Oral glutamine prevents DMBA-induced mammary carcinogenesis via upregulation of glutathione production.

OBJECTIVE: Glutamine is suggested to participate in glutathione synthesis. Furthermore, there is a positive relation between glutathione level and natural killer (NK) cell activity. Previously we demonstrated that supplemental glutamine inhibited tumor growth in an implantable tumor model and 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral squamous cell carcinoma model; these reductions were associated with enhancing NK cell cytotoxicity, blood glutathione levels, and/or gut glutathione release. Therefore, we hypothesized that oral glutamine might suppress DMBA-induced mammary carcinogenesis by upregulation of glutathione production and/or augmentation of NK cell activity. METHODS: Rats were randomized to six groups: DMBA + glutamine, DMBA + Freamine, DMBA + water, oil + glutamine, oil + Freamine, or oil + water. At age 50 d, rats were gavaged with DMBA or sesame oil. Rats also received glutamine, Freamine, or water by gavage from 1 wk before DMBA administration until sacrifice at 1, 2, 4, or 11 wk after DMBA. Tumor appearance, blood, gut mucosa and breast glutamine and/or glutathione concentrations, and NK cell cytotoxicity were measured. The gut extractions, defined as the difference of concentrations across the gut, were calculated. RESULTS: Oral glutamine reduced the tumorigenesis of DMBA by 50% in this model. DMBA altered the difference of glutathione concentrations across the gut; however, oral glutamine maintained the normal gut glutathione release. NK cell activities were lower in DMBA groups at early (week 1) and late (week 11) time points, but oral glutamine recovered the NK cell activity only at week 11. In addition, blood, gut, and breast glutathione concentrations were enhanced by glutamine supplementation. CONCLUSION: These results indicate that one of the mechanisms of dietary glutamine anticancer action is through upregulating gut glutathione metabolism.

Conductive interstitial thermal therapy device for surgical margin ablation: in vivo verification of a theoretical model.

PURPOSE: To demonstrate the efficacy and predictability of a new conductive interstitial thermal therapy (CITT) device to ablate surgical margins. METHOD: The temperature distributions during thermal ablation of CITT were calculated with finite element modelling in a geometrical representation of perfused tissue. The depth of ablation was derived using the Arrhenius and the Sapareto and Dewey (S&D) models for the temperature range of 90 to 150 degrees C. The female pig animal model was used to test the validity of the mathematical model. Breast tissues were ablated to temperatures in the range of 79-170 degrees C, in vivo. Triphenyltetrazolium chloride viability stain was used to delineate viable tissue from ablated regions and the ablation depths were measured using digital imaging. RESULTS: The calculations suggest that the CITT can be used to ablate perfused tissues to a 10-15 mm width within 20 minutes. The measured and calculated depths of ablation were statistically equivalent (99% confidence intervals) within +/- 1mm at 170 degrees C. At lower temperatures the equivalence between the model and the observations was within +/- 2 mm. CONCLUSION: The CITT device can reliably and uniformly ablate a 10-15 mm wide region of soft tissue. Thus, it can be used to secure negative margins following the resection of a primary tumor, which could impede local recurrences in the treatment of local diseases such as early staged, non-metastatic, breast cancer.

Conductive interstitial thermal therapy (CITT) device evaluation in VX2 rabbit model.

We have developed a conductive interstitial thermal therapy (CITT) device to precisely and reliably deliver controlled thermal doses to the surgical margins at the cavity site following tumor resection, intraoperatively. The temperature field created by CITT ablation of a perfused tissue was modeled with a finite element package Femlab. The modeling suggested that a maximum probe temperature of 120 degrees C and an ablation time of 20 minutes were required to ablate highly perfused tissue such as the VX2 carcinoma. Deployable pins enable faster and more reliable thermal ablation. The model predictions were tested by thermal ablation of VX2 carcinoma tumors implanted in adult New Zealand rabbits. The size of the ablated region was confirmed with a viability stain, triphenyltetrazolium chloride (TTC). Histopathological examination revealed 3 regions in the ablated area: a carbonized region (1-3 mm); a region that contained thermally fixed cells; and an area of coagulated necrosis cells. Cells in the thermally fixed region stained for PCNA (proliferating cell nuclear antigen) and were bounded by the carbonized layer at the cavity wall, and by necrotic cells that exhibit nuclear fragmentation and cell dissociation, 5 to 10 mm away from the CITT probe. Adjacent tissue outside the target region was spared with a clear demarcation between ablated and normal viable tissue. It is suggested that the CITT device can be used, clinically, to inhibit local recurrence by creating negative surgical margins following the resection of a primary tumor in non-metastatic early staged tumors.