% in Group IV (Th- BO), or in overall tumor control induced by the high-dose beam only, i.e. 60 ± 7% in Group V (Th+ hdBO) and 47 ± 10% in Group VI (Th- hdBO). BPA-BNCT alone (Group II) induced mucositis in precancerous tissue that reached Grades 3-4 in 80% of the animals, whereas pretreatment with thalidomide (Group I) prevented mucositis Grades 3 and 4 completely. Beam-only Group III (Th+ BO) exhibited only Grade 1 mucositis in precancerous tissue, whereas 17% of the animals in beam-only Group IV (Th- BO) ...

Therapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch model

“…To evaluate toxicity, the clinical signs and bw of all animals were monitored twice per week. The tumor and precancerous tissue responses were assessed by visual inspection and tumor volume assay before treatment and at 1, 7, 14, 21, and 28 d posttreatment in keeping with the previously established follow-up period for tumor control studies in this model (12,32,40,49). When possible, the animals were followed for longer periods of time (up to 16 wk from the first treatment).…”

“…Tumor volume was determined by external caliper measurement of the three largest orthogonal diameters and expressed in cubic millimeters (32). Any degree of reduction from initial tumor volume was considered as partial tumor response (PR) as defined in previous studies (49). 3 mm 3 ) and tumor 2 (7 mm 3 ) exhibited CR, whereas tumor 3 (17.9 mm 3 ) exhibited PR, with a reduction in volume to 6.6 mm 3 .…”

“…CR was defined as disappearance of the tumor on visual inspection. OR was defined as PR plus CR (49). Tumor response was evaluated considering three arbitrary tumor sizes (small, <10 mm 3 ; medium, 10-100 mm 3 ; and large, >100 mm 3 ) defined to categorize tumor size at the time of irradiation and evaluate potential differential response according to size (49).…”

“…OR was defined as PR plus CR (49). Tumor response was evaluated considering three arbitrary tumor sizes (small, <10 mm 3 ; medium, 10-100 mm 3 ; and large, >100 mm 3 ) defined to categorize tumor size at the time of irradiation and evaluate potential differential response according to size (49). The severity of mucositis was evaluated semiquantitatively in dose-limiting precancerous tissue as previously described (3, 50, 51) (SI Materials and Methods, S4).…”

‘Close-to-ideal’ Tumor Boron Targeting for Boron Neutron Capture Therapy is Possible With ‘less-than-ideal’ Boron Carriers Approved for Use in Humans

“…Blood-vessel normalization seeks to distribute drugs effectively to a larger proportion of tumor cells rather than increase total drug uptake. Hence, pretreatment to normalize aberrant tumor blood vessels prior to administration of BPA did not increase gross boron concentration in tumor but did enhance tumor control from 67 to 84% [16]. This increase in therapeutic efficacy is attributed to a rise in homogeneity in tumor boron microdistribution.…”