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Neuro-Oncology  2014;16(Suppl 2):ii101.
BACKGROUND: Glioblastoma is the most aggressive adult primary malignant brain tumor. It is associated with poor prognosis (median survival of 12-15 months) despite treatment. Combination chemotherapy with carmustine (BCNU) or temozolomide (TMZ) with the MGMT inhibitor O6-benzylguanine (O6BG) has been used but it has been associated with dose limiting hematopoietic toxicity. OBJECTIVE: To assess safety and efficacy of a retroviral vector encoding the O6BG-resistant MGMTP140K gene for transduction and autologous transplantation of hematopoietic stem cells (HSCs) in MGMT unmethylated, newly diagnosed GBM patients in an attempt to chemoprotect bone marrow during combination O6BG/TMZ therapy. METHODS: Seven patients have been enrolled in the first cohort of the study. Following tumor resection, patients underwent standard radiation therapy without TMZ followed by G-CSF mobilization, aphaeresis and conditioning with 600 mg/m2 BCNU prior to infusion of gene-modified cells. Post transplant, patients were treated with 28-day cycles of single dose TMZ (472mg/m2) with 48-hour intravenous O6BG (120mg/m2 bolus, followed by 30mg/m2/24h). RESULTS: The BCNU dose was nonmyeloablative. Gene marking in pre-infusion colony forming units (CFUs) was robust in most patients. Similarly, following engraftment, gene marking in white blood cells and sorted granulocytes assessed by real-time PCR was high. Patients have received up to nine cycles of O6BG/TMZ with evidence for selection of gene-modified cells and tolerable hematologic toxicity. This is significantly more cycles compared to recurrent patients receiving O6BG/TMZ in the absence of gene modified, chemoprotected cells (Quinn et al., 2005) (p < 0.05). No extra-hematopoietic toxicity has been observed thus far and all seven patients exhibited improved survival over historical controls. The longest surviving patient is 56+ months from the diagnosis without evidence of disease progression. CONCLUSIONS: These data demonstrate feasibility of achieving significant engraftment of MGMTP140K- modified cells with a well-tolerated dose of BCNU. Combination of TMZ and O6BG is well tolerated in this setting and patients with newly diagnosed GBM exhibiting unmethylated MGMT promoter achieve prolonged survivals.
PMCID: PMC4185758
2.  Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice 
British Journal of Cancer  2010;103(8):1182-1191.
Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma.
We used two in vivo models to investigate the effects of these common dietary components on tumour metastasis. In a model of experimental metastasis, immunocompromised mice were fed diets containing linoleic acid (LA) at 2% (LLA), 8% (HLA) or 12% (VHLA) by weight and inoculated intraperitoneally (i.p.) with human gastric carcinoma cells (OCUM-2MD3). To model spontaneous metastasis, OCUM-2MD3 tumours were grafted onto the stomach walls of mice fed with the different diets. In in vitro assays, we investigated invasion and ERK phosphorylation of OCUM-2MD3 cells in the presence or absence of LA. Finally, we tested whether a cyclooxygenase (COX) inhibitor, indomethacin, could block peritoneal metastasis in vivo.
Both the HLA and VHLA groups showed increased incidence of tumour nodules (LA: 53% HLA: 89% VHLA: 100% P<0.03); the VHLA group also displayed increased numbers of tumour nodules and higher total volume relative to LLA group in experimental metastasis model. Both liver invasion (78%) and metastasis to the peritoneal cavity (67%) were more frequent in VHLA group compared with the LLA group (22% and 11%, respectively; P<0.03) in spontaneous metastasis model. We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro. Linoleic acid also increased invasion of other scirrhous gastric carcinoma cells, OCUM-12, NUGC3 and MKN-45. Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK. The data suggest that invasion and phosphorylation of ERK were dependent on COX. Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups. Finally, COX-1, which is known to be an important enzyme in the generation of bioactive metabolites from dietary fatty acids, appears to be responsible for the increased metastatic behaviour of OCUM-2MD3 cells in the mouse model.
Dietary LA stimulates invasion and peritoneal metastasis of gastric carcinoma cells through COX-catalysed metabolism and activation of ERK, steps that compose pathway potentially amenable to therapeutic intervention.
PMCID: PMC2967057  PMID: 20842125
gastric carcinoma; dietary fatty acid; cyclooxygenase; metastasis; invasion

Results 1-2 (2)