ABSTRACT: Viral therapy of cancer (viral oncolysis) is dependent on selective destruction of the tumor tissue compared with healthy tissues. Several factors, including receptor expression, extracellular components, and intracellular mechanisms, may influence viral oncolysis. In the present work, we studied the potential oncolytic activity of herpes simplex virus type 1 (HSV-1), using an organ culture system derived from colon carcinoma and healthy colon tissues of mouse and human origin. HSV-1 infected normal colons ex vivo at a very low efficiency, in contrast to high-efficiency infection of colon carcinoma tissue. In contrast, adenoviral and lentiviral vectors infected both tissues equally well. To investigate the mechanisms underlying the preferential affinity of HSV-1 for the carcinoma tissue, intracellular and extracellular factors were investigated. Two extracellular components, collagen and mucin molecules, were found to restrict HSV-1 infectivity in the healthy colon. The mucin layer of the healthy colon binds to HSV-1 and thereby blocks viral interaction with the epithelial cells of the tissue. In contrast, colon carcinomas express small amounts of collagen and mucin molecules and are thus permissive to HSV-1 infection. In agreement with the ex vivo system, HSV-1 injected into a mouse colon carcinoma in vivo significantly reduced the volume of the tumor. In conclusion, we describe a novel mechanism of viral selectivity for malignant tissues that is based on variance of the extracellular matrix between tumor and healthy tissues. These insights may facilitate new approaches to the application of HSV-1 as an oncolytic virus.
Journal of Virology 02/2008; 82(2):999-1010. · 5.40 Impact Factor
ABSTRACT: To study fibroblasts and mast cells in human peritoneal adhesions and to evaluate whether their interaction plays a role in adhesion development.
Myofibroblasts play a critical role in wound repair/fibrosis. Mast cells influence the formation of peritoneal adhesions in a rat model, and they are modulators of fibroblast functions.
Peritoneal adhesion biopsies were processed for either histology (H&E, toluidine blue) or immunohistochemistry (tryptase, laminin, collagen type IV and VIII, and alpha-SMA) or grown as explants for obtention of fibroblasts. The effects of mast cell (HMC-1) sonicate and selected mast cell mediators and cytokines on fibroblast proliferation ([ (3)H]thymidine) and collagen synthesis ([ (3)H]proline) and on fibroblast contractile activity (tridimensional collagen lattice) were evaluated. Mast cell mediators influencing fibroblast proliferation were partially characterized by enzymatic susceptibility and FPLC gel filtration column chromatography.
Most of the fibroblasts in peritoneal adhesions were identified as alpha-SMA-positive myofibroblasts. Mast cell hyperplasia was observed and more than one third of the mast cells were degranulated. Few mast cells showed a faint staining for laminin or collagen type IV and VIII. Mast cell sonicate increased fibroblast proliferation and contractile activity while decreasing collagen synthesis. Mast cell sonicate proliferating activities were found to be proteinase-sensitive with a molecular weight of more than 158 kd, of approximately 40 kd, and of less than 10 kd. TGF-beta and tryptase enhanced collagen synthesis; TNF-alpha and chymase decreased it. None of the selected mediators increased fibroblast proliferation.
Myofibroblasts are the main connective tissue cells present in human peritoneal adhesions, and mast cells play a direct role in peritoneal adhesion formation.
Annals of Surgery 11/2002; 236(5):593-601. · 7.49 Impact Factor
ABSTRACT: Surgical resection of rectal cancer is associated with a high pelvic recurrence rate. Preoperative large-fraction radiotherapy (RT) with a short interval after local excision has been associated with a significant improvement in locoregional recurrence rates and overall survival, but with high rates of toxicity. We here present the results of our combined-modality treatment protocol for patients with locally advanced rectal cancer.
Between September 1999 and June 2005, 98 patients were prospectively entered into the protocol. Eligibility criteria included any of the following: cT3-4 disease, clinically positive lymph nodes, or tumor located less than 6 cm from the anal verge. RT was delivered with a three-field technique to a dose of 45 Gy, plus an optional 5.4-9 Gy boost. Chemotherapy, administered concomitantly with RT, consisted of bolus 5-fluorouracil (5-FU) 500 mg days 1-5 followed by 5-FU 600 mg/m2 and leucovorin 50 mg on days 16, 23, 30 and 37. Surgery was performed 6-8 weeks after RT completion and was followed by 8 courses of 5-FU 900 mg/m2 and leucovorin 100 mg/m2 every 14 days.
Low anterior resection was performed in 64.5% of the patients and in 38.8% of those with tumors located less than 6 cm from the anal verge. All patients except one had clear pathological margins, 68.8% had negative nodes, and pathological complete response was seen in 13.5%. With a median follow-up of 31.5 months, 3 patients (3.0%) had locoregional recurrence, 19 (19.3%) developed distant metastasis, and 10 patients (10.1%) died. The estimated median disease-free survival was 70.6 months. Grade 3 or 4 gastrointestinal toxicity was seen in 24.5% of the patients and 3.0% had neutropenic fever. One fatal toxicity occurred during treatment.
Our results suggest that our combined-modality treatment protocol is well tolerated and achieves high locoregional control in this unselected population. The overall survival results are also encouraging. Further studies are required to confirm the toxicity profile and survival results of this regimen.
Tumori 96(5):709-12. · 0.86 Impact Factor