Troponin I overexpression inhibits tumor growth, perfusion, and vascularization of morris hepatoma.

Antiangiogenic gene transfer inhibiting growth of new blood vessels is a promising approach in cancer therapy. Human troponin I (TnI) efficiently inhibits endothelial cell proliferation, migration, as well as angiogenesis and tumor growth in vivo. However, little is known about its effects on perfusion and tumor biology. METHODS: Stable Morris hepatoma (MH3924A) cells overexpressing human TnI (TnI-MH3924A) were cocultured with human umbilical vein endothelial cells (HUVECs) followed by measurements of endothelial apoptosis and proliferation. Furthermore, tumor growth and perfusion were determined using H(2)(15)O and (68)Ga-DOTA-albumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid) PET as well as functional MRI. Additionally, histologic measurements of vascularization, apoptosis, proliferation, and gene array analyses were performed. RESULTS: Apoptosis of HUVECs was increased and proliferation was decreased after coculture with TnI-MH3924A cells. TnI-MH3924A tumors showed a significant inhibition of growth (90%) and a decreased perfusion (25%), whereas blood volume remained unchanged. MRI investigations demonstrated a significant decrease of the rate constant k(ep). Immunohistochemical analyses showed decreased microvessel density and proliferation and significant induction of apoptosis. Furthermore, TnI-expressing hepatomas demonstrated changes in the expression of genes related to angiogenesis, apoptosis, signal transduction, or stress. CONCLUSION: TnI regulates tumor growth by modulating vascularization including apoptosis induction and decrease of proliferation. In addition, changes in expression of genes associated with angiogenesis, apoptosis, signal transduction, or stress were found. The upregulation of angiogenesis and stress-related genes indicates a cross-talk of different mechanisms as part of the tumor's reaction to TnI. Because the decrease of vascularization led to lower perfusion values as measured by PET and MRI, these noninvasive methods are promising tools for the monitoring of antiangiogenic gene therapy.     

Angiopoietin-2 overexpression in morris hepatoma results in increased tumor perfusion and induction of critical angiogenesis-promoting genes.

Monitoring of angiogenesis-relevant approaches with functional imaging and histomorphometric analyses is desirable to evaluate the biologic effects. In this study we wished to examine the complex effects of angiopoietin-2 (Ang-2) gene transfer in a rat hepatoma model. METHODS: Using a bicistronic retroviral vector for Ang-2, Morris hepatoma (MH3924A) cell lines with Ang-2 expression were generated (Ang-2-MH3924A). In human umbilical vein endothelial cells (HUVECs) cocultured with Ang-2-MH3924A, the proliferative action with or without growth factors were determined. Furthermore, animal experiments were performed to measure effects on tumor growth and perfusion. Finally, tumors were examined by immunohistochemistry and DNA chip analysis. RESULTS: Ang-2-expressing MH3924A enhanced basic fibroblast growth factor-mediated endothelial cell proliferation. Perfusion, as measured by H(2)(15)O PET, was increased in genetically modified tumors. Consistent with the increased perfusion, micro- and macrovascularization were increased. However, tumor growth was similar to wild-type MH3924A (WT-MH3924A). Proliferating cell nuclear antigen and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) staining revealed an increased number of positive cells, indicating a compensation of increased proliferation by enhanced apoptosis. DNA chip analysis showed an induction of angiogenesis-promoting genes, including crucial vascular growth factor receptors, as well as genes related to extracellular matrix (ECM), apoptosis, signal transduction, and oxidative stress. CONCLUSION: Our results suggest that Ang-2 expression increases perfusion or vascularization, especially in interaction with the vascular growth factor system, without affecting tumor growth. Simultaneous, enhanced expression of genes for ECM, apoptosis, and signal transduction indicates Ang-2's versatile role in angiogenesis including its destabilizing function on ECM and endothelium.     

Changes in glucose metabolism and gene expression after transfer of anti-angiogenic genes in rat hepatoma

Purpose Human troponin I (TROP), the soluble receptor for vascular endothelial growth factor (sFLT) and angiostatin (ASTAT) are potent inhibitors of endothelial cell proliferation, angiogenesis and tumour growth in vivo. Transfer of these genes into tumours may induce changes not only in perfusion, but also more general ones such as changes in metabolism. The aim of this study was to assess these reactions using FDG-PET and high-throughput methods such as gene profiling. Methods We established Morris hepatoma (MH3924A) cell lines expressing TROP, sFLT or ASTAT and quantified ¹⁸F-fluorodeoxyglucose (¹⁸FDG) uptake by dynamic positron emission tomography (PET) after tumour inoculation in ACI rats. Furthermore, expression of glucose transporter-1 and -3 (GLUT-1 and GLUT-3) as well as hexokinase-1 and -2 were investigated by RT-PCR and immunohistomorphometry. In addition, gene array analyses were performed. Results ¹⁸FDG uptake, vascular fraction and distribution volume were significantly higher in all genetically modified tumours. Immunohistomorphometry showed an increased percentage of hexokinase-1 and -2 as well as GLUT-1 and -3 immunoreactive (ir) cells. Using gene arrays and comparing all three groups of genetically modified tumours, we found upregulated expression of 36 genes related to apoptosis, signal transduction, stress or metabolism. Conclusion TROP-, sFLT- or ASTAT-expressing MH3924A tumours show enhanced influx of ¹⁸FDG, which seems to be caused by several factors: enhanced exchange of nutrients between blood and tumour, increased amounts of glucose transporters and hexokinases, and increased expression of genes related to apoptosis, matrix and stress, which induce an increased demand for glucose.     

PET of vascular endothelial growth factor receptor expression.

For solid tumors and metastatic lesions, tumor vascularity is a critical factor in assessing response to therapy. Here we report the first example, to our knowledge, of (64)Cu-labeled vascular endothelial growth factor 121 (VEGF(121)) for PET of VEGF receptor (VEGFR) expression in vivo. METHODS: VEGF(121) was conjugated with 1,4,7,10-tetraazadodecane-N,N',N',N'-tetraacetic acid (DOTA) and then labeled with (64)Cu for small-animal PET of mice bearing different sized U87MG human glioblastoma xenografts. Blocking experiments and ex vivo histopathology were performed to confirm the in vivo results. RESULTS: There were 4.3 +/- 0.2 DOTA molecules per VEGF(121), and the VEGFR2 binding affinity of DOTA-VEGF(121) was comparable to VEGF(121). (64)Cu labeling of DOTA-VEGF(121) was achieved in 90 +/- 10 min and the radiolabeling yield was 87.4% +/- 3.2%. The specific activity of (64)Cu-DOTA-VEGF(121) was 3.2 +/- 0.1 GBq/mg with a radiochemical purity of >98%. Small-animal PET revealed rapid, specific, and prominent uptake of (64)Cu-DOTA-VEGF(121) in small U87MG tumors (high VEGFR2 expression) but significantly lower and sporadic uptake in large U87MG tumors (low VEGFR2 expression). No appreciable renal clearance of (64)Cu-DOTA-VEGF(121) was observed, although the kidney uptake was relatively high likely due to VEGFR1 expression. Blocking experiments, immunofluorescence staining, and western blot confirmed the VEGFR specificity of (64)Cu-DOTA-VEGF(121). CONCLUSION: Successful demonstration of the ability of (64)Cu-DOTA-VEGF(121) to visualize VEGFR expression in vivo may allow for clinical translation of this radiopharmaceutical for imaging tumor angiogenesis and guiding antiangiogenic treatment, especially patient selection and treatment monitoring of VEGFR-targeted cancer therapy.     

Changes of intratumoral microvessels and blood perfusion during establishment of hepatic metastases in mice

PURPOSE: To prospectively evaluate the stepwise changes that occur in intratumoral microvessels and microcirculation during the establishment of murine colonic hepatic metastases by using in vivo fluorescent microscopy and to compare the changes with tumor angiogenesis evaluated with an immunohistochemical study. MATERIALS AND METHODS: This study was approved by the institutional animal care and use committee. Twenty-five mice with hepatic metastases created with injection of murine colonic adenocarcinoma (colon 26) tumor cells into the spleen were examined with in vivo microscopy and immunohistochemical study for CD34, intracellular adhesion molecule (ICAM-1), and alpha smooth muscle actin (alpha-SMA). The tumor size, microcirculation in tumors, intratumoral microvessel density (MVD), afferent MVD, and CD34-positive MVD were evaluated. The data among the tumors that showed different hemodynamic or immunohistochemical patterns were compared with the Kruskal-Wallis test and the Student t test. RESULTS: Four stepwise patterns were observed according to the changes in morphology, hemodynamics, and immunohistochemical characteristics of intratumoral microvessels during the establishment of hepatic metastases, as follows: metastases without definite intratumoral blood perfusion or any intratumoral microvessels (mean diameter, approximately 180 microm), metastases with portal perfusion and intratumoral ICAM-1-positive residual hepatic sinusoids (mean diameter, approximately 290 microm), metastases with mixed portal and arterial perfusion and increased CD34-positive microvessels and alpha-SMA-positive arterioles (mean diameter, approximately 520 microm), and metastases with exclusively arterial perfusion and increased CD34-positive microvessels and alpha-SMA-positive arterioles (mean diameter, >2000 microm). The differences among the mean sizes of the tumors that showed these four patterns were statistically significant (P < .01). CONCLUSION: Stepwise changes of intratumoral microcirculation were revealed from direct diffusion, to portal perfusion, to mixed portal and arterial perfusion, and finally to arterial perfusion in accordance with stepwise tumor neovascularization during the growth of murine colonic hepatic metastases.     

Human Glioblastoma and Carcinoma Xenograft Tumors Treated by Combined Radiation and Imatinib (Gleevec®)

BACKGROUND AND PURPOSE: Imatinib (Gleevec, Glivec) is an inhibitor of alpha- and beta-platelet-derived growth factor receptors and other tyrosine kinases, that are also associated with the function of growth factors. Imatinib has been approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors and is under investigation for the therapy of several other malignant tumors. Since radiotherapy is an important treatment option in many tumors, combined effects of imatinib and radiation were analyzed here. MATERIAL AND METHODS: In vitro, U87 cells (human glioblastoma), A431 cells (human epidermoid carcinoma), and HUVECs (human umbilical venous endothelial cells) were treated with imatinib alone and in combination with radiation. Clonogenic survival and cell proliferation were determined with and without additional radiation (0-10 Gy). In vivo, U87 and A431 cells (5 x 10(6)) were subcutaneously injected into hind limbs of balb c nu/u mice. Drug and radiation treatments started on day 0 when tumor volumes were approximately 400-500 mm(3). Tumors were treated with 5 x 5 Gy (U87) or 6 x 5 Gy (A431) on consecutive days from day 0. Imatinib was administered orally via the mouse diet starting on day 0 until the end of observation. Tumor growth and microvessel density (CD31 IHC) were analyzed. RESULTS: In vitro, imatinib increased radiosensitivity of U87 and A431 tumor cells as well as HUVECs in both clonogenic and cell number/proliferation assays. The enhancement of radiosensitivity in HUVECs was comparable to that observed in the tumor cells. In vivo, the concurrent and continuous administration of imatinib increased tumor growth delay of fractionated radiotherapy in the carcinoma and the glioblastoma models at reduced microvessel densities. No apparent additional toxicity by the combination of radiation and imatinib versus monotherapies was observed in terms of weight, skin, or general behavior. CONCLUSION: Imatinib (Gleevec), a "molecular targeted" approved drug for human malignancies, can enhance the tumor growth reduction induced by fractionated radiotherapy in glioblastoma and carcinoma models. The data provides a rationale to further investigate the combination.     

Tumor angiogenesis targeting using imaging agents.

The inhibition of tumor induced angiogenesis is an emerging therapeutic strategy in clinical oncology aimed at halting cancer progression by suppressing tumor blood supply. As anti-angiogenic therapy is primarily cytostatic and not cytotoxic, the established criteria for assessing tumor response to chemo- and radiotherapy cannot be applied to anti-angiogenic therapy. Therefore, functional and molecular parameters for imaging of tumor angiogenesis are being intensively studied. Computed tomography, magnetic resonance imaging, ultrasound and scintigraphic techniques can assess changes in vascular permeability and tumor blood flow during anti-angiogenic therapy. Scintigraphic techniques, especially positron emission tomography (PET), may be used to monitor the consequences of anti-angiogenic therapy on tumor cell metabolism, proliferation and apoptosis. The high sensitivity of PET which allows measurements of tracer concentrations in the picomolar range is promising for the visualization of specific molecular targets prior to therapy thus identifying patients most likely benefit from a particular form of anti-angiogenic therapy.     

乳腺癌多层螺旋CT灌注成像与微血管生成的相关性研究

目的 探讨乳腺癌多层螺旋CT (MSCT)灌注成像(PI)与微血管生成的关系.资料与方法 38例乳腺实质肿瘤患者行PI后,切除肿瘤标本53个,以免疫组化法评价癌(28个)、良性实质肿瘤(25个)、癌旁无浸润腺体(26个)的血管内皮生长因子(VEGF)和微血管密度(MVD).结果 乳腺实质肿瘤的MVD与VEGF呈正相关(r=0.82,P＜ 0.05),且时间-密度曲线(TDC)为流出型和平台型的MVD高于流入型和平坦型(F=6.47,P＜ 0.01),乳腺癌的MVD高于良性实质肿瘤及癌旁正常腺体(t=17.67、15.99,P＜ 0.05).乳腺癌的最大密度投影(MIP)、增强平均值(AV)、血流量(BF)、血容量(BV)、血管表面通透性(PS)、Patlak血容量(PBV)与MVD呈正相关(r=0.44、0.46、0.50、0.49、0.52、0.47,P＜0.05).结论 MSCT PI是一种可以较好地反映乳腺癌的血管生成情况的无创性检查方法,对乳腺癌的诊断、鉴别诊断、活检定位有重要价值.     

导管室内平板探测器CT定量评估兔肝肿瘤血管生成研究

目的 探讨导管室内平板探测器CT(FDCT)技术定量评估肝肿瘤血管生成的可行性.方法 25只新西兰大白兔VX2肝肿瘤模型构建后行FDCT检查,重建肿瘤血容量(BV)灌注图,分别检测肝肿瘤和肝实质BV值.FDCT检查后处死所有实验兔,取相应部位肝肿瘤标本检测微血管密度(MVD)和血管内皮细胞生长因子(VEGF)表达,分析肝肿瘤BV值与MVD和VEGF表达的关系.结果 25只实验兔中22只兔(88％)成功完成FDCT检查,BV灌注图均清晰显示肝组织和肿瘤,肝肿瘤表现为高灌注环伴低灌注中心的环状强化模式.肿瘤BV值与MVD和VEGF分级均存在良好相关性(P值均＜0.05),MVD与VEGF分级呈正相关(r=0.504,P＜0.001).结论 导管室内FDCT检查可定量评估肝肿瘤血管生成情况,可能有助于肝肿瘤介入诊疗.     

Glucose metabolism of breast cancer assessed by 18F-FDG PET: histologic and immunohistochemical tissue analysis.

Breast cancer is characterized by elevated glucose consumption resulting in increased uptake of 18F-FDG. However, tracer uptake varies considerably among tumors imaged with PET. This study compared histologic and immunohistochemical tissue analysis of breast carcinomas with preoperative FDG uptake assessed by PET to identify tumor characteristics that define the degree of tracer accumulation. METHODS: FDG uptake in breast tumors was quantified by calculating standardized uptake values (SUVs) corrected for partial-volume effect and normalized to blood glucose level at the time of tracer injection. The histologic sections of 50 invasive and 6 noninvasive breast carcinomas were analyzed for histologic type, microscopic tumor growth pattern, percentage of tumor cells, presence of inflammatory cells, density of blood vessels, histopathologic grading, tumor cell proliferation (mitotic rate and antibody binding of MIB-1), expression of estrogen and progesterone receptors, and expression of the glucose transporter protein Glut-1. RESULTS: A positive correlation was found between FDG uptake and histologic tumor type (ductal vs. lobular; P = 0.003), microscopic tumor growth pattern (nodular vs. diffuse; P = 0.007), and tumor cell proliferation (MIB-1; P = 0.009). Tumors with diffuse growth patterns had significantly lower SUVs compared with clearly defined tumors. A weak relationship was found between FDG uptake and the percentage of tumor cells (P = 0.06). Lower densities of blood vessels corresponded to higher FDG uptakes (P = 0.08). However, even significant correlations showed poor correlation coefficients. No relationship was found between FDG uptake and the following: tumor size; axillary lymph node status; percentage of necrotic, fibrotic, and cystic compounds; presence of inflammatory cells; steroid receptor status; and expression of Glut-1. CONCLUSION: Histologic and immunohistochemical tissue analysis was unable to sufficiently explain the variation of FDG uptake in breast cancer. The degree of metabolic changes after malignant transformation is most likely explained by a complex interaction between cellular energy demand and tumoral microenvironment. Therefore, FDG PET imaging may not be used to estimate tumor biologic behavior of breast cancer such as differentiation, histopathologic grading, cell proliferation, or axillary lymph node status.     

PET预测及评价肿瘤疗效的新进展

临床上评价及预测肿瘤疗效的手段很多,包括体格检查、普通影像学检查(X线摄片、CT、MRI等)和肿瘤标志物检测等,但这些方法均有很大的局限性,如主观性强、敏感性差等。PET可以早期准确地反映肿瘤相关生物特征,如血管生成、凋亡、乏氧和增殖等。因此,利用相应的可反映上述生物特征的显像剂行PET,可对肿瘤进行早期诊断、评价和预测肿瘤治疗的疗效,协助临床医生制定治疗方案。     

兔VX2肝癌HIFU治疗前后肿瘤新生血管MSCT灌注成像研究

目的通过对兔肝VX2种植瘤高强度聚焦超声(HIFU)治疗前后MSCT灌注参数与肿瘤微血管密度(MVD)、血管内皮生长因子(VEGF)表达的相关性研究,探讨MSCT灌注成像活体评价肝肿瘤血管生成的价值。方法 30只VX2肝种植瘤模型兔,分为对照组和治疗组,治疗组进行HIFU治疗,分别对两组试验动物行MSCT灌注成像检查,并用免疫组织化学方法测定MVD、VEGF表达情况,分析MSCT灌注参数与MVD和VEGF的相关性。结果治疗组灌注参数、MVD及VEGF表达程度均明显低于对照组,VEGF和MVD的表达呈显著正相关,MSCT灌注参数中,肝总血流灌注量(HBF),毛细血管表面通透性(PS)和肝灌注指数(HAI)与VEGF、MVD的表达均呈高度正相关,而肝血容积(HBV)、平均通过时间(MTT)与VEGF、MVD的表达无相关性。结论 MSCT灌注参数与MVD、VEGF表达有明显相关性,可用于活体评价肿瘤血管生成。     

Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide–paclitaxel conjugate in mice with breast cancer

PURPOSE: Targeting drugs to receptors involved in tumor angiogenesis has been demonstrated as a novel and promising approach to improve cancer treatment. In this study, we evaluated the anti-tumor efficacy of a dimeric RGD peptide-paclitaxel conjugate (RGD2-PTX) in an orthotopic MDA-MB-435 breast cancer model. METHODS: To assess the effect of conjugation and the presence of drug moiety on the MDA-MB-435 tumor and normal tissue uptake, the biodistribution of (3)H-RGD2-PTX was compared with that of (3)H-PTX. The treatment effect of RGD2-PTX and RGD2+PTX was measured by tumor size, (18)F-FDG/PET, (18)F-FLT/PET, and postmortem histopathology. RESULTS: By comparing the biodistribution of (3)H-RGD2-PTX and (3)H-PTX, we found that (3)H-RGD2-PTX had higher initial tumor exposure dose and prolonged tumor retention than (3)H-PTX. Metronomic low-dose treatment of breast cancer indicated that RGD2-PTX is significantly more effective than PTX+RGD2 combination and solvent control. Although in vivo (18)F-FLT/PET imaging and ex vivo Ki67 staining indicated little effect of the PTX-based drug on cell proliferation, (18)F-FDG/PET imaging showed significantly reduced tumor metabolism in the RGD2-PTX-treated mice versus those treated with RGD2+PTX and solvent control. Terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining also showed that RGD2-PTX treatment also had significantly higher cell apoptosis ratio than the other two groups. Moreover, the microvessel density was significantly reduced after RGD2-PTX treatment as determined by CD31 staining. CONCLUSION: Our results demonstrate that integrin-targeted delivery of paclitaxel allows preferential cytotoxicity to integrin-expressing tumor cells and tumor vasculature. The targeted delivery strategies developed in this study may also be applied to other chemotherapeutics for selective tumor killing.     

Effects of Lovastatin Alone or Combined with Irradiation on Tumor Cells in Vitro and in Vivo

PURPOSE: To evaluate the effect of lovastatin alone or combined with radiation on U87MG and FaDu cells in vitro and U87MG tumors in vivo. MATERIAL AND METHODS: Cell number, p21(WAF1) expression, apoptosis, reproductive cell death, and cell-cycle distribution were investigated after incubation of U87MG and FaDu cells in vitro. The effect of lovastatin (50 mg/kg/day) on tumor growth and on tumor growth delay after single-dose irradiation with 20 Gy was investigated using U87MG tumors in nude mice. RESULTS: Lovastatin dose dependently decreased cell number and proliferation of U87MG and FaDu cells. The proportion of cells in G0/G1 phase, apoptosis and p21 protein expression increased after lovastatin alone or combined with 4-Gy irradiation in both cell lines. Effects of lovastatin on cell cycle and cell number were more pronounced in U87MG compared to FaDu. No radiosensitization of clonogenic cells by lovastatin could be demonstrated in both cells lines, but the colony-forming ability after lovastatin alone was decreased in FaDu cells. In vivo, lovastatin decreased tumor volume over time but did not increase growth delay after irradiation of U87MG tumors with 20 Gy. CONCLUSION: The data support effects of lovastatin on proliferation, apoptosis and colony-forming ability in vitro and tumor volume in vivo. At the drug concentration achievable, lovastatin did not improve the effects of radiation on U87MG tumors in vivo.     

18F-CPFPX PET identifies changes in cerebral A1 adenosine receptor density caused by glioma invasion.

Adenosine plays a critical role in both tumor proliferation and the cerebral response to tumor invasion. We used 8-cyclopentyl-3-(3-18F-fluoropropyl)-1-propylxanthine (18F-CPFPX) PET to investigate A1 adenosine receptor (A1AR) density as a potential indicator of the local cerebral response to glioma invasion. METHODS: A1AR density in F98 glioma-bearing rats was examined by 18F-CPFPX and 3H-CPFPX using PET, quantitative in vitro and ex vivo double-label receptor autoradiography, and immunohistochemical analyses. RESULTS: For all imaging modalities, A1AR signal intensity was increased in a zone surrounding experimental tumors (136%-146% that in control tissue) (P < 0.01). Immunostaining identified activated astrocytes as the main origin of peritumoral A1AR upregulation. The results of a pilot 18F-CPFPX PET study on a patient with recurrent glioblastoma multiforme confirmed increases in A1AR density in the immediate vicinity of the tumor. CONCLUSION: 18F-CPFPX PET is suitable for the detection of peritumoral changes in A1AR density. Molecular imaging with 18F-CPFPX PET may open novel possibilities for gaining experimental and clinical insights into the cerebral response to tumor invasion.     

Peripheral lung cancer: relationship between multi-slice spiral CT perfusion imaging and tumor angiogenesis and cyclin D1 expression

The aim of this study was to investigate the relationship between 16-slice spiral CT perfusion imaging and tumor angiogenesis and cyclin D1 expression in patients with peripheral lung cancer. Fifty-eight patients with peripheral lung cancer underwent 16-slice spiral CT perfusion imaging. The CT perfusion imaging was analyzed for time density curve (TDC), perfusion parametric maps, and the respective perfusion parameters. Correlation between the respective perfusion parameters and immunohistochemical findings of microvessel density measurement and cyclin D1 expression was evaluated.     

Multimodality molecular imaging of glioblastoma growth inhibition with vasculature-targeting fusion toxin VEGF121/rGel.

Vascular endothelial growth factor A (VEGF-A) and its receptors, Flt-1/FLT-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2), are key regulators of tumor angiogenesis and tumor growth. The purpose of this study was to determine the antiangiogenic and antitumor efficacies of a vasculature-targeting fusion toxin (VEGF(121)/rGel) composed of the VEGF-A isoform VEGF(121) linked with a G(4)S tether to recombinant plant toxin gelonin (rGel) in an orthotopic glioblastoma mouse model by use of noninvasive in vivo bioluminescence imaging (BLI), MRI, and PET. METHODS: Tumor-bearing mice were randomized into 2 groups and balanced according to BLI and MRI signals. PET with (64)Cu-1,4,7,10-tetraazacyclododedane-N,N',N',N'-tetraacetic acid (DOTA)-VEGF(121)/rGel was performed before VEGF(121)/rGel treatment. (18)F-Fluorothymidine ((18)F-FLT) scans were obtained before and after treatment to evaluate VEGF(121)/rGel therapeutic efficacy. In vivo results were confirmed with ex vivo histologic and immunohistochemical analyses. RESULTS: Logarithmic transformation of peak BLI tumor signal intensity revealed a strong correlation with MRI tumor volume (r = 0.89, n = 14). PET with (64)Cu-DOTA-VEGF(121)/rGel before treatment revealed a tumor accumulation (mean +/- SD) of 11.8 +/- 2.3 percentage injected dose per gram at 18 h after injection, and the receptor specificity of the tumor accumulation was confirmed by successful blocking of the uptake in the presence of an excess amount of VEGF(121). PET with (18)F-FLT revealed significant a decrease in tumor proliferation in VEGF(121)/rGel-treated mice compared with control mice. Histologic analysis revealed specific tumor neovasculature damage after treatment with 4 doses of VEGF(121)/rGel; this damage was accompanied by a significant decrease in peak BLI tumor signal intensity. CONCLUSION: The results of this study suggest that future clinical multimodality imaging and therapy with VEGF(121)/rGel may provide an effective means to prospectively identify patients who will benefit from VEGF(121)/rGel therapy and then stratify, personalize, and monitor treatment to obtain optimal survival outcomes.     

Molecular imaging in cancer treatment

The success of cancer therapy can be difficult to predict, as its efficacy is often predicated upon characteristics of the cancer, treatment, and individual that are not fully understood or are difficult to ascertain. Monitoring the response of disease to treatment is therefore essential and has traditionally been characterized by changes in tumor volume. However, in many instances, this singular measure is insufficient for predicting treatment effects on patient survival. Molecular imaging allows repeated in vivo measurement of many critical molecular features of neoplasm, such as metabolism, proliferation, angiogenesis, hypoxia, and apoptosis, which can be employed for monitoring therapeutic response. In this review, we examine the current methods for evaluating response to treatment and provide an overview of emerging PET molecular imaging methods that will help guide future cancer therapies.