Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1­AKT/ERK­Snail signaling pathway.

Cyclovirobuxine D (CVB­D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB­D has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVB­D on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVB­D and further elucidate its molecular mechanism(s). DLD­1 and LoVo cell lines were selected to evaluate the antitumor effect of CVB­D. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVB­D­treated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVB­D in vivo. It was identified that CVB­D inhibited the proliferation, migration, stemness, angiogenesis and epithelial­mesenchymal transition of CRC cells, and induced apoptosis and S­phase arrest. In addition, CVB­D significantly inhibited the growth of xenografts. It is notable that CVB­D exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVB­D exerted anticancer effects through the CTHRC1­AKT/ERK­Snail signaling pathway. Targeted therapy combining CTHRC1 with CVB­D may offer a promising novel therapeutic approach for CRC treatment.

[The inhibition of angiogenic pathway in second line treatment of metastatic colorectal cancer.] / Adenocarcinoma del colon metastatico. L'inibizione del pathway angiogenico come opzione di trattamento in seconda linea.

The inhibition of the antiangiogenic pathway in association with chemotherapy significantly improved disease control and overall survival both in the upfront and in second line treatment of metastatic colorectal cancer patients. The VELOUR study had showed a significant improvement in overall survival with the addition of aflibercept, an antiangiogenic chimeric protein, to FOLFIRI (5-flourouracil, leucovorin, irinotecan) in patients who progressed after an oxaliplatin based chemotherapy (with or without bevacizumab) in first line treatment or within 6 months from the completion of adjuvant chemotherapy. Subgroup analyses from VELOUR trial show that the benefit of aflibercept is independent from previous exposure to bevacizumab in first line. We reported the case of a patient affected by metastatic colorectal adenocarcinoma RAS/ BRAF wild-type, with an initial liver-limited presentation. In this case we used a second line treatment with FOLFIRI aflibercept after a first-line oxaliplatin-based chemotherapy plus an anti-EGFR antibody.

Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma.

HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH-), induces cytotoxicity and oxidative stress selectively in cancer cells by acting as a pro-drug for the delivery of hydrogen peroxide (H2O2); early clinical data suggest improved survival and inhibition of metastasis in patients being actively treated with P-AscH-. Previous studies have demonstrated that activation of HIF-1α is necessary for P-AscH- sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH- via H2O2-mediated inhibition of HIF-1α stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1α by P-AscH-. Additionally, P-AscH- decreased VEGF secretion in a dose-dependent manner that was reversible with catalase, consistent with an H2O2-mediated mechanism. Pharmacological and genetic manipulations of HIF-1α did not alter P-AscH--induced cytotoxicity. In vivo, P-AscH- inhibited tumor growth and VEGF expression. We conclude that P-AscH- suppresses the levels of HIF-1α protein in hypoxic conditions through a post-translational mechanism. These findings suggest potential new therapies specifically designed to inhibit the mechanisms that drive metastases as a part of PDAC treatment.

Prostatic angiogenic responses in late life: antiangiogenic therapy influences and relation with the glandular microenvironment in the transgenic adenocarcinoma of mouse prostate (TRAMP) model.

BACKGROUND: Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. METHODS: Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1α, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count. RESULTS: Senescence led to increased MVD and VEGF, HIF-1α and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1α levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride. CONCLUSIONS: Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy.

PSA-PSMA profiles and their impact on sera PSA levels and angiogenic activity in hyperplasia and human prostate cancer.

AIM: The relevance of prostate specific antigen (PSA)-prostate specific membrane antigen (PSMA) profiles in pathologic prostate (hyperplasia and cancer) has not been fully understood. The aim of this study is to investigate the impact of PSA-PSMA profiles on sera PSA levels and angiogenic activity in benign prostate hyperplasia (BPH) and prostate carcinoma (PC). PATIENTS AND METHODS: The study has been carried out in 6 normal prostate (NP), 29 BPH and 33 PC with dominant Gleason grade>8. Immunohistochemical analysis has been performed. Monoclonal antibodies 3E6 and ER-PR8 have been used to assess PSMA and PSA expression respectively. The evaluation of angiogenesis has been made by CD34 immune marker. Serum levels of PSA have been assayed by Immulite autoanalyser. RESULTS: The study of each protein separately among sera PSA levels showed that PSMA expression and angiogenic activity have the highest intensity in PC patients with serum PSA levels>20 ng/mL. Nevertheless, the lowest tissue PSA expression was found in PC patients with this latter sera PSA group. The most relevant results showed that in PC patients (PSA+, PSMA+) and (PSA-, PSMA+) profile were found to be inversely related to sera PSA levels. In PC patients, a high immunoexpression of (PSA+, PSMA+) profile has detected in the sera PSA group>20 ng/mL; whereas a high immunoexpression of (PSA-, PSMA+) profile was detected in the sera PSA group between 0 and 4 ng/mL. The highest angiogenic activity was found in PC patients with (PSA+, PSMA+) profile. CONCLUSIONS: Our findings clearly have supported the feasibility of PSA-PSMA profiles to improve in vivo diagnostic and therapeutic approaches in prostate cancer patients.

Terrestrosin D, a steroidal saponin from Tribulus terrestris L., inhibits growth and angiogenesis of human prostate cancer in vitro and in vivo.

OBJECTIVE: The aim of this study was to investigate whether terrestrosin D (TED) inhibits the progression of castration-resistant prostate cancer and consider its mechanism. METHODS: Cell cycle, mitochondrial membrane potential (ΔΨm) and apoptosis were determined by flow cytometry. Caspase-3 activity and vascular endothelial growth factor secretion were detected by a caspase-3 assay and human vascular endothelial growth factor kit, respectively. A PC-3 xenograft mouse model was used to evaluate the anticancer effect of TED in vivo. RESULTS: In vitro, TED strongly suppressed the growth of prostate cancer cells and endothelial cells in a dose-dependent manner. TED induced cell cycle arrest and apoptosis in PC-3 cells and human umbilical vascular endothelial cells (HUVECs). TED-induced apoptosis did not involve the caspase pathway. TED also decreased ΔΨm in PC-3 cells and HUVECs. In vivo, TED significantly suppressed tumor growth in nude mice bearing PC-3 cells, without any overt toxicity. Immunohistochemical analysis showed TED induced apoptotic cell death and inhibited angiogenesis in xenograft tumor cells. CONCLUSION: Cell cycle arrest and induction of apoptosis in cancer cells and endothelial cells might be plausible mechanisms of actions for the observed antitumor and antiangiogenic activities of TED.

[Effects of qingre xiaoji recipe on the migration, chemotaxis, and tube formation capability of human lung adenocarcinoma cell induced human umbilical vein endothelial cells].

OBJECTIVE: To study the effects of Qingre Xiaoji Recipe (QXR) on the migration, chemotaxis, and tube formation capability of human umbilical vein endothelial cells (HUVECs) induced by human lung adenocarcinoma cells (SPC-A-1). METHODS: The QXR groups at different final concentrations (2.5, 5.0, 10.0, and 20.0 mg/mL) and a control group were set up. Then the chemotaxis and tube formation capabilities were observed using Erasion trace test, Transwell chamber assay, and Matrigel matrix tube formation assay. RESULTS: QXR at three concentrations (2.5, 5.0, and 10.0 mg/mL) had inhibition on the migration of HUVECs cultured by SPC-A-1 cell supernatant (P<0.05). Besides, the migration rate decreased along with increased concentrations. The number of chemotactic HUVECs was significantly less than that of the positive control group (P <0.01), and the inhibition rate of chemokine increased along with increased concentrations. Furthermore, the number of chemotactic HUVECs was negatively correlated to the drug concentration (r = -0.830, P <0.01). The area of HUVEC cell tubule formation was significantly lower than that of the positive control group (P <0.01). The inhibition rate of HUVEC cell tubule formation increased along with increased drug concentration. Besides, the area of HUVEC cell tubular formation was negatively correlated with the drug concentration (r = -0.937, P <0.01). CONCLUSION: The mechanism of QXR for fighting against tumor angiogenesis might be correlated with its inhibition on the migration, chemotaxis, and tube formation of tumor vascular endothelial cells.

Anti-angiogenic activity of salvicine.

CONTEXT: Salvicine is a pharmacologically active derivative from Chinese medicinal plant Salvia prionitis Hance (Labiatae). It has been reported that salvicine inactivates ß1 integrin and inhibits integrin-mediated cell adhesion to fibronectin. Given the emerging correlation between integrins and angiogenesis, we propose that salvicine abolishes cell adhesion and subsequent metastasis by inhibiting angiogenisis. OBJECTIVE: The anti-angiogenesis activities of salvicine were investigated for the first time. MATERIALS AND METHODS: The cytotoxicity of salvicine on human microvascular endothelial cells (HMECs) and non-small cell lung adenocarcinoma A549 cells were measured at doses between 0.625 and 200 µM. Changes of cell migration were detected with doses of salvicine at 1.25-5 µM, and basement membrane matrigel matrix was used for the assessment of tube formation at concentrations ranging from 0.078 to 1.25 µM. In addition, mRNA expression of basic fibroblast growth factor (bFGF) in A549 cells was studied with the RT-PCR assay. RESULTS: In vitro studies revealed that the IC50 of salvicine on A549 cells (18.66 µM) was two-fold higher than that of HMECs (7.91 µM). Salvicine (1.25, 2.5 and 5.0 µM) inhibited significantly the endothelial cell migration up to 56, 73 and 82%, respectively. Salvicine decreased capillary-like tube formation of HMECs with high potency. Furthermore, it (30 µM) markedly reduced the mRNA expression of bFGF in A549 cells, while vascular endothelial growth factor (VEGF) mRNA expression remained unchanged. DISCUSSION AND CONCLUSION: Our results suggest that salvicine has potent anti-angiogenic activity through the inhibition on the sequential angiogenic cascades: proliferation, migration and tube formation and is associated with influence on the expression of bFGF of tumor cell.

Antiangiogenic effects of p-coumaric acid in human endothelial cells.

p-Coumaric acid, a hydroxy derivative of cinnamic acid, has been known to possess antioxidant and anticancer activities. Despite its potential contribution to chemopreventive effects, the mechanism by which p-coumaric acid exerts its antiangiogenic actions remains elusive. In this study, we revealed that p-coumaric acid inhibited the sprouting of endothelial cells in rat aortic rings and inhibited the tube formation and migration of endothelial cells. We observed that p-coumaric acid could downregulate mRNA expression levels of the key angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. Also, we demonstrated that p-coumaric acid inhibited both the AKT and ERK signaling pathways, which are known to be crucial for angiogenesis. Using a mouse model, we also showed that p-coumaric acid effectively suppressed tumor growth in vivo by lowering hemoglobin contents. Collectively, these findings indicate that p-coumaric acid possesses potent anticancer properties due to the inhibition of angiogenesis in vivo.

Effects of hydroxy safflower yellow-A on tumor capillary angiogenesis in transplanted human gastric adenocarcinoma BGC-823 tumors in nude mice.

OBJECTIVE: To study the effects of hydroxy safflower yellow A (HSYA) on tumor capillary angiogenesis in transplanted human gastric adenocarcinoma BGC-823 tumors in nude mice. METHODS: BGC-823 cells were injected subcutaneously into the right anterior armpit of nude mice to establish an animal model of transplanted tumors. After 24 h, 18 nude mice injected with tumor cells were randomized into model, control, and HSYA 0.028 g/L groups, with six mice in each group. Transplanted tumors were excised on day 20. Tumor inhibition ratios were calculated for the transplanted tumors. Pathological changes and capillary angiogenesis in the tumors were observed by light microscopy. RESULTS: Tumors in the model group grew more quickly than those in the control and HSYA groups, with inhibition ratios of 48% and 30%, respectively. The microvessel count in the HSYA group was lower than in the model group (P < 0.01), and microvessel density was also lower in the HSYA group (P < 0.05). Pathological changes were more obvious in tumors in the model group compared to the HSYA group. CONCLUSION: HSYA inhibits the growth of transplanted BGC-823 tumors, and its effects on tumor capillary angiogenesis may represent one of the mechanisms responsible for this antineoplastic effect.

Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival.

Yin Yang-1 inhibits tumor cell growth and inhibits p21WAF1/Cip1 complex formation with cdk4 and cyclin D1.

The GLI-Krüppel zinc finger factor yin yang-1 (YY1) is a complex protein that regulates a variety of processes including transcription, proliferation, development and differentiation. YY1 inhibits cell growth in a cell type-specific manner. The role played by YY1 in its control of tumor cell growth is unclear and controversial. We show here that YY1 can suppress the growth of different tumor cell types in vitro, including human breast carcinoma cells and glioblastoma cells. YY1 also blocked the growth of 13762 MAT mammary adenocarcinoma isografts in rats. YY1 inhibited 13762 MAT tumor growth by approximately 80% compared with the GFP alone group 21 days after injection. YY1 inhibited proliferating cell nuclear antigen (PCNA) expression and pRbSer249/Thr252 phosphorylation without influencing tumor microvascular density. Moreover, YY1 inhibited p21WAF1/Cip1 complex formation with cdk4 and cyclin D1. These findings demonstrate that YY1 can negatively regulate the growth of multiple malignant cell types.

Astragalus saponins modulate cell invasiveness and angiogenesis in human gastric adenocarcinoma cells.

AIM OF THE STUDY: We had reported that Astragalus saponins (AST) exert promising anti-tumorigenic effects by suppressing the growth of HT-29 human colon cancer cells and tumor xenograft. In the present study, we further investigated the anti-angiogenic property of AST in human gastric adenocarcinoma cells (AGS) and attempted to elucidate the underlying mechanism. MATERIALS AND METHODS: Viability of AGS cells was measured by using the MTT reduction method. Western blotting was performed to examine the effect of AST on apoptotic- and cell growth-related protein expression. Effect of AST on cell cycle progression was also evaluated using PI staining. A Matrigel invasion assay was then employed to demonstrate the effect of AST on the invasiveness of gastric cancer cells. The expression of invasion-associated proteins (VEGF and MMPs) was also investigated. RESULTS: AST could induce apoptosis in AGS cells by activating caspase 3 with subsequent cleavage of poly(ADP-ribose) polymerase. Besides, cell cycle arrest at the G2/M phase had been observed in AST-treated cells, leading to substantial growth inhibition. The anti-proliferative effect of AST was associated with the regulation of cyclin B1, p21 and c-myc. Results indicate that the number of AGS cells invaded through the Matrigel membrane was significantly reduced upon AST treatment, with concomitant down-regulation of the pro-angiogenic protein vascular endothelial growth factor (VEGF) as well as the metastatic proteins metalloproteinase (MMP)-2 and MMP-9. CONCLUSION: AST derived from the medicinal plant Astragalus membranaceus could modulate the invasiveness and angiogenesis of AGS cells besides its pro-apoptotic and anti-proliferative activities. These findings also suggest that AST has the potential to be further developed into an effective chemotherapeutic agent in treating advanced and metastatic gastric cancers.

Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin.

BACKGROUND: Recent prospective clinical trials of low molecular weight heparins (LMWHs) have demonstrated that these agents may provide significant advantages in terms of progression-free and overall survival in certain subgroups of cancer patients. The mechanisms of improved survival associated with LMWHs are not known, and may involve direct and/or indirect effects on tumor growth. The purpose of this study was to investigate the effects of LMWH and a sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake and chemoresponse. MATERIALS AND METHODS: LMWH and S-NACH were tested for their ability to reduce tumor growth and tumor-associated angiogenesis using three different in vivo models. Biodistribution studies were undertaken to determine the effect of these agents on uptake of paclitaxel (PACL) and doxorubicin (Dox) by breast cancer tumor xenografts. RESULTS: LMWH and S-NACH (10 mg/kg s.c. daily) effectively limited tumor growth of human A549 lung adenocarcinoma xenografts in the nude mouse. In an MDA453/LCC6 breast tumor xenograft model, PACL plus S-NACH showed significant (p < 0.01) tumor growth suppression and improved survival when compared to PACL alone. LMWH increased [(124-)I]-PACL uptake into MDA453/LCC6 tumors, with tumor:muscle ratios several fold greater than that of [(124-)I]-PACL alone 24 h post-injection. Similarly, LMWH and S-NACH significantly (p < 0.01) increased the uptake of Dox by 1.5-2 fold in MCF7 Dox-resistant tumor xenografts. CONCLUSION: Protocols utilizing adjuvant or neo-adjuvant therapy with LMWH or S-NACH could lead to increased tumor chemo responsiveness, potentially overcoming tumor chemoresistance.

Bioelectromagnetic field effects on cancer cells and mice tumors.

We present possibilities and trends of ELF bioelectromagnetic effects in the mT amplitude range on cancer cells and on mice bearing tumors. In contrast to invasive electrochemotherapy and electrogenetherapy, using mostly needle electrodes and single high-amplitude electropulses for treatment, extremely low-frequency (ELF) pulsating electromagnetic fields (PEMF) and sinusoidal electromagnetic fields (SEMF) induce tumor cell apoptosis, inhibit angiogenesis, impede proliferation of neoplastic cells, and cause necrosis non invasively, whereas human lymphocytes are negligibly affected. Our successful results in killing cancer cells-analyzed by trypan blue staining or by flow cytometry-and of the inhibition of MX-1 tumors in mice by 15-20 mT, 50 Hz treatment in a solenoid coil also in the presence of bleomycin are presented in comparison to similar experimental results from the literature. In conclusion, the synergistic combinations of PEMF or SEMF with hyperthermia (41.5°C) and/or cancerostatic agents presented in the tables for cells and mice offer a basis for further development of an adjuvant treatment for patients suffering from malignant tumors and metastases pending the near-term development of suitable solenoids of 45-60 cm in diameter, producing >20 mT in their cores.

Vascular endothelial growth factor gene polymorphisms in patients with colorectal cancer.

BACKGROUND: Angiogenesis plays an important role in tumor progression. The vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. In the present study we evaluated single nucleotide polymorphisms (SNPs) -2578C > A, -1154G > A, and +936C > T in the VEGF gene, and their prognostic value for patients operated on for colorectal cancer (CRC). PATIENTS AND METHOD: VEGF polymorphisms have been analyzed in 177 patients who had undergone surgical resection at Hospital Clínico San Carlos. The analysis of these polymorphisms was performed with specific probes for each nucleotide in a multiplex reaction using real-time PCR. RESULTS: We only found a statistically significant relationship for one of these three polymorphisms, +936C > T, with gender and tumor location; 10.7% of patients heterozygotes for this SNP had tumors located in proximal colon, 35.2% in distal segment and 54.1% in rectum (p = 0.03). Patients with the +936T/T genotype had 100% overall survival (OS). CONCLUSION: Patients with a +936T/T genotype showed increased survival, therefore the +936C > T SNP could be a useful marker in the follow-up and clinical management of patients with colorectal cancer.

Deoxyelephantopin, a novel multifunctional agent, suppresses mammary tumour growth and lung metastasis and doubles survival time in mice.

BACKGROUND AND PURPOSE: Elephantopus scaber L. (Asteraceae) is a traditional herbal medicine with anti-cancer effects. We evaluated the in vitro and in vivo efficacy of a major sesquiterpene lactone constituent of E. scaber, deoxyelephantopin (DET), against mammary adenocarcinoma and the underlying molecular mechanism. EXPERIMENTAL APPROACH: A variety of cellular assays, immunoblotting and immunohistochemistry, as well as both orthotopic and metastatic TS/A tumour models in BALB/c mice, were used. Test mice were pretreated and post-treated with DET or paclitaxel and mammary tumour growth evaluated. KEY RESULTS: DET (< or =2 microg x mL(-1)) significantly inhibited colony formation, cell proliferation, migration and invasion of TS/A cells and induced G(2)/M arrest and apoptosis in TS/A cells. c-Jun N-terminal kinase-mediated p21(Waf1/Cip1) expression and caspase activation cascades were up-regulated by DET, effects suppressed by N-acetyl-L-cysteine. Moreover, tumour necrosis factor alpha-induced matrix metalloproteinase-9 enzyme activity and expression and nuclear factor-kappa B activation were abolished by DET. Pretreatment with DET was more effective than paclitaxel, for profound suppression of orthotopic tumour growth (99% vs. 68% reduction in tumour size) and lung metastasis of TS/A cells (82% vs. 63% reduction in metastatic pulmonary foci) and prolonged median survival time (56 vs. 37 days, P < 0.01) in mice. The levels of cyclooxygenase-2 and vascular endothelial growth factor in metastatic lung tissues of TS/A-bearing mice were attenuated by DET. CONCLUSIONS AND IMPLICATIONS: Our data provide evidence for the suppression of mammary adenocarcinoma by DET with several mechanisms and suggest that DET has potential as a chemopreventive agent for breast cancer.

Outcomes of adjuvant chemoradiation after pancreaticoduodenectomy with mesenterico-portal vein resection for adenocarcinoma of the pancreas.

PURPOSE: Surgery followed by chemotherapy and radiation (CRT) offers patients with pancreatic adenocarcinoma a chance for extended survival. In some patients, however, resection is difficult because of vascular involvement by the carcinoma, necessitating resection and grafting of the mesenterico-portal vessels. The purpose of this study was to compare outcomes between pancreaticoduodenectomy (PD) with and without mesenterico-portal vein resection (VR) in patients receiving adjuvant CRT for pancreatic adenocarcinoma. METHODS AND MATERIALS: Between 1993 and 2005, 160 patients underwent PD with 5-FU-based adjuvant CRT followed by maintenance chemotherapy at the Johns Hopkins Hospital; 20 (12.5%) of the 160 underwent VR. Clinical outcomes, including median survival, overall survival, and complication rates were assessed for both groups. RESULTS: Patients who underwent VR had significantly longer operative times (p = 0.009), greater intraoperative blood loss (p = 0.01), and longer postoperative lengths of stay (p = 0.03). However, postoperative morbidity, median survival, and overall survival rates were similar between the two groups. Most patients (70%) from both groups were able to complete CRT, and a subgroup analysis demonstrated no appreciable differences in terms of complications. None of the VR patients who received adjuvant CRT developed veno-oclusive disease or graft failure/leakage. CONCLUSION: In a cohort of patients treated with adjuvant 5-FU-based CRT at the Johns Hopkins Hospital, having a VR at the time of PD resulted in similar complication rates and survival. These data support the feasibility and safety of adjuvant CRT in patients undergoing VR at the time of PD.

Stromal aminopeptidase N expression: correlation with angiogenesis in non-small-cell lung cancer.

PURPOSE: Aminopeptidase-N (APN) is a membranebound protein that acts as a zinc-binding protease and participates in extracellular proteolysis. APN plays important roles in tumor progression through promoting invasion and metastasis, prolonging survival of tumor cells, and tumor angiogenesis. METHODS: We evaluated APN expression in non-small-cell lung cancer patients by immunohistochemistry. RESULTS: Of the 95 patients reviewed in the present study, 9 (9.5%), all with adenocarcinoma (Ad), showed positive APN expression on the tumors' cells. In all, 31 (32.6%) and 19 (20.0%) patients showed positive APN expression on the tumors' stromal cells (fibroblasts) and microvessels, respectively. APN expression on the tumors' stromal cells was more frequently observed in squamous cell carcinoma patients than in adenocarcinoma patients (P = 0.005). The mean microvessel density (MVD) for APNpositive tumor stromal cells was 59.9, which was significantly higher than that for APN-negative tumor stromal cells (mean MVD 27.4; P = 0.001). The 5-year survival rates for APN-positive and APN-negative tumor stromal cells were 66.0% and 69.8%, respectively, showing no difference in patient survival according to APN status on the tumors' stromal cells. CONCLUSION: That APN expression on stromal cells was observed predominantly in squamous cell carcinoma may account for the efficacy of ubenimex in the postoperative adjuvant setting for squamous cell carcinoma.