Biomedical subjects

Mitchell C Posner

Publications and source records attributed to Mitchell C Posner.

25 records · Page 2Linked to original sources

PubMed2003

Dual induction of the Epo-Egr-TNF-alpha- plasmid in hypoxic human colon adenocarcinoma produces tumor growth delay.

Gene therapy is a modality for the treatment of solid tumors that involves the introduction of a suicide gene into the tumor cells. Genetic radiotherapy involves the placement of a radiation-sensitive promoter upstream from a suicide gene. Because of their irregular vasculature some solid tumors are chronically hypoxic and hence are resistant to conventional treatment with chemotherapy and ionizing radiation (IR). The purpose of this study was to demonstrate that regional tumor hypoxia could be exploited to improve local tumor control. The cDNA coding the erythropoietin hypoxia-responsive element (EPO) was placed upstream from the Egr-TNF-alpha construct. WIDR human colon adenocarcinoma cells were injected into the right hind limb of nude mice and treated with Epo-Egr-TNF-alpha plasmid with or without IR. Tumor volumes were measured by calipers and tumor necrosis factor (TNF)-alpha content of the tumor was determined by enzyme-linked immunosorbent assay. Treatment with the combined regimen of Epo-Egr-TNF-alpha plasmid + IR resulted in significant tumor growth delay. Tumor TNF-alpha content was increased by 30 per cent in the combined treatment group compared with each treatment alone. Regional tumor hypoxia can be exploited successfully to induce tumor growth delay, enhance local control, and enhance the therapeutic ratio.

Adenocarcinoma↗

PubMed2002

Combined gene therapy and ionizing radiation is a novel approach to treat human esophageal adenocarcinoma.

BACKGROUND: The ability to infect tumor cells limits the antitumor effects of gene therapy. The addition of radiotherapy to treatment with Ad.Egr.TNF.11D, a replication-deficient adenovirus containing a radiation-inducible promoter, early growth response-1, and the tumor necrosis factor-alpha (TNFalpha) complementary DNA may enhance the therapeutic ratio. METHODS: Seg-1 human esophageal adenocarcinoma cells were treated with Ad.Egr.TNF.11D with or without radiation. TNFalpha levels were quantified with enzyme-linked immunosorbent assay. Athymic nude mice bearing Seg-1 tumors were randomized to buffer, ionizing radiation, Ad.Egr.TNF.11D, and combination therapy. Tumor growth delay was used to compare treatment regimens. TNFalpha levels were measured in tumor homogenates and plasma. RESULTS: Seg-1 cells treated with Ad.Egr.TNF.11D and ionizing radiation demonstrated increased TNFalpha levels at 72 hours compared with cells exposed to vector alone (124 +/- 0 pg/mL vs. 31.11 +/- 22 pg/mL; P =.008). In vivo, Ad.Egr.TNF.11D-treated tumors expressed low TNFalpha levels (151.5 +/- 107.11 pg/mg protein) compared with tumors receiving combined treatment (793.92 +/- 489.13 pg/mg protein; P =.067). Increased TNFalpha levels were associated with increased tumor growth delay after combined treatment (P <.05). CONCLUSIONS: Radiotherapy enables focal stimulation of TNFalpha expression in Ad.Egr.TNF.11D-infected cells and thus improves local tumor control.

Adenocarcinoma↗

PubMed2002

Standard surgical approaches in the management of esophageal cancer.

Much controversy remains regarding the optimal treatment for patients with carcinoma of the esophagus. Further studies are necessary to examine the utility and efficacy of each approach in treating esophageal cancer either alone or in combination with other modalities. Until data from prospective randomized trials showing a clear benefit using a particular approach are available, surgeons should use their better judgement in individualizing and selecting the most appropriate surgical approach to provide the best chance of cure or lasting palliation for this disease that challenges both patient and surgeon.

Esophageal Neoplasms↗

PubMed2002

Transcriptional control of viral gene therapy by cisplatin.

Ionizing radiation (IR) and radical oxygen intermediates (ROIs) activate the early growth response-1 (Egr1) promoter through specific cis-acting sequences termed CArG elements. Ad.Egr.TNF.11D, a replication-deficient adenoviral vector containing CArG elements cloned upstream of the cDNA for human recombinant TNF-alpha was used to treat human esophageal adenocarcinoma and rat colon adenocarcinoma cells in culture and as xenografts in athymic nude mice. Cisplatin, a commonly used chemotherapeutic agent, causes tumor cell death by producing DNA damage and generating ROIs. The present studies demonstrate induction of TNF-alpha production in tumor cells and xenografts treated with the combination of Ad.Egr.TNF.11D and cisplatin. The results show that the Egr1 promoter is induced by cisplatin and that this induction is mediated in part through the CArG elements. These studies also demonstrate an enhanced antitumor response without an increase in toxicity following treatment with Ad.Egr.TNF.11D and cisplatin, compared with either agent alone. Chemo-inducible cancer gene therapy thus provides a means to control transgene expression while enhancing the effectiveness of commonly used chemotherapeutic agents.

Adenocarcinoma↗

PubMedDate not supplied

Vascular endothelial growth factor enhances endothelial cell survival and tumor radioresistance.

PURPOSE: Vascular endothelial growth factor (VEGF) is an important mediator of endothelial cell proliferation and survival. The purpose of the present studies was to investigate the role of VEGF in the tumor response to ionizing radiation. METHODS: Two ras-transformed murine fibrosarcoma cell lines, VEGF+/+ and VEGF-/- were exposed to ionizing radiation (0, 1, 3, 5, 7 or 9 Gy) in vitro, and clonogenic survival was determined. VEGF+/+ and VEGF-/- xenografts were generated in athymic nude mice and then treated with ionizing radiation (ten 5-Gy fractions = 50 Gy). Mean fractional tumor volume was used to evaluate treatment efficacy. To determine whether VEGF enhances tumor radioresistance by targeting endothelial cells, we performed clonogenic survival assays with human umbilical vein endothelial cells. Surviving fractions were calculated after treatment with ionizing radiation (5 Gy) and recombinant hVEGF165 (0, 1, 10, and 100 ng/mL). To determine whether VEGF neutralization enhances tumor radiosensitivity, we employed anti-VEGF165 monoclonal antibody to treat human tumor xenografts. Tumors were exposed to ionizing radiation (four 5-Gy fractions = 20 Gy) and treated with anti-VEGF antibody (0, 5, and 25 microg/kg in four intraperitoneal doses). Mean fractional tumor volume was used to evaluate treatment efficacy. To elucidate the molecular mechanism contributing to the observed anti-VEGF/ionizing radiation interaction, we exposed human umbilical vein endothelial cells to ionizing radiation (5 Gy) in the presence of anti-VEGF antibody (1 microg/mL). Sodium dodecyl sulfate polyacrylamide gel electrophoresis of cell lysates was probed for mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK1/MEK2). RESULTS: The in vitro radiosensitivities of the VEGF+/+ and VEGF-/- clones were equivalent (D0 = 146 vs 149). However, the VEGF+/+ xenografts were more resistant to the cytotoxic effects of ionizing radiation than the VEGF-/- xenografts. VEGF+/+ xenografts demonstrated a faster doubling time (4.5 vs 6.0 days) and a shorter growth delay (15 vs 23 days) than VEGF-/- xenografts. The surviving fraction of human umbilical vein endothelial cells after exposure to ionizing radiation was significantly enhanced in the presence of VEGF (6.4% vs 12.5%). Western blot analysis demonstrated that stimulation of MAPK and MEK1/MEK2 was abrogated after exposure to anti-VEGF antibody. DISCUSSION: These findings represent the first genetic evidence that factors other than inherent tumor cell radiosensitivity are important determinants of radiocurability. Antitumor strategies targeting VEGF and other endothelial cell survival mechanisms may be used to enhance the cytotoxic effects of radiotherapy.

Animals↗

PubMedDate not supplied

Hand-assisted laparoscopic surgery for cancer.

Minimally invasive surgical approaches were designed to enhance quality of care and improve patient outcome by minimizing postoperative pain, shortening hospital stay, reducing costs, and facilitating early return to work and presurgical lifestyle. The hand-assisted laparoscopic approach for resection of cancer is still in its formative stage, and this review places it in proper perspective within the context of minimally invasive surgery currently being performed for both benign and malignant disease. The review also outlines the potential advantages and disadvantages, techniques, and site-specific procedures of hand-assisted laparoscopic surgery for cancer.

Abdominal Neoplasms↗

PubMedDate not supplied

Isolated pulmonary recurrence after resection of colorectal hepatic metastases--is resection indicated?

BACKGROUND: Resection of colorectal hepatic metastases is an accepted treatment modality for stage IV colorectal cancer. Concurrent or sequential pulmonary metastasectomy continues to be a controversial strategy. We analyzed factors that predicted pulmonary recurrence in patients with resected hepatic metastases and examined the efficacy of these combined interventions in the treatment of metastatic colorectal cancer. METHODS: A retrospective review of a database of patients who underwent resection of colorectal hepatic metastases was performed to identify patients who either had synchronous pulmonary metastases (defined as pulmonary recurrence at the time of or within 3 months of hepatic metastasectomy) or subsequently experienced pulmonary metastases. Patient demographics, operative interventions, and overall survival were analyzed. Statistical methods included unpaired Student's t-test, actuarial survival and log-rank analysis. RESULTS: Twenty-one patients (19%) had pulmonary metastases after hepatic resection, of which 12/21(57%) underwent pulmonary resection. No differences were observed between the resection group, the nine patients with pulmonary metastases who did not undergo resection, and the 87 patients without pulmonary metastases with regard to age, sex, race, or extent of hepatic metastases. When comparing the resected versus the unresected pulmonary recurrences, the disease-free interval from hepatic resection to detection of pulmonary metastases was 21 +/- 20 months (range, 3-72 months) versus 16 +/- 8 months (range, 4-25 months), respectively. All patients with pulmonary recurrence who underwent pulmonary metastasectomy had unilateral disease. Seven of 12 (58%) underwent wedge/segmental resections, and the remaining five (42%) required lobectomy in order to obtain a complete resection. Four patients who underwent pulmonary resection had multiple lung metastases (two to four lesions), and eight had isolated metastasis. There were no perioperative deaths in the pulmonary metastasectomy group. Contraindications to pulmonary resection included extensive pulmonary disease and concurrent extrapulmonary disease. A survival benefit was noted at 3 years for the resected versus the unresected group (60% vs 31%). Survival was no different between the resected pulmonary recurrence patients and the resected hepatic metastases only patients (60% vs 54%). CONCLUSIONS: Pulmonary metastasectomy can be performed safely and effectively in patients with recurrent disease after hepatic resection for colorectal metastases. Prolonged survival can be achieved with resection of isolated pulmonary recurrence after hepatic resection for colorectal cancer. Further studies that delineate selection criteria for pulmonary resection of colorectal metastases are warranted.

Colorectal Neoplasms↗