Multiple Molecular pathways explain the anti-proliferative effect of valproic acid on prostate cancer cells in vitro and in vivo

BACKGROUND: Valproic acid (VPA), is a drug approved by the FDA for epilepsy and bipolar disorders. It is a known Histone Deacetylase Inhibitor (HDACI). We tested VPA, for its anti-proliferative activity in prostate cancer (PCa) cell lines in vitro and in vivo. METHODS: DU-145 and PC-3 PCa cell lines were cultured with different doses of VPA. Cells were examined for their viability, cell cycle status and expression of cell cycle arrest, and proliferation markers. Nude mice bearing xenografts of human PCa cell lines, DU-145, and PC-3, were administered VPA in their drinking water. RESULTS: VPA displayed a dose- and time-dependent anti-proliferative effect on DU-145 and PC-3 PCa cell lines in vitro. A sustained effect of the drug was seen on cell cycle arrest even at 24 hr after removal of the drug, after which the effects returned to the basal state. Administration of 0.4% w/v VPA in drinking water (resulting in 0.4 mM VPA, in plasma) was effective in inducing growth arrest, cell death, and senescence in vivo and was also anti-angiogenic. The activation of all or some of these anti-proliferative pathways may be contingent on acetylation status of histones, confirmed by detection of increased acetyl-H3K9 in VPA-treated samples when compared with untreated controls. Pharmacodynamic studies showed an increase in expression of p21 and decrease in PCNA in xenografts of VPA-treated mice compared with protein expression in untreated controls. CONCLUSIONS: VPA may be functioning as an HDACI to inhibit growth of PCa cells in vitro and in vivo by modulating multiple pathways including cell cycle arrest, apoptosis, angiogenesis, and senescence.     

Specific targeting of tumor vasculature by diphtheria toxin-vascular endothelial growth factor fusion protein reduces angiogenesis and growth of pancreatic cancer

Tumor vessels abundantly express receptors for vascular endothelial growth factor (VEGF), a mediator of neoangiogenesis. The aim of this study was to specifically target and damage the vasculature of pancreatic cancer (PaCa) by fusing VEGF to diphtheria toxin (DT), which inhibits protein synthesis of target cells. DT-VEGF fusion protein was produced in vector pGEX-KG and expressed in E. coli SG12036. Human PaCa cell lines (HPAF-2 and AsPC-1) and human endothelial cells (HUVEC) were exposed to DT-VEGF (10 ng/ml – 10,000 ng/ml). Proliferation was assessed after 3 days. One mm3 fragments of subcutaneous PaCa donor tumors were implanted into the pancreas of nude mice that received either DT-VEGF (200 ώg/kg) every other day) or phosphate-buffered saline intraperitoneally for 14 weeks. Tumor volume, metastatic spread, and animal weight were determined at autopsy. Microvessel density was analyzed in CD31 -stained tumor sections. Proliferation of PaCa cells was inhibited at high concentrations of DT-VEGF (≥1000 ng/ml). DT-VEGF decreased the growth of HUVEC at 10 ng/ml. In vivo, DT-VEGF reduced tumor volume (HPAF-2, 76%; AsPC-1, 53%), microvessel density (HPAF-2, 54%; AsPC-1, 62%), and tumor spread (HPAF-2, 89%; AsPC-1, 50%). Survival was increased (HPAF-2, 7/8 vs. 4/8 animals; AsPC-1, 6/8 vs. 1/8 animals). Weight was not influenced by DT-VEGF. The DT-VEGF effect is due to its toxic action on the tumor vasculature rather than to direct inhibition of PaCa cell growth. DT-VEGF therapy was not associated with systemic side effects. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001. Supported by the R.S. Hirshberg Foundation and the Deutsche Forschungsgemeinschaft (grant HO 1843–1).     

The HDAC inhibitor trichostatin A inhibits growth of small cell lung cancer cells

BACKGROUND: An estimated 162,460 people will die of lung cancer in the United States in 2006, making it the leading cause of cancer deaths. Small cell lung cancer (SCLC) accounts for 20% of all lung cancers and exhibits aggressive behavior with early metastases. Current treatments yield five-year survival rates of 5 to 10%, indicating a need for novel therapeutic approaches. Histone deacetylase inhibitors (HDACIs) represent a new class of anticancer agents. Trichostatin A (TSA), an HDACI, has been shown to inhibit growth in several cancers. We hypothesized that TSA may inhibit proliferation of SCLC cells. MATERIALS AND METHODS: Human SCLC DMS53 cells were treated with TSA (0 to 400 nM). Light microscopy was used to assess changes in cell morphology. Western analysis was performed for acetylated histone 4 to confirm HDAC inhibition. The effect of TSA treatment on cellular growth was measured by the MTT assay. Finally, levels of BCL-2, cleaved poly(ADP-ribose) polymerase, p21, and p27 proteins were measured to look for induction of cell cycle arrest and/or apoptosis. RESULTS: DMS53 cells treated with TSA underwent dramatic changes in cell appearance. Treated cells assumed round and spindle shapes with distinct cellular borders. Western analysis demonstrated increased levels of acetylated histone 4. TSA treatment resulted in a dose-dependent inhibition of growth. Lastly, elevated p21, p27, and cleaved poly(ADP-ribose) polymerase along with decreased BCL-2 protein levels were observed. CONCLUSIONS: TSA causes morphological differentiation and dose-dependent inhibition of cell growth via cell cycle arrest and subsequent apoptosis. This suggests that TSA and other HDACIs may represent a new potential therapy for patients with SCLC.     

Valproic acid induces Notch1 signaling in small cell lung cancer cells

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy. Current treatments yield dismal survival rates. We have previously demonstrated that histone deacetylase (HDAC) inhibitors can inhibit neuroendocrine tumor growth. Activation of the Notch1 signaling pathway also impairs SCLC cell viability. In this study, we investigated the ability of the HDAC inhibitor valproic acid (VPA) to activate Notch1 signaling and inhibit proliferation in SCLC cells. MATERIALS AND METHODS: DMS53 human SCLC cells were treated with VPA (0-10 mM) for 2 d. Light microscopy was used to examine changes in cell morphology. Western analysis was performed using antibodies against various Notch1 pathway proteins to assess Notch1 activation. Additionally, immunoblotting was performed for two neuroendocrine tumor markers, chromogranin A and achaete-scute complex-like 1. Finally, a cell proliferation assay was used to measure the effects of VPA on SCLC growth over 8 d. RESULTS: After treatment with VPA, DMS53 cells underwent dramatic changes in morphology. VPA induced expression of the full-length and active forms of Notch1 protein. Furthermore, VPA suppressed levels of neuroendocrine tumor markers chromogranin A and ASLC-1. Importantly, VPA treatment led to dose-dependent inhibition of SCLC cell proliferation. CONCLUSIONS: The HDAC inhibitor VPA activates Notch1 signaling in SCLC cells. VPA induces changes in cell morphology and suppresses neuroendocrine tumor markers, indicating a change in phenotype. Additionally, VPA profoundly inhibits SCLC cell growth. These results suggest that VPA has potential as a novel therapeutic agent for SCLC.     

雷公藤内酯醇对前列腺癌细胞PC-3及血管内皮生长因子的影响

目的:探讨雷公藤内酯醇对雄激素非依赖性前列腺癌细胞株PC-3的抑制作用及对血管内皮生长因子(VEGF)表达的影响.方法:分别用0、6.25、12.5、25、50 nmol/L浓度的雷公藤内酯醇作用于PC-3细胞,24 h、48 h、72 h后,以MTT法检测细胞生长活性,24 h后流式细胞仪测定细胞周期及细胞凋亡的变化,透射电镜观察细胞超微结构变化;ELISA法测定培养上清液VEGF的水平.结果:雷公藤内酯醇能以剂量与时间依赖性的方式抑制PC-3细胞的生长,促进其凋亡;细胞周期主要阻滞于S期,部分细胞出现凋亡的形态学改变;VEGF表达较对照组明显降低.结论:雷公藤内酯醇能显著抑制PC-3细胞的体外生长,促进其凋亡,并降低VEGF的表达.     

Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate

BACKGROUND: The growth and dissemination of tumors has been associated with angiogenesis, which is regulated by a group of polypeptide factors including vascular endothelial growth factor-C (VEGF-C). VEGF-C binds its receptor, vascular endothelial growth factor receptor-3 (VEGFR-3) to promote growth of tumor-associated lymphatic vessels. METHODS: In this study, microarray technology was used to build tissue arrays of normal prostate, benign prostate hyperplasia (BPH) and prostate carcinomas (PCa) using tissues from 640 patients. Slides were sectioned and stained with a polyclonal antibody to VEGFR-3 using a standard immunoperoxidase method and digitized. Immunoreactivity was scored using a 0-3+ semiquantitation scoring system for both intensity and percentage. The sum index was obtained by totaling the scores. RESULTS: VEGFR-3 is expressed in normal prostate, BPH, and PCa, but VEGFR-3 expression is up-regulated in PCa. We also found that VEGFR-3 is correlated with pre-operative prostate-specific antigen (Pre-PSA), Gleason score, and lymph node metastasis. The recurrence-free 5-year survival in cases with lower sum index (0-3) was significantly higher than that in cases with higher sum index (4-6) (77.3, 69.6%, respectively, P = 0.037) by Kaplan-Meier actuarial model. CONCLUSIONS: Our data suggest that VEGFR-3 expression is associated with tumor progression and may play an important role in facilitating lymphatic spread of PCa; high-level of VEGFR-3 expression in prostate cancer cells increases the risk of biochemical recurrence in prostate cancer patients treated by radical prostatectomy.     

Increased expressions of vascular endothelial growth factor （VEGF）, VEGF-C and VEGF receptor-3 in prostate cancer tissue are associated with tumor progression

Aim： To investigate the differences in microvessel densities （MVD） and the expressions of vascular endothelial growth factor （VEGF）, VEGF-C and VEGF receptor-3 （VEGFR-3） between prostate cancer （PCa） tissues and adjacent benign tissues, and to explore the correlations among MVD, Jewett-Whitmore staging, Gleason scores and expressions of VEGF, VEGF-C and VEGFR-3 in the progression of PCa. Methods： An immunohistochemical approach was adopted to detect the expressions of CD34, VEGF, VEGF-C and VEGFR-3 in both cancer areas and peripheral benign areas of 71 primary prostatic adenocarcinoma specimens. A statistic analysis was then performed according to the experimental and clinic data. Results： Significantly upregulated expressions of VEGF, VEGF-C and VEGFR-3 were all found in malignant epithelium/cancer cells compared with adjacent benign epithelium （P 〈 0.01）. Patients in stage D had a significantly higher score than patients in stage A, B or C when comparing the expression of VEGF-C or VEGFR-3 in the tumor area （P 〈 0.01）. In addition, significant correlations were observed between Jewett-Whitmore staging and VEGF-C （rs = 0.738, P 〈 0.01）, clinical staging and VEGFR-3 （rs = 0.410, P 〈 0.01）, VEGF-C and Gleason scores （rs = 0.401, P 〈 0.01）, VEGFR-3 and Gleason scores （rs = 0.581, P 〈 0.001） and MVD and VEGF （rs = 0.492, P 〈 0.001）. Conclusion： Increased expressions of VEGF and VEGF-C were closely associ- ated with progression of PCa. The main contribution of increased VEGF expression for PCa progression was to upregulate MVD, which maintained the growth advantage of tumor tissue. However, the chief role of increased expressions of VEGF-C and VEGFR-3 was to enhance lymphangiogenesis and provide a main pathway for cancer cells to disseminate. （Asian J Androl 2006 Mar; 8： 169-175）     

Vascular endothelial growth factor inhibits mitogen-induced vascular smooth muscle cell proliferation

INTRODUCTION: Delivery of vascular endothelial growth factor (VEGF) protein or gene transfer has been shown to accelerate re-endothelialization and attenuate neointimal hyperplasia in various arterial injury models, including balloon injury, stent implantation, and vein grafts. In addition to stimulating re-endothelialization, we hypothesize that VEGF has further vascular protective functions to prevent neointimal hyperplasia by directly inhibiting mitogen-induced proliferation of vascular smooth muscle cells (VSMCs) via the mitogen-activated protein kinase pathway. MATERIALS AND METHODS: Human aortic VSMCs were seeded and serum starved for 24 h. The cells were then stimulated with a mitogen, recombinant human platelet derived growth factor at 20 ng/mL together with 0, 10, 20, 30, 40, 50 ng/mL recombinant human VEGF. A proliferation assay was used to quantitate bromodeoxyuridine uptake into newly synthesized DNA. Western immunoassay was used to quantify extracellular signal-regulated kinase (ERK) 2 protein and phosphorylation of retinoblastoma and ERK 1/2 protein. RESULTS: VEGF inhibited bromodeoxyuridine incorporation into mitogen-induced VSMC in a dose-dependent manner, reaching statistical significance at concentrations of 30 (P < 0.05), 40 (P < 0.05), and 50 ng/mL (P < 0.01). Densitometry of western immunoblots revealed an inhibition of phosphorylation of retinoblastoma at VEGF concentrations of 40 and 50 ng/mL and ERK 1/2 phosphorylation at concentrations of 30, 40 and 50 ng/mL. CONCLUSION: In addition to stimulating re-endothelialization, VEGF appears to have a vascular protective function by directly inhibiting VSMC proliferation. This effect occurs in the absence of endothelial cells and via the mitogen-activated protein kinase pathway. VEGF may serve as an important modulator of mitogen-induced VSMC proliferation after vascular injury.     

Endothelial cells support the growth of prostate tissue in vivo

INTRODUCTION: The contribution of vascular endothelial cells to prostate growth has not been investigated. We examined whether endothelial cells support growth of prostate tissue when co-inoculated with prostate epithelial cells under the renal capsule. METHODS: Vascular endothelial cells were isolated from mice and co-inoculated under the renal capsule with a prostate luminal or basal epithelial cell line. After 60 days, kidneys were examined for growth of prostate tissue. Prostatic tissues were examined by immunohistochemistry for expression of cytokeratins 5 and 8, and vascular density was determined. To determine if increased expression of VEGF-A would increase prostatic growth, transfected endothelial cells overexpressing VEGF-A were co-inoculated with the prostate luminal or basal epithelial lines. RESULTS: Co-inoculation of endothelial cells and prostate luminal or basal epithelial cells resulted in significant growth of prostatic tissue, whereas inoculation of any of the cell lines alone resulted in little growth. The growths from co-inoculation of endothelial cells and luminal epithelial cells contained duct-like structures that stained with antibodies to cytokeratin 8, whereas those from co-inoculation of endothelial cells and basal epithelial cells contained cords of cells that stained with antibodies to cytokeratin 5. Overexpression of VEGF-A had no effect on growth of the prostatic tissues. CONCLUSION: Endothelial cells contribute to the growth of prostatic epithelial cells.     

Insulin-like growth factor binding protein-3 induces early apoptosis in malignant prostate cancer cells and inhibits tumor formation in vivo

BACKGROUND: Insulin-like growth factor binding protein (IGFBP-3) levels are significantly reduced in malignant prostate epithelial cells. In this study, we evaluated the role of endogenous IGFBP-3 on prostate cancer cell growth and tumorigenesis. METHODS: IGFBP-3 was re-expressed by stable transfection of human IGFBP-3 cDNA in a model of human prostate cancer, M12, a malignant subline in which IGFBP-3 levels are undetectable in comparison to the parent epithelial cell, P69. Effect of IGFBP-3 re-expression (M12-BP-3) on growth kinetics, morphology, propensity to apoptosis, and in vivo tumor formation were studied. RESULTS: M12-BP-3 cells secreted IGFBP-3 and growth arrested at a cell density that was threefold lower than control cells and this was associated with marked alteration in cell morphology. Control cells when grown in conditioned media secreted by M12-BP-3 also showed altered morphology compared to when cultured in IGFBP-3-immunodepleted conditioned media. The M12-BP-3 clones showed altered mitochondrial membrane potential, increased PARP cleavage, increase in sub-G1 peak, decreased levels of neuron specific enolase, and decreased tumor formation in athymic, nude mice. CONCLUSIONS: These data suggest that IGFBP-3 induces early apoptosis and has potential tumor suppressive effect in prostate cancer. Prostate 51: 141-152, 2002.     

双氢青蒿素对前列腺癌细胞PC-3M生长的影响及其机制探讨

目的:观察双氢青蒿素对雄激素非依赖性前列腺癌细胞株PC-3M细胞凋亡和血管内皮生长因子(VEGF)表达的影响。方法:不同浓度(0、25、50、100μmol/L)的双氢青蒿素分别作用于PC-3M细胞48 h,MTT法检测细胞生长活性;流式细胞仪测定细胞凋亡率;分光光度法检测细胞凋亡过程中caspase-3、caspase-8活性变化;半定量RT-PCR法检测PC-3M细胞内VEGF mRNA的表达;Western印迹法检测细胞VEGF蛋白表达。结果:双氢青蒿素能显著抑制PC-3M细胞的增殖,与对照组(0μmol/L)的细胞凋亡率(2.92±0.45)%相比,各剂量组(25、50、100μmol/L)的细胞凋亡率[(8.85±0.74)%,(12.83±0.84)%,(18.65±1.24)%]显著增加,caspase-8[(0.47±0.05)U/μg vs(1.22±0.15)U/μg,(1.76±0.07)U/μg,(2.91±0.24)U/μg]、caspase-3[(0.44±0.07)U/μg vs(0.95±0.08)U/μg,(1.48±0.14)U/μg,(2.92±0.45)U/μg]活性显著增加,呈剂量依赖性(P<0.01)。PC-3M细胞内VEGF mRNA的表达和蛋白表达呈剂量依赖性降低。结论:双氢青蒿素能显著抑制体外PC-3M细胞的生长,并促进其凋亡,机制可能与增加凋亡蛋白酶和抑制VEGF表达有关。     

表没食子儿茶素没食子酸酯抑制胃癌生长和血管生成及其分子机制的研究

目的探讨表没食子儿茶素没食子酸酯（EGCG）抑制胃癌生长和血管生成的分子机制。方法建立裸鼠异位胃癌肿瘤模型．检测肿瘤生长及肿瘤组织微血管密度（MVD）。培养SGC-7901胃癌细胞．Western印迹方法检测肿瘤细胞及其组织血管内皮生长因子（VEGF）、总信号转导、转录活化因子（Star3）和磷酸化形式Stat3的表达,同时采用ELISA方法检测肿瘤细胞培养液中VEGF蛋白水平．RT-PCR方法检测胃癌细胞VEGFmRNA的表达水平。结果EGCG组肿瘤组织平均质量（0．32±0．08）g,显著低于对照组（0．81±0．12）g,t=7．24,P〈0．01。EGCG组平均肿瘤抑制率为（60．4±6．1）％：其肿瘤生长曲线也显著低于对照组、EGCG组的肿瘤组织MVD（15．2±4．3）也显著低于对照组（24．6±6．6）（t=3．41,P〈0．01）。EGCG组胃癌组织的VEGF表达也减少78．6％．并呈剂量依赖性地下降：其肿瘤组织中Stat3磷酸化活化也减少了53．5％,也呈剂量依赖性地下降：但并未影响总的Stat3表达。结论EGCG通过抑制Stat3活化减少胃癌细胞VEGF表达．从而抑制胃癌生长和血管生成。     

丙戊酸与碱性成纤维细胞生长因子联合应用对神经干细胞增殖的影响

目的探讨丙戊酸(VPA)与碱性成纤维细胞生长因子(bFGF)联合应用对神经干细胞增殖的影响。方法原代培养胎鼠大脑大脑皮层来源的神经干细胞,在条件培养基中加入bFGF和VPA,分为VPA bFGF混合组,bFGF组和VPA组,观察各组神经干细胞球增殖的差异。结果原代培养后第1 d,混合组中神经干细胞球数量比VPA组和bFGF组中稍多(P>0.05),但神经干细胞球直径相差并不明显(P>0.05);第3 d时,VPA和bFGF混合组中神经干细胞球数量比另两组中明显增多,直径也明显大于对照组(P<0.01);第7 d和第10 d时,混合组神经干细胞球直径大约是VPA组和bFGF组的1.5倍(P<0.01)。结论VPA能增强bFGF对神经干细胞的增殖作用。     

肾细胞癌VEGF表达和MVD检测的临床意义

目的 探讨肾细胞癌（RCC）组织中血管内皮细胞生长因子（VEGF）的表达与肿瘤间质微血管密度（MVD）检测的临床意义。方法 采用免疫组化方法对65例肾细胞癌（RCC）及10例正常肾组织进行VEGF单克隆抗体及CD34单克隆抗体染色，观察RCC的VEGF表达与MVD之间的相关性。结果 VEGF的表达与肿瘤间质微血管密度之间存在正相关性，二者均与RCC的病理分级、临床分期及远处转移显著相关（P〈0.05，P〈O．001）。结论 VEGF与MVD可客观准确反映RCC的生物学行为，上述二项指标可作为评估RCC恶性程度、转移及预后的重要指标。     

姜黄素对雄激素非依赖性前列腺癌细胞PC-3及血管内皮生长因子的影响

目的：研究姜黄素对雄激素非依赖性前列腺癌细胞株PC-3细胞体外作用及其对血管内皮生长因子（VEGF）表达的影响，探讨其抗肿瘤的作用机制。方法：分别用0、6．25、12．5、25、50μmol／L浓度的姜黄素作用于PC-3细胞，12、24、36、48、72、96h后台盼蓝拒染法、四甲基偶氮唑蓝（MTT）法检测细胞生长活性；24h后流式细胞仪测定细胞周期及凋亡的变化，透射电镜观察细胞超微结构变化；半定量RT-PCR法检测PC-3细胞内VEGF mRNA的表达；ELISA检测细胞上清液中VEGF浓度。结果：姜黄素能显著抑制PC-3细胞的增殖，呈剂量与时间依赖性，不同浓度姜黄素组之间及不同时间组之间差异均有统计学意义（P〈0．01）。不同浓度姜黄素诱导PC-3细胞出现剂量依赖性G2／M期阻滞（P〈0．01），且各浓度组凋亡细胞比例均显著高于空白对照组（P〈0．01），差异有统计学意义；姜黄素作用24h后PC-3细胞出现凋亡的形态学改变；PC-3细胞内VEGF mRNA的表达和细胞上清液中VEGF呈剂量依赖性降低。结论：姜黄素能显著抑制体外PC-3细胞的生长，并促进其G2／M期阻滞和凋亡，VEGF mRNA及蛋白的表达也明显降低，可能是其抑制肿瘤和血管生长的机制之一。     

姜黄素对雄激素非依赖性前列腺癌细胞PC-3及血管内皮生长因子的影响

目的:研究姜黄素对雄激素非依赖性前列腺癌细胞株PC-3细胞体外作用及其对血管内皮生长因子(VEGF)表达的影响,探讨其抗肿瘤的作用机制。方法:分别用0、6.25、12.5、25、50μmol/L浓度的姜黄素作用于PC-3细胞,12、24、36、48、72、96h后台盼蓝拒染法、四甲基偶氮唑蓝(MTT)法检测细胞生长活性;24h后流式细胞仪测定细胞周期及凋亡的变化,透射电镜观察细胞超微结构变化;半定量RT-PCR法检测PC-3细胞内VEGFmRNA的表达;ELISA检测细胞上清液中VEGF浓度。结果:姜黄素能显著抑制PC-3细胞的增殖,呈剂量与时间依赖性,不同浓度姜黄素组之间及不同时间组之间差异均有统计学意义(P<0.01)。不同浓度姜黄素诱导PC-3细胞出现剂量依赖性G2/M期阻滞(P<0.01),且各浓度组凋亡细胞比例均显著高于空白对照组(P<0.01),差异有统计学意义;姜黄素作用24h后PC-3细胞出现凋亡的形态学改变;PC-3细胞内VEGF mRNA的表达和细胞上清液中VEGF呈剂量依赖性降低。结论:姜黄素能显著抑制体外PC-3细胞的生长,并促进其G2/M期阻滞和凋亡,VEGFmRNA及蛋白的表达也明显降低,可能是其抑制肿瘤和血管生长的机制之一。     

Vascular endothelial growth factor-mediated angiogenesis inhibition and postoperative wound healing in rats

BACKGROUND: Vascular endothelial growth factor (VEGF) is an angiogenic factor that acts by binding to specific high-affinity tyrosine kinase receptors. SU5416 is an antiangiogenic agent that acts as a potent and selective inhibitor of the VEGF Flk-1/KDR receptor tyrosine kinase. SU5416 has been shown to inhibit VEGF-dependent mitogenesis of human endothelial cells and to decrease the growth of xenografts of melanoma, lung carcinoma, ovarian carcinoma, and gliomas. The effect of pre- or perioperative use of this drug on angiogenesis and wound healing in the postoperative setting has not been shown. We sought to analyze the efficacy and safety with respect to functional dosing of SU5416 in the setting of wound healing. This represents an important step forward in the use of this and similar drugs in the perioperative setting of treatment for multiple types of cancers. The use of an inhibitor of VEGF receptors such as SU5416 is distinct and it is likely complementary to other agents in the treatment of such cancers. METHODS: We injected 8-week-old male Sprague-Dawley rats with SU5416 (8 or 12 mg/kg) or dimethyl sulfoxide intraperitoneally, daily for 14 days. We then performed a right pulmonary lobectomy and 6-mm full-thickness punch biopsies of the back. Tissue perfusion measured via laser Doppler on Postoperative Day 2 was 1.65, 1.22, and 1.14 perfusion units (P < 0.0004) for control, 8 mg/kg, and 12 mg/kg groups, respectively. RESULTS: We successfully treated a murine model with functional doses of the anti-VEGF drug SU5416 so as to achieve decreased vascularity and blood flow in postoperative wounds. There was no effect on gross wound healing or infection in either control or treatment groups. Also, no drug-related impairment of histologic healing or decrease in wound tensile strength was demonstrated at either 6 or 14 days. CONCLUSION: Preoperative therapy with functional dosing of SU5416 does not appear to have any major effect on postoperative morbidity or mortality in rats. We additionally conclude that preoperative therapy with SU5416 should be investigated further with careful attention to wound integrity.