Metastasis is the primary cause of death from many tumors, and novel anti-metastatic therapies are necessary. Recently, we showed that metastatic tumors down-regulate key oxidative phosphorylation (OXPHOS) genes in favor of glycolysis, a further enhancement of the Warburg effect. Therefore, we sought to determine if restriction of glycolysis using 2-deoxy-D-glucose (2DG) would lead to increased utilization of OXPHOS and inhibition of the metastatic phenotype. Noncytotoxic concentrations of 2DG dose-dependently inhibited in vitro migration and invasion in the highly metastatic DLM8-luc-M1 osteosarcoma (OS) cell line, as well as other metastatic human, canine, and murine cancer cells of different histotypes. This was associated with cytoskeletal rearrangement and inhibition of cathepsin L expression. A dose-dependent shift toward OXPHOS was confirmed by demonstrating increased oxygen utilization and decreased lactate production in 2DG treated cells. Finally, 2DG treatment significantly delayed metastasis and prolonged survival in an orthotopic postsurgical OS model. In conclusion, this work suggests that forcing cells away from glycolysis may inhibit key components of the metastatic phenotype, providing a novel avenue for metastasis prevention.
Canine B‐cell lymphoma is a clinically heterogenous disease; however, it is generally treated as a single disease entity. The purpose of this clinical trial was to prospectively evaluate naïve canine B‐cell lymphoma patients using histopathology, flow cytometry (FC) and a standardized chemotherapy protocol to better define subsets of this disease that may respond differently to treatment. Sixty‐four dogs with naïve multicentric B‐cell lymphoma were treated with a standardized 19‐week CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy protocol. Most of the dogs (84.3%) were diagnosed with diffuse large B‐cell lymphoma (DLBCL), followed by nodal marginal zone (7.8%), small B‐cell (4.7%), Burkitt‐like (1.6%) and follicular lymphoma (1.6%). FC confirmed the diagnosis of B‐cell lymphoma in all cases. There were no clear phenotyping differences between the subtypes of B‐cell lymphoma detectable by our FC panel. The histologic subtypes in this study exhibited a range of forward scatter values on flow cytometry, but all of the DLBCL cases were higher than a value of 469, while the only cases with a lower forward scatter value were follicular lymphoma and diffuse small B‐cell lymphoma. Dogs with DLBCL had a significantly better objective response rate to the CHOP protocol (96.3%) than the non‐DLBCL subtypes (70%, P = .024). The median progression‐free survival time for patients with DLBCL (233 days) was significantly longer than that of all other histopathologic subgroups combined (163 days, P = .0005).
Median survival times (STs) for doxorubicin-treated canine lymphoma range from 5.7 to 9 months. Because dogs treated with multi-agent protocols have longer STs, we sought to evaluate whether adding cyclophosphamide would improve outcome in canine lymphoma patients while maintaining an acceptable level of toxicity. Thirty-two dogs with stage III–V multicentric lymphoma were treated with doxorubicin every 3 weeks for five total cycles and prednisone at a tapering dose for the first 4 weeks. Dogs were randomized to receive either cyclophosphamide or placebo concurrently. Seventeen dogs received doxorubicin and placebo, while 15 dogs received doxorubicin and cyclophosphamide. Response, toxicity, progression-free interval (PFI) and ST were evaluated. The combination of doxorubicin and cyclophosphamide was well tolerated, causing no increase in adverse events over doxorubicin alone. Despite a numeric improvement in outcome in cyclophosphamide treated dogs, the addition of cyclophosphamide did not result in statistically improved response rate, PFI or ST.
Background In humans geographical differences in the incidence and presentation of various cancers have been reported. However, much of this information has not been collected in veterinary oncology. Aim The purpose of this study was to determine if a geographic difference in progression free survival exists for dogs with lymphoma treated within the US. Materials and Methods Medical records of 775 cases of canine lymphoma from 3 US regions (west, south and north), treated with CHOP chemotherapy, were retrospectively evaluated. Cases were collected from referral institutions and were required to have received at least one doxorubicin treatment and have follow up information regarding time to progression. Results Significant differences in sex (p = 0.05), weight (p = 0.049), stage (p < 0.001), immunophenotype (p = <0.001), and number of doxorubicin doses (p = 0.001) were seen between regions. Upon univariate analysis, progression free survival (PFS) differed by region (p = 0.006), stage (p = 0.009), sub‐stage (p = 0.0005), and immunophenotype (p = 0.001). A multivariable Cox regression model showed that dogs in the western region had a significantly shorter PFS when compared to the south and east. Conclusion PFS was significantly affected by stage, sub‐stage and phenotype.
We recently reported on a re-analysis of previously published gene expression data from a large set of primary solid and metastatic tumors originating from different tissues using the latest available tools for normalization, identification of differentially expressed genes and pathway analysis (Ptitsyn A., et al, BMC Bioinformatics 2008;9 Suppl: S8). Analysis of multiple independent datasets indicated significantly reduced oxidative phosphorylation in metastases compared to primary solid tumors, implying a potential enhancement of the Warburg phenotype in metastatic progression. We thus sought to determine if inhibition of anaerobic glycolysis with the competitive inhibitor 2-deoxy-D-glucose (2-DG) would reverse this metastatic bioenergetic phenotype in highly metastatic cancer cells. We evaluated the effects of 2-DG on DLM8 osteosarcoma cell migration and Matrigel invasion via Boyden chamber assays, and modulation of in vitro production of matrix metalloproteases, VEGF, and cathepsin L were evaluated by gelatin zymography, ELISA and western analysis respectively. The effects of 2-DG administration in vivo was evaluated in an orthotopic, spontaneously metastatic, luciferase-transfected postsurgical model of murine osteosarcoma utilizing DLM8, which is syngeneic to C3H mice. DLM8 cells were implanted into the distal tibias of C3H mice, followed by amputation of the affected limb 16 days later. 2-DG or saline were administered postoperatively (500 mg/kg IP 3x/week, n=5 per group) until sacrifice. Presence of metastasis was evaluated using biweekly bioluminescence imaging and metastasis-free interval calculated using the Kaplan-Meier method. Concentrations of 2-DG associated with minimal antiproliferative activity dramatically inhibited DLM8 cell migration and invasion. There was a dose-dependent decrease in cathepsin L expression upon 2-DG exposure, and VEGF production was inhibited at high 2-DG concentrations, but there were no repeatable changes in MMP activity within the concentration range associated with inhibition of migration and invasion. Postoperative administration of 2-DG significantly delayed DLM8 metastasis (median metastasis-free interval 8 vs 34 days, p = 0.049). In conclusion, glycolysis inhibition with 2-DG is associated with an inhibition of osteosarcoma migration, invasion and in vivo metastasis, at concentrations associated with minimal antiproliferative activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-106.
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