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Biomedical subjects

Roger A Vertrees

Publications and source records attributed to Roger A Vertrees.

7 recordsLinked to original sources
PubMed2005

Synergistic interaction of hyperthermia and Gemcitabine in lung cancer.

Hyperthermia increases cytotoxicity of various antineoplastic agents. We investigated the cytotoxic effects of Gemcitabine and/or hyperthermia on BZR-T33 (human non-small-cell lung cancer cells) in vitro and in immune-suppressed athymic nude mice. Isobologram analysis of monolayer cell cultures for cytotoxicity demonstrates a synergistic interaction between hyperthermia and Gemcitabine. Clonogenic results show significant reductions in surviving fractions and colony size for both therapies; greatest reduction was for the combined therapy group. Using cell cycle analysis, hyperthermia enhanced Gemcitabine-induced G2-M arrest resulting in destruction of 3.5 log cells. Apoptotic studies (Annexin-V FITC staining) showed that hyperthermia augmented Gemcitabine-induced apoptosis. Transmission electron microscopy demonstrated pathology observed in cultures exposed to either therapy present in cultures exposed to both therapies. Studies in nude mice show that the combination therapy group had both an initial decrease in tumor size, and a significantly delayed rate of growth. Additionally, using tumor material harvested from nude mice two days after end to treatment reveals a significantly greater apoptotic index and significantly smaller mitotic index for the combined therapy group. Western blots of the same tumor material, showed that heat shock protein 70 was not significantly increased, however, caspase-3 activity of was significantly increased because of the combined therapy. In conclusion, the combined therapy is synergistic in effect because of hyperthermia enhancing Gemcitabine-induced apoptosis.

Antimetabolites, Antineoplastic↗
PubMed2005

A mechanism of hyperthermia-induced apoptosis in ras-transformed lung cells.

Lung cancer, the leading cause of cancer-related deaths in both men and women, is the consequence of disordered apoptosis, induction of which may have therapeutic utility. Hyperthermia has been identified as a stimulus for apoptosis. We investigated the mechanism of hyperthermia-induced cell death in ras-transformed lung cells. Effect of hyperthermia (43 degrees C for 180 min) was compared between two cell lines, an immortalized (sv-40) normal human bronchial epithelial (BEAS2-B) and its malignant transformed (H-ras transfected) counterpart (BZR-T33). Survival after hyperthermia: 7-d growth culture BEAS2-B, 1.03 +/- 0.007 and BZR-T33, 0.39 +/- 0.008 (P < 0.05); clonogenic assays BEAS2-B, 0.76 +/- 0.003 and BZR-T33, 0.41 +/- 0.004 (P < 0.05). Hoechst positive (apoptotic) cells: BEAS2-B, 11 +/- 3% and BZR-T33, 78 +/- 5% (P < 0.05). TUNEL, DNA fragmentation, and Annexin-V all corroborate this result. Western blot comparing the effect of hyperthermia in BZR-T33 cells to BEAS2-B cells revealed: TRAIL and FAS-L displayed significant increases (threefold and twofold, respectively); caspase-3 showed a decrease in uncleaved form and an increase in cleaved form, and a 50-fold increase in activity effectively blocked with the caspase-3 inhibitor DEVD-fmk; caspase-9 showed near depletion of uncleaved; poly (ADP-ribose) polymerase (PARP) degradation was clearly visible during heating. After hyperthermia, gene expression demonstrates a 5.7-fold increase in TRAIL and insignificant changes in tumor necrosis factor-alpha (TNF-alpha), FAS-L, and caspases 3, 8, 9 in transformed cells. Data demonstrated that hyperthermia induces apoptosis in transformed cells, and that apoptosis is mediated by caspase-3 as a result of activation of cell-death membrane receptors of the tumor-necrosis-factor family. In summary, these data suggest that hyperthermia could become an additional modality in the multidisciplinary approach to the treatment of lung cancer.

Apoptosis↗
PubMed2004

Percutaneous venovenous perfusion-induced systemic hyperthermia for lung cancer: a phase I safety study.

BACKGROUND: Veno-venous perfusion-induced systemic hyperthermia (VV-PISH) homogeneously raises core body temperature potentially improving outcomes from metastatic lung cancer. METHODS: Patients (n = 10) with stage IV lung cancer, received VV-PISH (>or= 42 degrees C to or= 70. Time to target temperature was 47 +/- 2 minutes, as electrolytes remained normal, without patient or circuit complications. Extubation occurred between 6 and 18 hours. Hospital stay was 4.6 +/- 1.1 days; median length-of-survival after hyperthermia was 271 days. For concurrent controls (n = 16, stage IV lung cancer), median length-of-survival from time of diagnosis to death was 96 days, but for the VV-PISH patients it was significantly longer at 450 days (p < 0.05). All patients returned to pretreatment status following treatment and died from progression of lung cancer. CONCLUSIONS: Venovenous perfusion-induced systemic hyperthermia is safe, technically feasible, and achieves target temperature. Survival may be enhanced in stage IV lung cancer.

Adenocarcinoma↗
PubMed2004

Invited commentary.

Explore the source record for details and available documents.

Antineoplastic Agents↗
PubMed2004

Smoke/burn injury-induced respiratory failure elicits apoptosis in ovine lungs and cultured lung cells, ameliorated with arteriovenous CO2 removal.

STUDY OBJECTIVE: s: The purpose of this study was to examine the effects of two supportive therapies, conventional mechanical ventilation (CMV) and arteriovenous CO(2) removal (AVCO(2)R), during treatment of severe smoke/burn injury-induced ARDS. DESIGN: Sheep were exposed to a smoke/burn injury (lethal dose causing death in 40% of animals); lung tissue and blood was collected prior to injury (control), when an ARDS criterion was met (PaO(2)/fraction of inspired oxygen ratio < 200), then after 72 h of either CMV (group 1) or AVCO(2)R (group 2). Lung tissue was studied by standard histopathologic techniques; cultured lung cells were studied in media supplemented with serum from all four groups. MEASUREMENTS AND RESULTS: In vivo assays demonstrate less apoptotic cell death, and in vitro assays show significantly greater (p < 0.05) cell survival in group 2 (AVCO(2)R) than in group 1 (CMV) or baseline. Differential gene expression demonstrates significantly higher messenger RNA levels of proapoptotic and tumor necrosis factor (TNF)-alpha in cells incubated in baseline media. After exposure of cultured lung cells to conditioned media, protein expression assay of the culture medium revealed no TNF-alpha, TNF receptor (TNFR)-1, or TNFR-2, however, cultured cell lysate reveals elevated levels of TNF-alpha, TNFR-1 and caspase-3 in all groups; most occurred in cells incubated in baseline media (p < 0.05). HOECHST stain, DNA fragmentation, and caspase-3 cleavage show that AVCO(2)R ameliorates apoptosis in this model. CONCLUSIONS: This in vitro work specifically examines cell death in lung cells as a result of smoke/burn injury and effects of therapeutic interventions. Our in vivo studies temporally correlate the clinical pathology to that studied in these lung cells and show that both in vivo and in vitro cell death is predominantly apoptotic and is significantly reduced by AVCO(2)R.

Animals↗
PubMed2002

Leukocyte filtration in lung transplantation.

Controlled reperfusion of the transplanted lung has been used in nine consecutive patients to decrease manifestations of lung reperfusion injury. An extracorporeal circuit containing a roller pump, heat exchanger and leukodepleting filter is primed with substrate-enhanced reperfusion solution mixed with approximately 2000 ml of the patient's blood. This solution is slowly recirculated to remove leukocytes prior to reperfusion. When the pulmonary anastomoses are completed, the pulmonary artery is cannulated through the untied anastomosis using a catheter containing a pressure lumen for measurement of infusion pressure. An atrial clamp is left in place on the patient's native atrial cuff to decrease the risk of systemic air embolism during the brief period of reperfusion from the extracorporeal reservoir. During reperfusion, the water bath to the heat exchanger is kept at 35 degrees C and the flow rate for reperfusion solution is between 150 and 200 m/min, keeping the pulmonary artery pressure <14 mmHg. Eight of nine patients were ventilated on 40% inspired oxygen within a few hours of operation and 7/9 were extubated on or before postoperative day 1. Six of nine patients are long-term survivors.

Animals↗