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Biomedical subjects

Yun Shin Chun

Publications and source records attributed to Yun Shin Chun.

5 recordsLinked to original sources
PubMed2006

Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma.

BACKGROUND: NV1066, a replication-competent oncolytic herpes simplex virus type 1 (HSV-1) attenuated by a deletion in the gene gamma(1)34.5, preferentially replicates in and kills malignant cells. gamma(1)34.5 encodes ICP34.5, a viral protein essential for productive replication, which has homology with mammalian stress response induced GADD34 (growth arrest and DNA damage-inducible protein). We hypothesized that cisplatin upregulates GADD34 expression, which enhances NV1066 replication and oncolysis. METHODS: Ten human malignant pleural mesothelioma (MPM) cell lines were infected with NV1066 at multiplicities of infection (MOI; ratio of viral particles per tumor cell) 0.005 to 0.8 in vitro, with and without cisplatin (1 to 4 microM). In the MPM cell line VAMT, viral replication was determined by plaque assay, cell kill by lactate dehydrogenase assay, and GADD34 induction by quantitative RT-PCR and Western blot. Synergistic efficacy was confirmed by the isobologram and combination index methods of Chou-Talalay. GADD34 upregulation by cisplatin was inhibited with GADD34 siRNA to further confirm the synergistic efficacy dependence with GADD34. RESULTS: Combination therapy with NV1066 and cisplatin showed strong synergism in epithelioid (H-2452, H-Meso), sarcomatoid (H-2373, H-28), and biphasic (JMN, Meso-9, MSTO-211H) MPM cell lines, and an additive effect in others. In VAMT cells combination therapy enhanced viral replication 4 to 11-fold (p < 0.01) and cell kill 2 to 3-fold (p < 0.01). Significant dose reductions for both agents (2 to 600-fold) were achieved over a wide range of therapeutic-effect levels (LD50-LD99) without compromising cell kill. Synergistic cytotoxicity correlated with GADD34 upregulation (2 to 4-fold, p < 0.01) and was eliminated following transfection with GADD34 siRNA. CONCLUSION: Cisplatin-induced GADD34 expression selectively enhanced the cytotoxicity of the gamma(1)34.5-deficient oncolytic virus, NV1066. This provides a cellular basis for combination therapy with cisplatin and NV1066 to treat MPM and achieve synergistic efficacy, while minimizing dosage and toxicity.

Antigens, Differentiation↗
PubMed2005

Employing tumor hypoxia for oncolytic therapy in breast cancer.

Hypoxia is a common tumor condition associated with metastases, therapeutic resistance, and poor patient survival. Forty percent of breast cancers are hypoxic, with a median oxygen concentration of 3.9%, and a third of tumors have regions less than 0.3%. Normal breast tissue is reported to have oxygen concentrations greater than 9%. This tumor hypoxia in breast cancer confers resistance to conventional radiation therapy and chemotherapy, as well as making estrogen-receptor-positive tumors less sensitive to hormonal therapy. Novel treatment modalities are needed to target hypoxic tumor cells. Lower tumor oxygen levels compared with surrounding normal tissues may be utilized to target and enhance herpes oncolytic viral therapy in breast cancer. Attenuated oncolytic herpes simplex viruses offer a unique cancer treatment by specifically infecting, replicating within, and lysing tumor cells. They carry genetically engineered mutations to reduce their virulence and attenuate their ability to infect normal tissues. Studies have shown the safety and efficacy of oncolytic herpes simplex viruses in treating breast cancer both in humans and in preclinical models. The placement of essential viral genes under the control of a hypoxia-responsive enhancer, which is upregulated selectively in hypoxic tissue, represents a promising strategy to target oncolytic viruses precisely to hypoxic cancer cells. In this review we describe strategies to harness hypoxia as a trigger for oncolytic viral gene expression in breast cancer, thereby increasing the specificity of viral infection, replication, and cytotoxicity to hypoxic areas of tumor. Such a targeted approach will increase efficacy in the therapy of hypoxic tumors while achieving a reduction in total dose of viral therapy.

Breast Neoplasms↗
PubMed2005

Colonoscopic perforations: a retrospective review.

Colonic perforation is no longer a rare complication of colonoscopy. Our previous report identified 45 such iatrogenic injuries from 1980 through 1994 (3082 colonoscopies per year). This follow-up of the ensuing 7 years examines changing trends of endoscopic usage in addition to management and prognosis of patients with colonoscopic perforations. Retrospective analysis of 78,702 colonoscopies (1994 through 2000, 11,243 colonoscopies per year) allowed assessment of medical records in all patients treated at our institution for colonic perforation. Sixty-six patients from our institution (perforation rate, 0.084%; 1 per 1192 procedures) and six patients from outside institutions were treated for colonic perforation following colonoscopy (41 women, 31 men; ages, 30-92 years; median, 73 years). Sixty-two patients underwent laparotomy, while 10 were managed nonoperatively. All 10 patients managed nonoperatively were void of peritoneal irritation by physical examination; eight patients did well (median hospital stay, 5.5 days; range, 0-12), but one death (family declined operative intervention) and one pelvic abscess requiring percutaneous drainage were noted. Peritoneal irritation by physical examination was evident in 57 of 62 patients undergoing laparotomy. Perforations occurred throughout the colon: right, 22 (31%); transverse, 5 (7%); left, 44 (61%); and unknown, 1 (1%). Thirty-eight patients (61%) underwent primary repair or resection with anastomosis. Fecal diversion was used in 100% of patients with extensive peritoneal contamination (n = 12) and 40% of patients with moderate contamination (12 of 30). Perioperative morbidity (39%) and mortality (8%) were significant. Factors predicting a poor outcome included delayed diagnosis, extensive peritoneal contamination, and patients using anticoagulants (P < .05). Compared with our prior study, the present review highlights a higher prevalence of injury based on more frequent use of colonoscopy. Perforation rates remain around 0.08%. While nonoperative management is viable in patients void of peritonitis, expedient surgical intervention seems to facilitate patient recovery.

Adult↗
PubMed2005

Virally directed fluorescent imaging improves diagnostic sensitivity in the detection of minimal residual disease after potentially curative cytoreductive surgery.

Completeness of cytoreduction is an independent prognostic factor after cure-intended surgery for peritoneal carcinomatosis. NV1066, a genetically engineered herpes simplex virus carrying the transgene for green fluorescent protein, selectively infects cancer cells. We sought to determine the feasibility of virally directed fluorescent imaging in the intraoperative detection of minimal residual disease after cytoreductive surgery. NV1066 infected human gastric cancer cells, OCUM-2MD3, and mesothelioma JMN cells at all doses. The infected cells expressed green fluorescent protein and were killed. OCUM-2MD3, and mesothelioma JMN cells at all doses. Peritoneal carcinomatosis was established in mice by injection of OCUM cells into the peritoneal cavity. Forty-eight hours after intraperitoneal injection of NV1066, two experienced surgeons resected all visible disease and identified mice free of disease. Eight of 13 mice thought to be free of disease were found to have residual disease as identified by green fluorescence (mean number of observations: 5; range: 1-9). Residual disease was most frequently observed in the retroperitoneum, pelvis, peritoneal surface, and liver. Specificity of NV1066 infection to tumor nodules was confirmed by immunohistochemistry and by polymerase chain reaction for viral gene. Virally directed fluorescent imaging, a novel molecular imaging technology, can be used for real-time visualization of minimal residual disease after cytoreductive surgery and can improve the completeness of cure-intended resection.

Animals↗