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International audience; We have created a dendrimer complex suitable for preferential accumulation within liver tumors and luminescence imaging by substituting thirty-two naphthalimide fluorophores on the surface of the dendrimer and incorporating eight europium cations within the branches. We demonstrate the utility and performance of this luminescent dendrimer complex to detect hepatic tumors generated via direct subcapsular implantation or via splenic injections of colorectal cancer cells (CC531) into WAG/RijHsd rats. Luminescence imaging of the tumors after injection of the dendrimer complex via hepatic arterial infusion revealed that the dendrimer complex can preferentially accumulate within liver tumors. Further investigation indicated that dendrimer luminescence in hepatic tumors persisted in vivo. Due to the incorporation of lanthanide cations, this luminescence agent presents a strong resistance against photobleaching. These studies show the dendrimer complex has great potential to serve as an innovative accumulation and imaging agent for the detection of metastatic tumors in our rat hepatic model.

When microbubble contrast agents are loaded with genes and systemically injected, ultrasound-targeted microbubble destruction (UTMD) facilitates focused delivery of genes to target tissues. A mouse model of squamous cell carcinoma was used to test the hypothesis that UTMD would specifically transduce tumor tissue and slow tumor growth when treated with herpes simplex virus thymidine kinase (TK) and ganciclovir. UTMD-mediated delivery of reporter genes resulted in tumor expression of luciferase and green fluorescent protein (GFP) in perivascular areas and individual tumor cells that exceeded expression in control tumors (p = 0.02). The doubling time of TK-treated tumors was longer than GFP-treated tumors (p = 0.02), and TK-treated tumors displayed increased apoptosis (p = 0.04) and more areas of cellular drop-out (p = 0.03). These data indicate that UTMD gene therapy can transduce solid tumors and mediate a therapeutic effect. UTMD is a promising nonviral method for targeting gene therapy that may be useful in a spectrum of tumors.

There is a paucity of African-American Cancer researchers. To help address this, an educational collaboration was developed between a Comprehensive Cancer Center and a distant undergraduate biology department at a minority institution that sought to teach students introductory cancer biology while modeling research culture. A student-centered active learning curriculum was established that incorporated scientific poster presentations and simulated research exercises to foster learning of cancer biology. Students successfully mined primary literature for supportive data to test cancer-related hypotheses. Student feedback indicated that the poster project substantially enhanced depth of understanding of cancer biology and laid the groundwork for subsequent laboratory work. This inter-institutional collaboration modeled the research process while conveying facts and concepts about cancer.

Endothelial cells (EC) of angiogenic tumor vasculature are characterized by altered expression of molecular markers on their surface. Numerous peptides have been identified that specifically bind tumor angiogenic endothelium, including the tripeptide arginine-arginine-leucine (RRL). We hypothesized that ultrasound contrast microbubbles (MB) targeted via linkage with RRL would specifically adhere to tumor angiogenic endothelium versus normal myocardium, and that this selective adhesion could be detected ultrasonically. Microbubbles were conjugated to cyclic peptides containing either RRL (RRL-MB) or a glycine control sequence (control-MB). As measured in a parallel plate flow chamber, in vitro adhesion of RRL-MBs was three times greater to cultured tumor–derived ECs than to normal ECs (P < 0.01), demonstrating selective binding of RRL-MBs to tumor endothelium. Mice bearing s.c. Clone C or PC3 tumors were given i.v. injections of fluorescent RRL to show in vivo localization to tumor vasculature or were ultrasonically imaged following i.v. injections of targeted contrast MBs. Ultrasound images showed strong RRL-MB contrast enhancement within the tumors but not the control tissue myocardium. Control-MBs caused minimal enhancement in either tissue. Quantitative acoustic videointensity was significantly greater for the tumors than the hearts (5 ± 1 versus 0.5 ± 1 intensity units; P = 0.001). These data show that ultrasound contrast MBs targeted to tumor vasculature via RRL preferentially adhere to tumor versus normal vasculature and that this selective adherence can be detected with ultrasound. Targeted microbubbles may thus offer a noninvasive contrast-enhanced ultrasound imaging technique for the functional imaging of tumor neovascularization, and may have further implications for therapeutic tumor targeting.

Objective: Calcitriol, 1α,25-dihydroxyvitamin D3 (1,25-D3) has potent antiproliferative effects and potentiates the antitumor activity of many other cytotoxic drugs. 1,25-D3 plasma pharmacokinetic (PK) parameters associated with antitumor activity in experimental animal models are unknown. The objective of this study was to determine plasma calcitriol PK in normal mice at doses of calcitriol which are active in suppressing tumor growth. Methods: Plasma 1,25-D3 PK were examined in normal C3H/HeJ mice after a single intraperitoneal dose of 0.125 or 0.5 µg 1,25-D3/mouse. PK blood samples were collected from groups of 5–9 mice at each time point up to 24 h after 1,25-D3 administration. Plasma 1,25-D3 concentrations were measured by radioimmunoassy. Plasma 1,25-D3 concentration diurnal variation was determined in blood samples from untreated animals collected in the morning (9:00–11:00 a.m.) and in the evening (4:00–9:00 p.m.). Results: Median baseline plasma 1,25-D3 concentration measured in the morning and in the evening were 0.082 ng/ml (CI 95%, 0.076–0.099) and 0.067 ng/ml (CI 95%, 0.058–0.075), respectively (p = 0.004). After 0.125 and 0.5 µg dosing, peak plasma 1,25-D3 concentrations (Cpmax) were 12.0 ng/ml (CI 95%, 10.8–12.6) and 41.6 ng/ml (CI 95%, 40.8–53.6), respectively. The corresponding areas under the curve (AUC0–>24 h) were 47.0 (CI 95%, 43.2–51.1) and 128.0 (CI 95%, 127.0–130.0) ng·h/ml. No dose-related changes in time to Cpmax and apparent total plasma clearance were observed. Conclusions: These results demonstrate diurnal variation in baseline plasma 1,25-D3 concentrations in mice. Plasma 1,25-D3 PK in mice receiving doses that are effective in slowing tumor growth, inducing cell cycle arrest and apoptosis, and potentiating taxanes and platinum analogue antitumor activity are at least 5–10 times higher than those easily achieved and nontoxic in patients receiving high-dose intermittent oral therapy.

Although there is abundant evidence that 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] inhibits the growth of several cancer cell types, inhibition of angiogenesis may also play a role in mediating the antitumor effects of 1,25-(OH)(2)D(3.) We examined the ability of 1,25-(OH)(2)D(3) to inhibit the growth of tumor-derived endothelial cells (TDECs) and normal endothelial cells and to modulate angiogenic signaling. 1,25-(OH)(2)D(3) inhibited the growth of TDECs from two tumor models at nanomolar concentrations, but was less potent against normal aortic or yolk sac endothelial cells. The vitamin D analogs Ro-25-6760, EB1089, and ILX23-7553 were also potent inhibitors of TDEC proliferation. Furthermore, the combination of 1,25-(OH)(2)D(3) and dexamethasone had greater activity than either agent alone. 1,25-(OH)(2)D(3) increased vitamin D receptor and p27(Kip1) protein levels in TDECs, whereas phospho-ERK1/2 and phospho-Akt levels were reduced. These changes were not observed in normal aortic endothelial cells. In squamous cell carcinoma and radiation-induced fibrosarcoma-1 cells, 1,25-(OH)(2)D(3) treatment caused a reduction in the angiogenic signaling molecule, angiopoietin-2. In conclusion, 1,25-(OH)(2)D(3) and its analogs directly inhibit TDEC proliferation at concentrations comparable to those required to inhibit tumor cells. Further, 1,25-(OH)(2)D(3) modulates cell cycle and survival signaling in TDECs and affects angiogenic signaling in cancer cells. Thus, our work supports the hypothesis that angiogenesis inhibition plays a role in the antitumor effects of 1,25-(OH)(2)D(3).

Calcitriol (1,25-dihydroxycholecalciferol), the active form of Vitamin D, is anti-proliferative in tumor cells and tumor-derived endothelial cells (TDEC). However, endothelial cells isolated from normal tissues as cell lines or freshly isolated cells or from implanted Matrigel plugs (MDEC) are relatively resistant. Both TDEC and MDEC express similar amounts of Vitamin D receptor (VDR) protein. Although the VDR from TDEC has higher binding affinity for calcitriol than those from MDEC, VDR in both cell types translocates to the nucleus and transactivates the 24-hydroxylase promoter-luciferase construct. Calcitriol selectively inhibits the growth of TDEC but not MDEC by inducing G(0)/G(1) cell cycle arrest and by promoting apoptosis. This selectivity appears to be related to 24-hydroxylase (CYP24) expression. Calcitriol significantly induced CYP24 expression in MDEC but not in TDEC and inhibition of CYP24 activity in MDEC restores their sensitivity to calcitriol. These findings indicate that the induction of CYP24 expression differs in endothelial cells isolated from different microenvironments (TDEC versus MDEC) and that this distinction contributes to selective calcitriol-mediated growth inhibition in these cell types.

Administration of interleukin-1 alpha (IL-1 alpha) plus certain cytotoxic drugs causes substantially greater clonogenic tumor-cell kill and tumor-regrowth delay than does treatment with either agent alone. IL-1 alpha itself has little effect on tumor growth despite its ability to induce acute hemorrhagic necrosis, restrict tumor blood flow, and cause microvascular injury in a variety of murine model systems. To investigate further IL-1 alpha's ability to enhance the antitumor activity of cytotoxic drugs, we initiated studies to examine the effect of IL-1 alpha on cisplatin (cDDP)-mediated cytotoxicity using the RIF-1 tumor system. The antitumor activity of IL-1 alpha and cDDP was quantitated through standard clonogenic tumor-cell survival assays, a tumor hemorrhagic necrosis assay and tumor-regrowth delay studies, with the interaction between IL-1 alpha and cDDP being analyzed through median dose-effect. In vitro, IL-1 alpha had no enhancing effect on the cDDP-mediated tumor-cell kill. For examination of the in vivo efficacy of this regimen, RIF-1 tumor-bearing C3H/HeJ mice (14 days postimplantation) were treated concurrently with single i.p. injections of IL-1 alpha and/or cDDP at various doses. The increased clonogenic tumor-cell kill obtained with IL-1 alpha/cDDP was dose-dependent, with significant enhancement by IL-1 alpha being observed (P0.001), even at the lowest doses tested (2 mg/kg and 6 micrograms/kg for cDDP and IL-1 alpha, respectively), but it did not correlate with an increase in tumor hemorrhage. Using median dose-effect analysis, this interaction was determined to be strongly synergistic. When treated animals were monitored for long-term antitumor effects, combinations with IL-1 alpha significantly increased the tumor-regrowth delay and decreased the fractional tumor volume (P0.001). These results demonstrate that IL-1 alpha synergistically enhances cDDP mediated in vivo antitumor activity and suggest that the combination of IL-1 alpha and cDDP may have potential therapeutic application in the design of effective treatment modalities for cancer.

Exogenously supplied 1,N6-ethenoadenosine triphosphate (epsilon-ATP) and 1,N6-ethenodeoxyadenosine triphosphate (epsilon-dATP) are potent inducers of sister chromatid exchanges (SCEs) in murine spleen lymphocytes but not in peripheral blood lymphocytes cultured in vitro. Data suggest that spleen lymphocyte membranes are inherently more permeable than blood lymphocytes to transient uptake of epsilon-ATP and epsilon-dATP. The effect of media pH and divalent cations on SCE frequency and chromosomal aberrations in spleen cells pulse-treated with epsilon-ATP were studied. The most dramatic responses were observed at pH 8.0 in Ca2+/Mg2(+)-free Hank's balanced salt solution (HBSS). Under the latter conditions, SCE and chromosomal aberration responses (mean +/- SD) of lymphocytes from replicate mice were 69.4 +/- 13.1 SCE/cell and 49 +/- 8.5% of cells with aberrations respectively. Chromosomal aberrations included multiple complex breakage and rearrangements. In HBSS containing Ca2+ (0.575 mM) and Mg2+ (0.4 mM) in concentrations equivalent to those in RPMI 1640, maximum SCE and aberration responses of 31.8 and 28% were observed in cells treated at pH 6.0. Similarly, maximum SCE frequencies (46 +/- 1.6 SCE/cell) and percentage of cells with aberrations (8 +/- 1.4%) were present in spleen cells treated at pH 6.0 in RPMI media. SCEs and aberrations decreased with increasing pH in either media containing divalent cations. In Ca2+/Mg2(+)-free HBSS, the highest mitotic index and fastest cell cycling were seen at pH 6.0. Mitotic indices dropped dramatically at pH 7.4 but recovered considerably at pH 8.0, in spite of a high frequency of cells containing aberrant chromosomes. The most dramatic cytotoxicity occurred at pH 6.0 in HBSS containing Ca2+ and Mg2+. Decreased cytotoxicity was apparent at higher pH and in RPMI medium. Conditions for optimal growth of control cells were obtained following pulse-treatment in Ca2+/Mg2(+)-free HBSS medium at high pH (8.0). Because of the dramatic cytogenetic toxicity of exogenously supplied epsilon-ATP, and the ubiquitous occurrence and biological importance of intracellular ATP, the latter should be considered a potential target for adduct formation by electrophilic metabolites of carcinogenic agents.

Endothelial cells (EC) of angiogenic tumor vasculature are characterized by altered expression of molecular markers on their surface. Numerous peptides have been identified that specifically bind tumor angiogenic endothelium, including the tripeptide arginine-arginine-leucine (RRL). We hypothesized that ultrasound contrast microbubbles (MB) targeted via linkage with RRL would specifically adhere to tumor angiogenic endothelium versus normal myocardium, and that this selective adhesion could be detected ultrasonically. Microbubbles were conjugated to cyclic peptides containing either RRL (RRL-MB) or a glycine control sequence (control-MB). As measured in a parallel plate flow chamber, in vitro adhesion of RRL-MBs was three times greater to cultured tumor-derived ECs than to normal ECs (P0.01), demonstrating selective binding of RRL-MBs to tumor endothelium. Mice bearing s.c. Clone C or PC3 tumors were given i.v. injections of fluorescent RRL to show in vivo localization to tumor vasculature or were ultrasonically imaged following i.v. injections of targeted contrast MBs. Ultrasound images showed strong RRL-MB contrast enhancement within the tumors but not the control tissue myocardium. Control-MBs caused minimal enhancement in either tissue. Quantitative acoustic videointensity was significantly greater for the tumors than the hearts (5 +/- 1 versus 0.5 +/- 1 intensity units; P = 0.001). These data show that ultrasound contrast MBs targeted to tumor vasculature via RRL preferentially adhere to tumor versus normal vasculature and that this selective adherence can be detected with ultrasound. Targeted microbubbles may thus offer a noninvasive contrast-enhanced ultrasound imaging technique for the functional imaging of tumor neovascularization, and may have further implications for therapeutic tumor targeting.

Angiogenesis is a key phenomenon in the continued growth of clinically-significant tumors. Endothelial cells (ECs) of tumor vasculature are phenotypically dissimilar from those in normal tissues, and are characterized by altered expression of molecular markers on the EC surface. Various peptides have been identified that specifically bind to tumor angiogenic endothelium, including the tripeptide Arg-Arg-Leu (MW3). Previously, we have shown that lipid-based ultrasound contrast microbubbles (MBs) can be specifically targeted to EC inflammatory markers. Here, we hypothesized that MBs targeted via MW3 would specifically adhere to tumor angiogenic ECs in vitro. Microbubbles were conjugated via avidin/biotin bridging chemistry to cyclic peptides containing either MW3 or glycine control tripeptides. In a parallel plate chamber, MBs were perfused across coverslips of cultured human coronary artery ECs (HCAECs) or mouse tumor-derived ECs (TDECs) (3 min; wall shear rate 100s/sup -1/) and washed. Adhesion to ECs was quantified in 20 random microscopic fields per coverslip. MW3-MB adherence was 3 to 6-fold greater than glycine-MB (p

Calcitriol, 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)) has potent antiproliferative effects and potentiates the antitumor activity of many other cytotoxic drugs. 1,25-D(3) plasma pharmacokinetic (PK) parameters associated with antitumor activity in experimental animal models are unknown. The objective of this study was to determine plasma calcitriol PK in normal mice at doses of calcitriol which are active in suppressing tumor growth.Plasma 1,25-D(3) PK were examined in normal C3H/HeJ mice after a single intraperitoneal dose of 0.125 or 0.5 microg 1,25-D(3)/mouse. PK blood samples were collected from groups of 5-9 mice at each time point up to 24 h after 1,25-D(3) administration. Plasma 1,25-D(3) concentrations were measured by radioimmunoassay. Plasma 1,25-D(3) concentration diurnal variation was determined in blood samples from untreated animals collected in the morning (9:00-11:00 a.m.) and in the evening (4:00-9:00 p.m.).Median baseline plasma 1,25-D(3) concentration measured in the morning and in the evening were 0.082 ng/ml (CI 95%, 0.076-0.099) and 0.067 ng/ml (CI 95%, 0.058-0.075), respectively (p = 0.004). After 0.125 and 0.5 microg dosing, peak plasma 1,25-D(3) concentrations (Cp(max)) were 12.0 ng/ml (CI 95%, 10.8-12.6) and 41.6 ng/ml (CI 95%, 40.8-53.6), respectively. The corresponding areas under the curve (AUC(0-24 h)) were 47.0 (CI 95%, 43.2-51.1) and 128.0 (CI 95%, 127.0-130.0) ng.h/ml. No dose-related changes in time to Cp(max) and apparent total plasma clearance were observed.These results demonstrate diurnal variation in baseline plasma 1,25-D(3) concentrations in mice. Plasma 1,25-D(3) PK in mice receiving doses that are effective in slowing tumor growth, inducing cell cycle arrest and apoptosis, and potentiating taxanes and platinum analogue antitumor activity are at least 5-10 times higher than those easily achieved and nontoxic in patients receiving high-dose intermittent oral therapy.

Tumor neovascularization is necessary for continued tumor growth and metastasis. During the process of endothelial cell (EC) recruitment and tumor infiltration, specific molecular markers unique for this interaction are expressed on the EC surface. Targeting these molecular markers would, in effect, allow for specific tumor targeting. Tripeptide sequence motifs have previously been reported that will bind to angiogenic tumor ECs. These sequences were identified from in vivo phage peptide display libraries. The purpose of this study was to use a more simplified bacterial peptide display library in an in vitro system to seek out peptide motifs with unique binding to tumor microvasculature.FliTrx is a bacterial peptide display library containing the entire repertoire of possible random dodecapeptides expressed on the flagella tip of E. coli. Two EC populations were used for the screening process, Matrigel invading cells (MAGIC) and tumor-derived endothelial cells (TDEC). MAGIC are obtained from ECs that infiltrate a subcutaneous fibroblast growth factor-containing Matrigel deposit, and TDEC are ECs selectively obtained from tumor vasculature. FliTrx cells were incubated with MAGIC at 4 degrees C to remove any potential clones displaying peptides that will bind to nonspecific EC surface targets. The non-binding cells were then incubated with TDEC, allowing for clones displaying potential binding peptides to bind tumor specific targets on TDECs. The bacterial population was then expanded and this "panning" process was carried out a total of five times. Peptide insert sequences from 100 bacterial colonies were analyzed for potential repetitive peptide motifs.Recurring peptide sequences were detected that were 3-mers (13 sequences) and 4-mers (4 sequences). Of the 3-mers, four repeated 3 times, whereas none of the 4-mers repeated more than twice. All of the repeated sequences were basic in charge, and arginine was the most commonly seen amino acid. A tripeptide basic-basic-nonpolar amino acid arrangement was the most prevalent charge sequence in all repetitive motifs (17 repeat sequences). Two test peptides showed TDEC binding specificity, and both conformed to the basic-basic-nonpolar motif.We report peptide sequences derived from panning an in vitro system designed to detect tumor-EC specific markers. These putative motifs may serve as molecular determinants for a novel therapeutic modality aimed at specifically targeting tumors through tumor angiogenic vessels.

Background: The active metabolite of vitamin D, i.e., 1,25-dihydroxycholecalciferol (1,25-D 3 ), inhibits the growth of murine SCCVII/SF squamous cell carcinoma cells, both in vitro and in vivo. However, in vivo use of 1,25-D 3 is hampered as a result of hypercalcemia (i.e., elevated levels of calcium in the blood). Glucocorticoids, such as dexamethasone, affect calcium absorption and modulate vitamin D receptor binding and have been used to treat hypercalcemia. In this study, we examined the effect of dexamethasone on tumor growth inhibition by 1,25-D 3 . Methods: The effects of 1,25-D 3 and dexamethasone, alone and in combination, on the growth of SCCVII/SF cells in in vitro culture or in vivo in female C3H/HeJ mice were determined by clonogenic tumor cell assay and/or by actual changes in tumor volume. Vitamin D receptor-ligand-binding activities in whole-cell extracts from cells (in culture), tumors, and normal tissues were assayed by single-point saturation analysis and equilibrium binding. Results: Treatment of cultured SCCVII/SF cells with 500 nM dexamethasone for 24 hours before addition of 1,25-D 3 reduced their survival. The growth of SCCVII/SF tumors was inhibited in mice treated simultaneously with dexamethasone and 1,25-D 3 (as compared with no treatment or single-agent treatment); hypercalcemia was also reduced. Total vitamin D receptor content in SCCVII/SF cells was increased after treatment with dexamethasone. Treatment of tumor-bearing animals with dexamethasone (9 μg/day) for 7 days led to increased vitamin D receptor-ligand-binding activities in whole-cell extracts from tumor or kidneys and decreased activity in intestinal mucosa. Conclusions: Dexamethasone may enhance the antitumor effect of 1,25-D 3 by increasing vitamin D receptor-ligand-binding activity.

Cytokines or biological response modifiers have been utilized in combination with conventional chemotherapeutic agents to increase cytotoxic drug-mediated efficacy and to reduce the associated toxic side effects. Interleukin-1 (IL-1) is a multifunctional cytokine, primarily produced by monocyte/macrophages1–4, that plays a central role in the activation of T and B cells3,4, potentiates hematopoiesis both in vitro and in vivo5–9, and induces the synthesis of other cytokines and regulatory molecules3,10,11. Studies in our laboratories have demonstrated that IL-1α induces acute tumor hemorrhagic necrosis, changes in tumor blood flow, an increase of tumor clonogenic cell kill and enhancement of cytotoxic drug-mediated anti-tumor effects in murine tumor model systems12–20. We focus our discussion here on IL-1’s activities in the treatment of solid tumors either alone or in combination with the platinum agents, cisplatin or carboplatin.

The endothelium represents a potentially critical target for gene therapy because of its anatomical location and its importance in the viability in both normal and malignant tissues. Protecting the endothelium of normal tissues, such as the lungs, from the toxic effects of current antineoplastic agents and the destruction of the tumor vasculature are reasonable goals. As a target, however, the endothelium continues to represent a significant challenge. While gene delivery to cultured endothelial cells is possible, improved delivery systems are required, as well as cell-specific promoters, before in vivo gene therapy to important endothelial populations can be accomplished.

Background: Ultrasound contrast agents are gas-filled microbubbles (MB) that can be induced to vibrate or cavitate in an ultrasound field. When the MB are loaded with genes and systemically injected, ultrasound-targeted MB destruction (UTMD) has been shown to facilitate focused delivery and transduction of genes to the target site. An experimental model of mouse squamous cell carcinoma was used to test the hypothesis that delivery of a suicide gene via UTMD would slow tumor growth. Methods: Lipid based perfluorobutane gas-filled MBs (2 μm diameter) were synthesized incorporating a cationic phospholipid to enable loading with DNA (100 ug per 109 MB). DNA loading was confirmed using electrophoresis and DNAseI challenge. Primary cultured mouse squamous carcinoma cells were subcutaneously injected into mice. 3-5 days after cell injection, mice were intravenously infused over 30 min with MB (5 × 108) loaded with plasmids containing reporter genes GFP (n = 3) or luciferase (n = 6). During MB infusion, ultrasound (1.3MHz) was intermittently delivered using a clinical scanner at high acoustic power, with simultaneous ultrasound imaging used to confirm MB destruction within the tumor. To assess the therapeutic potential of the system, tumors were allowed to grow to 100 µl, and MB (5 × 108) loaded with plasmid containing either the suicide gene thymidine kinase (TK) (n = 6) or GFP control (n = 6) was given to separate groups of mice along with ultrasound treatment. Gancyclovir was administered 3 days after UTMD and tumors were serially measured until they were 2ml in volume, after which animals were euthanized and tissue harvested for histology. Results: UTMD-mediated delivery of reporter genes resulted in tumor expression of luciferase (1568 RLU/min/mg) and GFP ( Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 585.

3087 Background: TACE is an effective modality in the treatment of metastatic or primary hepatic malignancies of GI origin. One outcome from this effective therapy is hypoxia and cell death with tu...

3198 Background: Tumor endothelial cells (ECs) are phenotypically distinct and express unique surface molecular markers. Previous work show that a synthetic peptide containing the amino acid motif RRL will specifically bind (i) tumor ECs in vitro, (ii) the vasculature of experimental prostate and sarcoma tumors and (iii) the ECs within human prostate and sarcoma tumors. We hypothesized that ultrasound contrast microbubbles (MBs) linked to RRL peptide would preferentially and specifically adhere to tumor vasculature, allowing for direct, real-time, tumor imaging. Methods: Phospholipid MBs were conjugated via avidin/biotin bridging chemistry to cyclic peptides containing either RRL (MBRRL) or a glycine control sequence (MBControl). Solid 0.5 cm3 PC3 (human prostate) or Clone C (mouse sarcoma) tumors were established in the flank of 11 mice. MBRRL or MBControlwere injected i.v. (5x106 MBs/injection), and the tumors imaged with high-mechanical index triggered pulse inversion ultrasound at 120 and 135 sec. In ...