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Xiaoxin Chen - One of the best experts on this subject based on the ideXlab platform.

  • involvement of the 5 lipoxygenase leukotriene a4 hydrolase pathway in 7 12 dimethylbenz a anthracene dmba induced oral carcinogenesis in hamster Cheek Pouch and inhibition of carcinogenesis by its inhibitors
    Carcinogenesis, 2006
    Co-Authors: Xiaoxin Chen, Sandeep Sood, Chung S Yang, Zheng Sun, Divya Ramji, Peiying Yang, Robert A Newman
    Abstract:

    Previous studies have shown that aberrant arachidonic acid (AA) metabolism, especially cyclooxygenase-2 (Cox-2) and 5-lipoxygenase (5-Lox) pathways, are activated during oral carcinogenesis, and can be targeted for cancer prevention. This study was designed to investigate the importance of 5-Lox/leukotriene A4 hydrolase (LTA4H) pathway of AA metabolism in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster Cheek Pouch carcinogenesis. In a short-term study, topical application of DMBA for 3 weeks induced severe inflammation and aberrant AA metabolism. Subsequent topical treatment with zileuton, celecoxib, or their combination for 1 week significantly suppressed aberrant AA metabolism and cell proliferation in the oral epithelium. Interestingly, zileuton was effective in inhibiting biosynthesis of multiple AA metabolites, including leukotriene B4 (LTB4), 5-, 12-, 15-hydroxyeicosatetraenoic acid and prostaglandin E2 (PGE2), while celecoxib only suppressed PGE2 biosynthesis significantly at a high dose. In a long-term carcinogenesis study topical application of LTB4 or PGE2 enhanced oral carcinogenesis by increasing the incidence and volume of visible tumors, and the incidence of squamous cell carcinoma (SCC). To further examine the role of LTB4 in oral carcinogenesis, two LTA4H inhibitors, bestatin and SA6541, were evaluated in a long-term chemoprevention experiment. Both agents significantly inhibited SCC, and such an inhibition correlated with reduced levels of LTB4 in hamster Cheek Pouch. In summary, our studies have demonstrated that 5-Lox/LTA4H pathway is one of the major AA-metabolizing pathways involved in DMBA-induced oral carcinogenesis in hamsters, and may be targeted for chemoprevention.

  • chemoprevention of 7 12 dimethylbenz a anthracene dmba induced oral carcinogenesis in hamster Cheek Pouch by a cyclooxygenase 2 inhibitor celecoxib and a 5 lipoxygenase inhibitor zileuton
    Cancer Research, 2004
    Co-Authors: Ning Li, Mingzhu Fang, Sandeep Sood, Chung S Yang, Su Wang, Xiaoxin Chen
    Abstract:

    Proc Amer Assoc Cancer Res, Volume 45, 2004 2361 Previous studies have suggested an important role of aberrant arachidonic acid (AA) metabolism, especially the cyclooxygenase (Cox) and 5-lipoxygenase (5-Lox) pathways, in oral carcinogenesis. Overexpression of cyclooxygenase 2 (Cox2), and overproduction of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) have been clearly demonstrated in human oral cancers. Indomethacin and aspirin (non-specific Cox inhibitors) and curcumin (a dietary inhibitor of AA metabolism) exerted chemopreventive effects in the DMBA-induced oral carcinogenesis in hamster Cheek Pouch. In this study, we studied the effects of Celecoxib (a specific Cox2 inhibitor) and Zileuton (a specific 5-Lox inhibitor) on DMBA-induced oral carcinogenesis in hamsters. DMBA (0.5% in mineral oil, 0.1ml) was applied topically to the left Cheek Pouch of male Syrian golden hamsters 3 times/week for 6 weeks. The animals then received topical application (3 times/week) of Celecoxib (3% and 6%, 0.1ml), Zileuton (3% and 6%, 0.1ml), a combination of Celecoxib and Zileuton (both 3%, 0.1ml), or no treatment, for 18 weeks. Celecoxib (6%), Zileuton (6%) and the combination significantly decreased the tumor incidence from 84.6% (22/26) to 56% (14/25, P=0.025), 46.4% (13/28, P=0.003), and 44% (11/25, P=0.002), respectively. The number of tumor was also significantly inhibited by Celecoxib (6%, P=0.01), Zileuton (3%, P=0.02; and 6%, P=0.003) and the combination (P=0.002). All these treatments significantly reduced the tumor volume by 53% (Celecoxib 3%), 63% (Celecoxib 6%), 56% (Zileuton 3%), 74% (Zileuton 6%), and 76% (combination). Tissue levels of PGE2 and LTB4, as determined by enzyme immunoassay, were reduced by Celecoxib and Zileuton, respectively, and were well correlated with the histopathological observations. With in situ hybridization, we found overexpression of Cox2 in the DMBA-treated hamster oral mucosa. Cox2 expression was further enhanced in hyperplasia, dysplasia and squamous cell carcinoma. The results clearly demonstrated that Celecoxib and Zileuton had inhibitory effects against oral carcinogenesis at the post-initiation stage, and such inhibition was related to their specific effects on Cox2 and 5-Lox. (Supported by NIH grant CA101235)

M E Itoiz - One of the best experts on this subject based on the ideXlab platform.

  • Boron neutron capture therapy (BNCT) translational studies in the hamster Cheek Pouch model of oral cancer at the new “B2” configuration of the RA-6 nuclear reactor
    Radiation and Environmental Biophysics, 2017
    Co-Authors: Andrea Monti Hughes, Elisa M Heber, M E Itoiz, Juan Longhino, Esteban Boggio, Vanina A. Medina, Diego J. Martinel Lamas, Marcela A. Garabalino, Emiliano C. C. Pozzi, Romina F Aromando
    Abstract:

    Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster Cheek Pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster Cheek Pouch model of oral cancer at the new “B2” configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized Pouches were exposed to: BPA-BNCT; BPA-BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no-treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in “B1” experiments (86 vs 67%, respectively). BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94–96%) than in control (16%) and BO groups (9–38%), and did not differ significantly from the “B1” results (91%). Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control.

  • angiogenesis in potentially malignant lesions and carcinomas during experimental oral carcinogenesis a preliminary study in the hamster Cheek Pouch
    Anticancer Research, 2014
    Co-Authors: Romina F Aromando, Veronica A Trivillin, Amanda E Schwint, Ana R Raimondi, Miguel A Perez, M E Itoiz
    Abstract:

    AIM: To evaluate vascular morphology and density, angiogenic switch activation, vascular endothelial growth factor (VEGF) expression, and endothelial cell (EC) proliferation in the hamster Cheek Pouch (HCP) model of oral cancer. MATERIALS AND METHODS: Immunohistochemical detection of factor VIII, 5'-Bromo-2'-Deoxyuridine (BrdU) and VEGF was performed in pre-malignant and tumoral tissues. RESULTS: Activation of angiogenesis was detected adjacent to epithelial dysplasia. Vascularized area and perimeter (p<0.001) increased in dysplasias and tumors. Tumor blood vessels exhibited an enhanced vascular compression (p<0.001) and structural alterations. EC proliferation was similar in dysplasias and carcinomas. An increase in vascular density, EC proliferation and VEGF expression was found in potentially malignant tissues but not in carcinomas. CONCLUSION: The angiogenic switch occurs in the dysplastic stage preceding tumor development in the HCP model of oral cancer. In potentially malignant tissues, increased VEGF expression favors EC proliferation and an increase in vascular density. Conversely, in tumors, VEGF is no longer of pivotal importance.

  • sequential boron neutron capture therapy bnct a novel approach to bnct for the treatment of oral cancer in the hamster Cheek Pouch model
    Radiation Research, 2011
    Co-Authors: Ana J Molinari, Elisa M Heber, M E Itoiz, Marcela A. Garabalino, Emiliano C. C. Pozzi, Andrea Monti Hughes, S Thorp, Marcelo Miller, Romina F Aromando
    Abstract:

    In the present study the therapeutic effect and potential toxicity of the novel “Sequential” boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster Cheek Pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with “Sequential” BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the “Sequential” BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and...

  • biodistribution of gb 10 na 2 10 b10h10 compound for boron neutron capture therapy bnct in an experimental model of oral cancer in the hamster Cheek Pouch
    Archives of Oral Biology, 2004
    Co-Authors: Elisa M Heber, David W. Nigg, Veronica A Trivillin, Erica L Kreimann, M E Itoiz, Raul Jimenez Rebagliati, Daniel A Batistoni, Amanda E Schwint
    Abstract:

    Abstract Objective: We previously proposed the hamster Cheek Pouch model of oral cancer for BNCT studies. We herein present the biodistribution of a non-toxic boron compound, GB-10 ( Na 2 10 B 10 H 10 ), in this model to assess its potential for BNCT or BNCT enhanced Fast Neutron Therapy. Materials and methods: We evaluated the uptake and retention of GB-10 in tumour and precancerous tissue and in potentially dose-limiting, clinically relevant normal tissues. Results: Mean tumour boron concentration delivered by GB-10 (50 mg B/kg) peaked to 77.7±28.0 ppm at 20 min post-administration and remained at therapeutically useful values of 31.9±21.4 ppm at 3 h. The clearance rate for normal tissues was faster than for tumour tissue. The consistently low brain and spinal cord values would preclude normal tissue toxicity. The uptake of GB-10 by precancerous tissue may be of potential use in the treatment of field cancerized areas. GB-10 was deposited homogeneously in different tumour areas, an asset when treating heterogenous tumours. The data suggests that the joint administration of BPA and GB-10 may improve the therapeutic efficacy of BNCT. Conclusions: GB-10 is a potential boron carrier for BNCT of head and neck tumours and for BNCT-FNT.

  • the hamster Cheek Pouch as a model of oral cancer for boron neutron capture therapy studies selective delivery of boron by boronophenylalanine
    Cancer Research, 2001
    Co-Authors: Erica L Kreimann, M E Itoiz, Daniel A Batistoni, Alejandra Dagrosa, Ricardo N Garavaglia, Silvia Farias, Amanda E Schwint
    Abstract:

    Herein we propose and validate the hamster Cheek Pouch model of oral cancer for boron neutron capture therapy (BNCT) studies. This model serves to explore new applications of the technique, study the biology and radiobiology of BNCT, and assess the uptake of boron compounds and response of tumor, precancerous tissue, and clinically relevant normal tissues. These issues are central to evaluating and improving the therapeutic gain of BNCT. The success of BNCT is dependent on the absolute amount of boron in the tumor, and the tumor:blood and tumor:normal tissue boron concentration ratios. Within this context, biodistribution studies are pivotal. Tumors were induced in the hamsters with a carcinogenesis protocol that uses dimethyl-1,2-benzanthracene and mimics spontaneous tumor development in human oral mucosa. The animals were then used for biodistribution and pharmacokinetic studies of boronophenylalanine (BPA). Blood, tumor, precancerous Pouch tissue surrounding tumor, normal Pouch tissue, tongue, skin, Cheek mucosa, palate mucosa, liver, and spleen, were sampled at 0-12 h after administration of 300 mg BPA/kg. The data reveal selective uptake of BPA by tumor tissue and, to a lesser degree, by precancerous tissue. Mean tumor boron concentration was 36.9 +/- 17.5 ppm at 3.5 h and the mean boron ratios were 2.4:1 for tumor:normal Pouch tissue and 3.2:1 for tumor:blood. Higher doses of BPA (600 and 1200 mg BPA/kg) increased tumor uptake. Potentially therapeutic absolute boron concentrations, and tumor:normal tissue and tumor:blood ratios can be achieved in the hamster oral cancer model using BPA as the delivery agent.

Romina F Aromando - One of the best experts on this subject based on the ideXlab platform.

  • Boron neutron capture therapy (BNCT) translational studies in the hamster Cheek Pouch model of oral cancer at the new “B2” configuration of the RA-6 nuclear reactor
    Radiation and Environmental Biophysics, 2017
    Co-Authors: Andrea Monti Hughes, Elisa M Heber, M E Itoiz, Juan Longhino, Esteban Boggio, Vanina A. Medina, Diego J. Martinel Lamas, Marcela A. Garabalino, Emiliano C. C. Pozzi, Romina F Aromando
    Abstract:

    Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster Cheek Pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster Cheek Pouch model of oral cancer at the new “B2” configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized Pouches were exposed to: BPA-BNCT; BPA-BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no-treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in “B1” experiments (86 vs 67%, respectively). BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94–96%) than in control (16%) and BO groups (9–38%), and did not differ significantly from the “B1” results (91%). Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control.

  • angiogenesis in potentially malignant lesions and carcinomas during experimental oral carcinogenesis a preliminary study in the hamster Cheek Pouch
    Anticancer Research, 2014
    Co-Authors: Romina F Aromando, Veronica A Trivillin, Amanda E Schwint, Ana R Raimondi, Miguel A Perez, M E Itoiz
    Abstract:

    AIM: To evaluate vascular morphology and density, angiogenic switch activation, vascular endothelial growth factor (VEGF) expression, and endothelial cell (EC) proliferation in the hamster Cheek Pouch (HCP) model of oral cancer. MATERIALS AND METHODS: Immunohistochemical detection of factor VIII, 5'-Bromo-2'-Deoxyuridine (BrdU) and VEGF was performed in pre-malignant and tumoral tissues. RESULTS: Activation of angiogenesis was detected adjacent to epithelial dysplasia. Vascularized area and perimeter (p<0.001) increased in dysplasias and tumors. Tumor blood vessels exhibited an enhanced vascular compression (p<0.001) and structural alterations. EC proliferation was similar in dysplasias and carcinomas. An increase in vascular density, EC proliferation and VEGF expression was found in potentially malignant tissues but not in carcinomas. CONCLUSION: The angiogenic switch occurs in the dysplastic stage preceding tumor development in the HCP model of oral cancer. In potentially malignant tissues, increased VEGF expression favors EC proliferation and an increase in vascular density. Conversely, in tumors, VEGF is no longer of pivotal importance.

  • sequential boron neutron capture therapy bnct a novel approach to bnct for the treatment of oral cancer in the hamster Cheek Pouch model
    Radiation Research, 2011
    Co-Authors: Ana J Molinari, Elisa M Heber, M E Itoiz, Marcela A. Garabalino, Emiliano C. C. Pozzi, Andrea Monti Hughes, S Thorp, Marcelo Miller, Romina F Aromando
    Abstract:

    In the present study the therapeutic effect and potential toxicity of the novel “Sequential” boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster Cheek Pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with “Sequential” BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the “Sequential” BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and...

Elisa M Heber - One of the best experts on this subject based on the ideXlab platform.

  • Boron neutron capture therapy (BNCT) translational studies in the hamster Cheek Pouch model of oral cancer at the new “B2” configuration of the RA-6 nuclear reactor
    Radiation and Environmental Biophysics, 2017
    Co-Authors: Andrea Monti Hughes, Elisa M Heber, M E Itoiz, Juan Longhino, Esteban Boggio, Vanina A. Medina, Diego J. Martinel Lamas, Marcela A. Garabalino, Emiliano C. C. Pozzi, Romina F Aromando
    Abstract:

    Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster Cheek Pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster Cheek Pouch model of oral cancer at the new “B2” configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized Pouches were exposed to: BPA-BNCT; BPA-BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no-treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in “B1” experiments (86 vs 67%, respectively). BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94–96%) than in control (16%) and BO groups (9–38%), and did not differ significantly from the “B1” results (91%). Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control.

  • therapeutic efficacy of boron neutron capture therapy mediated by boron rich liposomes for oral cancer in the hamster Cheek Pouch model
    Proceedings of the National Academy of Sciences of the United States of America, 2014
    Co-Authors: Elisa M Heber, Marcela A. Garabalino, Emiliano C. C. Pozzi, Andrea Monti Hughes, S Thorp, Frederick M Hawthorne, Peter J Kueffer, Charles A Maitz, Satish S Jalisatgi, David W. Nigg
    Abstract:

    The application of boron neutron capture therapy (BNCT) mediated by liposomes containing 10B-enriched polyhedral borane and carborane derivatives for the treatment of head and neck cancer in the hamster Cheek Pouch oral cancer model is presented. These liposomes are composed of an equimolar ratio of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH3(CH2)15-7,8-C2B9H11] (MAC) in the bilayer membrane while encapsulating the hydrophilic species Na3[ae-B20H17NH3] (TAC) in the aqueous core. Unilamellar liposomes with a mean diameter of 83 nm were administered i.v. in hamsters. After 48 h, the boron concentration in tumors was 67 ± 16 ppm whereas the precancerous tissue contained 11 ± 6 ppm, and the tumor/normal Pouch tissue boron concentration ratio was 10:1. Neutron irradiation giving a 5-Gy dose to precancerous tissue (corresponding to 21 Gy in tumor) resulted in an overall tumor response (OR) of 70% after a 4-wk posttreatment period. In contrast, the beam-only protocol gave an OR rate of only 28%. Once-repeated BNCT treatment with readministration of liposomes at an interval of 4, 6, or 8 wk resulted in OR rates of 70–88%, of which the complete response ranged from 37% to 52%. Because of the good therapeutic outcome, it was possible to extend the follow-up of BNCT treatment groups to 16 wk after the first treatment. No radiotoxicity to normal tissue was observed. A salient advantage of these liposomes was that only mild mucositis was observed in dose-limiting precancerous tissue with a sustained tumor response of 70–88%.

  • sequential boron neutron capture therapy bnct a novel approach to bnct for the treatment of oral cancer in the hamster Cheek Pouch model
    Radiation Research, 2011
    Co-Authors: Ana J Molinari, Elisa M Heber, M E Itoiz, Marcela A. Garabalino, Emiliano C. C. Pozzi, Andrea Monti Hughes, S Thorp, Marcelo Miller, Romina F Aromando
    Abstract:

    In the present study the therapeutic effect and potential toxicity of the novel “Sequential” boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster Cheek Pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with “Sequential” BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the “Sequential” BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and...

  • biodistribution of gb 10 na 2 10 b10h10 compound for boron neutron capture therapy bnct in an experimental model of oral cancer in the hamster Cheek Pouch
    Archives of Oral Biology, 2004
    Co-Authors: Elisa M Heber, David W. Nigg, Veronica A Trivillin, Erica L Kreimann, M E Itoiz, Raul Jimenez Rebagliati, Daniel A Batistoni, Amanda E Schwint
    Abstract:

    Abstract Objective: We previously proposed the hamster Cheek Pouch model of oral cancer for BNCT studies. We herein present the biodistribution of a non-toxic boron compound, GB-10 ( Na 2 10 B 10 H 10 ), in this model to assess its potential for BNCT or BNCT enhanced Fast Neutron Therapy. Materials and methods: We evaluated the uptake and retention of GB-10 in tumour and precancerous tissue and in potentially dose-limiting, clinically relevant normal tissues. Results: Mean tumour boron concentration delivered by GB-10 (50 mg B/kg) peaked to 77.7±28.0 ppm at 20 min post-administration and remained at therapeutically useful values of 31.9±21.4 ppm at 3 h. The clearance rate for normal tissues was faster than for tumour tissue. The consistently low brain and spinal cord values would preclude normal tissue toxicity. The uptake of GB-10 by precancerous tissue may be of potential use in the treatment of field cancerized areas. GB-10 was deposited homogeneously in different tumour areas, an asset when treating heterogenous tumours. The data suggests that the joint administration of BPA and GB-10 may improve the therapeutic efficacy of BNCT. Conclusions: GB-10 is a potential boron carrier for BNCT of head and neck tumours and for BNCT-FNT.

Marcela A. Garabalino - One of the best experts on this subject based on the ideXlab platform.

  • Boron neutron capture therapy (BNCT) translational studies in the hamster Cheek Pouch model of oral cancer at the new “B2” configuration of the RA-6 nuclear reactor
    Radiation and Environmental Biophysics, 2017
    Co-Authors: Andrea Monti Hughes, Elisa M Heber, M E Itoiz, Juan Longhino, Esteban Boggio, Vanina A. Medina, Diego J. Martinel Lamas, Marcela A. Garabalino, Emiliano C. C. Pozzi, Romina F Aromando
    Abstract:

    Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster Cheek Pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster Cheek Pouch model of oral cancer at the new “B2” configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized Pouches were exposed to: BPA-BNCT; BPA-BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no-treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in “B1” experiments (86 vs 67%, respectively). BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94–96%) than in control (16%) and BO groups (9–38%), and did not differ significantly from the “B1” results (91%). Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control.

  • therapeutic efficacy of boron neutron capture therapy mediated by boron rich liposomes for oral cancer in the hamster Cheek Pouch model
    Proceedings of the National Academy of Sciences of the United States of America, 2014
    Co-Authors: Elisa M Heber, Marcela A. Garabalino, Emiliano C. C. Pozzi, Andrea Monti Hughes, S Thorp, Frederick M Hawthorne, Peter J Kueffer, Charles A Maitz, Satish S Jalisatgi, David W. Nigg
    Abstract:

    The application of boron neutron capture therapy (BNCT) mediated by liposomes containing 10B-enriched polyhedral borane and carborane derivatives for the treatment of head and neck cancer in the hamster Cheek Pouch oral cancer model is presented. These liposomes are composed of an equimolar ratio of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH3(CH2)15-7,8-C2B9H11] (MAC) in the bilayer membrane while encapsulating the hydrophilic species Na3[ae-B20H17NH3] (TAC) in the aqueous core. Unilamellar liposomes with a mean diameter of 83 nm were administered i.v. in hamsters. After 48 h, the boron concentration in tumors was 67 ± 16 ppm whereas the precancerous tissue contained 11 ± 6 ppm, and the tumor/normal Pouch tissue boron concentration ratio was 10:1. Neutron irradiation giving a 5-Gy dose to precancerous tissue (corresponding to 21 Gy in tumor) resulted in an overall tumor response (OR) of 70% after a 4-wk posttreatment period. In contrast, the beam-only protocol gave an OR rate of only 28%. Once-repeated BNCT treatment with readministration of liposomes at an interval of 4, 6, or 8 wk resulted in OR rates of 70–88%, of which the complete response ranged from 37% to 52%. Because of the good therapeutic outcome, it was possible to extend the follow-up of BNCT treatment groups to 16 wk after the first treatment. No radiotoxicity to normal tissue was observed. A salient advantage of these liposomes was that only mild mucositis was observed in dose-limiting precancerous tissue with a sustained tumor response of 70–88%.

  • sequential boron neutron capture therapy bnct a novel approach to bnct for the treatment of oral cancer in the hamster Cheek Pouch model
    Radiation Research, 2011
    Co-Authors: Ana J Molinari, Elisa M Heber, M E Itoiz, Marcela A. Garabalino, Emiliano C. C. Pozzi, Andrea Monti Hughes, S Thorp, Marcelo Miller, Romina F Aromando
    Abstract:

    In the present study the therapeutic effect and potential toxicity of the novel “Sequential” boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster Cheek Pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with “Sequential” BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the “Sequential” BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and...