fosbretabulin and Disease-Models--Animal

There is increasing interest in small-molecule drugs that can selectively disrupt the abnormal vasculature associated with disease processes such as cancer and macular degeneration. These agents are distinct from anti-angiogenic strategies, which do not target existing vessels but prevent additional vessel growth, althouglh they may potentially be complimentary with these antiangiogenic strategies. Several vascular disrupting agents (VDAs) are now undergoing clinical evaluation. The main focus of research has been on two drug classes: the first is comprised of agents that bind reversibly with tubulin and prevent microtubule assembly; the second are the flavanoids, which can induce intratumor cytokine release. Data from phase I studies have established that these agents can selectively reduce tumor blood flow at well-tolerated doses. Preclinical data indicate that VDAs can improve the tumor response to cytotoxic chemotherapy, radiation and antiangiogenic treatments. This activity has been attributed to the ability of these agents to selectively destroy the central regions of tumors, areas widely believed to contain cell populations resistant to cytotoxic therapies. The VDA compounds combretastatin A4 phosphate (CA4P) and 5,6-dimethylxantlenone-4-acetic acid (DMXAA) are being evaluated in phase II clinical trials in combination with conventional cytotoxic therapies for the potential treatment of cancer. This review discusses the small-molecule VDAs in clinical development. In addition, the potential for combination therapy with VDAs and traditional anticancer therapies, such as radiation, chemotherapy and anti-angiogenics is described.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; Disease Models, Animal; Drug Therapy, Combination; Humans; Neoplasms; Neovascularization, Pathologic; Regional Blood Flow; Stilbenes; Tubulin Modulators; Xanthones

Visualization of tumor necrosis can determine tumor response to therapy. Our previous study showed that the rhein-based magnetic resonance imaging (MRI) contrast agent with alkane linker (GdL. Three rhein-based MRI agents were synthesized with a tetracarbon ether (GdP1), a hexacarbon ether (GdP2), and a lysine (GdP3) linker, respectively. Their octanol-water partition coefficients (log P) and cytotoxicity were determined. Necrosis avidity of the leading agent was explored on HepG2 cells and ischemia reperfusion-induced liver necrosis (IRLN) rats by MRI. The effect of visualization of tumor necrosis was tested on nude mice with W256 tumor treated by combretastatin-A4 phosphate (CA4P). DNA binding assays were applied to evaluate the possible necrosis-avidity mechanism of the leading agent.. The log P of three agents (- 1.66 ± 0.09, - 1.74 ± 0.01, - 1.95 ± 0.01) decreased when compared with GdL. GdP1 may serve as a potential candidate for early evaluation of tumor response to CA4P treatment.

Topics: Animals; Anthraquinones; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Contrast Media; Disease Models, Animal; Drug Design; Humans; Liver Neoplasms, Experimental; Magnetic Resonance Imaging; Male; Mice; Mice, Nude; Necrosis; Rats; Rats, Sprague-Dawley; Stilbenes; Tissue Distribution

According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC.. In this study, the use of poly(L-Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects-enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models.. We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; B7-H1 Antigen; Carcinoma, Hepatocellular; Disease Models, Animal; Drug Synergism; Female; Humans; Liver Neoplasms; Mice; Mice, Inbred C57BL; Nanoparticles; Polyethylene Glycols; Stilbenes; Tumor Microenvironment

Here, we formulated and investigated the structure-activity relationships of novel N-substituted carbazole sulfonamide derivatives with improved physicochemical properties. Most of these new compounds displayed good aqueous solubility. Certain molecules presented strong in vitro antiproliferative and in vivo antitumor activity. Relative to the control, 50 mg/kg compound 3v substantially reduced human HepG2 xenograft mouse tumor growth by 54.5% and its efficacy was comparable to that of CA-4P. Compound 3h demonstrated anticancer efficacy in both subcutaneous and orthotopic HepG2 xenograft mouse models. We also developed a novel synthetic method for 7-hydroxy-substituted carbazole sulfonamides. Compared with the control, 25 mg/kg compound 4c inhibited human HepG2 xenograft mouse tumor growth by 71.7% and was more potent than 50 mg/kg CA-4P with only 50% tumor shrinkage efficacy. Among the three water-soluble carbazole sulfonamide derivatives formulated in the present study, compound 4c displayed the most effective tumor growth inhibition in vivo and merit further investigation as potential antitumor agents for cancer therapy.

Topics: Animals; Antineoplastic Agents; Carbazoles; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Rats; Solubility; Structure-Activity Relationship; Sulfonamides; Tumor Cells, Cultured; Water

Noninvasive imaging of cell necrosis can provide an early evaluation of tumor response to treatments. Here, we aimed to design and synthesize a novel diindole-based magnetic resonance imaging (MRI) contrast agent (Gd-bis-DOTA-diindolylmethane, Gd-DIM) for assessment of tumor response to therapy at an early stage.. The oil-water partition coefficient (Log P) and relaxivity of Gd-DIM were determined in vitro. Then, its necrosis avidity was examined in necrotic cells in vitro and in rat models with microwave ablation-induced muscle necrosis (MAMN) and ischemia reperfusion-induced liver necrosis (IRLN) by MRI. Visualization of tumor necrosis induced by combretastatin A-4 disodium phosphate (CA4P) was evaluated in rats bearing W256 orthotopic liver tumor by MRI. Finally, DNA binding assay was performed to explore the possible necrosis-avidity mechanism of Gd-DIM.. The Log P value and T1 relaxivity of Gd-DIM is - 2.15 ± 0.01 and 6.61 mM. Gd-DIM may serve as a promising necrosis-avid MRI contrast agent for early assessment of tumor response to therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Contrast Media; Disease Models, Animal; Liver Neoplasms; Lung Neoplasms; Magnetic Resonance Imaging; Male; Necrosis; Rats; Rats, Sprague-Dawley; Stilbenes

Nanomedicines can generally only reach cancer cells at the edges of tumors, leaving most tumor cells in the central regions untreated. Previous studies showed that treatment with the vascular disrupting agent combretastatin-A4-phosphate (CA4P) can disrupt tumor vasculature, causing vascular shutdown and leading to massive necrosis in the tumor core. In this research, we explored the effect of co-administration of CA4P on the antitumor activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in Walker 256 tumor-bearing rats. The iodine 131 isotope was used for tracing and biodistribution analysis of nab-paclitaxel uptake. Liquid chromatography coupled with tandem mass spectrometry was performed to detect the intratumoral concentration of paclitaxel. Magnetic resonance imaging (MRI) was used to evaluate the effect of tumor treatment. Biodistribution results demonstrated that the tumor accumulations of both nab-paclitaxel and paclitaxel in the

Topics: Albumins; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Female; Humans; Iodine Radioisotopes; Magnetic Resonance Imaging; Paclitaxel; Rats; Stilbenes; Tissue Distribution

Combretastatin A4 phosphate (CA4P) is a vascular disrupting agent that rapidly shuts down blood supply to tumors. Early monitoring of tumor perfusion plays a crucial role in determining the optimal strategy to managing treatment and guiding future therapy. The aim of this study was to investigate the potential value of dynamic contrast-enhanced ultrasound (CEUS) in quantitative evaluation of tumor perfusion at an early stage in CA4P therapy. Central and peripheral perfusion of tumors was detected by CEUS pre-treatment (0 h) and 2, 12 and 48 h after CA4P injection. Two perfusion parameters, maximum intensity (IMAX) and time to peak (TTP), were calculated from the time-intensity curve. After CEUS, the efficacy of CA4P was immediately confirmed by immunofluorescence assay and hematoxylin and eosin, Hoechst 33342 and fluorescein isothiocyanate-lectin staining. In CEUS of the center region of tumors, IMAX gradually decreased from 0 to 12 h and regrew at 48 h (p < 0.01). TTP increased only at 2 h. In the peripheral regions, IMAX did not change obviously from 0 to 12 h (p > 0.05) and just increased at 48 h (p < 0.01). The TTP of peripheral regions had the same tendency to vary tendency as that of center regions. In addition, microvascular density (MVD), vascular perfusion and necrotic area of the tumor were quantitatively analyzed. A close correlation between IMAX and MVD was observed in the center areas of tumors (r = 0.72, p < 0.01), whereas the correlation between IMAX and MVD in peripheral areas was weak (r = 0.37, p < 0.01). However, IMAX was positively correlated with tumor perfusion in both center and peripheral areas of tumors (r = 0.82, p < 0.01, and r = 0.63, p < 0.01, respectively). Consequently, IMAX was a reliable indicator of tumor perfusion evaluation by CEUS. The use of CEUS to quantify tumor perfusion could a promising method for the early detection of tumor responses in anti-vascular treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Contrast Media; Disease Models, Animal; Evaluation Studies as Topic; Female; Image Enhancement; Liver; Liver Neoplasms; Mice; Mice, Inbred BALB C; Phospholipids; Stilbenes; Sulfur Hexafluoride; Treatment Outcome; Ultrasonography

Blood vessel development is critical for the continued growth and progression of solid tumors and, therefore, makes an attractive target for improving cancer therapy. Indeed, vascular-targeted therapies have been extensively explored but they have shown minimal efficacy as monotherapies. Combretastatin A4 (CA-4) is a tubulin-binding vascular disrupting agent that selectively targets the established tumor endothelium, causing rapid vascular beak down. Despite its potent anticancer potential, the drug has dose-limiting side effects, particularly in the form of cardiovascular toxicity. Furthermore, its poor aqueous solubility and the resulting limited bioavailability hinder its antitumor activity in the clinic. To improve the therapeutic efficacy of CA-4, we investigated its application as a combination therapy with doxorubicin (Dox) in a tumor vasculature targeted delivery vehicle: peptide-modified cross-linked multilamellar liposomal vesicles (cMLVs). In vitro cell culture studies showed that a tumor vasculature-targeting peptide, RIF7, could facilitate higher cellular uptake of drug-loaded cMLVs, and consequently enhance the antitumor efficacy in both drug resistant B16 mouse melanoma and human MDA-MB-231 breast cancer cells. In vivo, upon intravenous injection, targeted cMLVs could efficiently deliver both Dox and CA-4 to significantly slow tumor growth through the specific interaction of the targeting peptide with its receptor on the surface of tumor vasculature. This study demonstrates the potential of our novel targeted combination therapy delivery vehicle to improve the outcome of cancer treatment.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Doxorubicin; Drug Delivery Systems; Drug Therapy, Combination; Humans; Mice; Models, Biological; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Stilbenes

A recent ultrasound imaging technique-shear wave elastography-showed its ability to image and quantify the mechanical properties of biological tissues, such as prostate or liver tissues. In the present study this technique was used to evaluate the relationship among tumor growth, stiffness and reduction of treatment with combretastatin (CA4 P) in allografted colon tumor CT26 in mice. During 12 d, CT26 tumor growth (n = 52) was imaged by ultrasound, and shear modulus was quantified, showing a good correlation between tumor volume and stiffness (r = 0.59). The treatment was initiated at d 12 and monitored every d during 4 d. Following the treatment, the tumor volume had decreased, while the elasticity of the tumor volume remained steady throughout the treatment. After segmentation using the shear modulus map, a detailed analysis showed a decrease in the stiffness after treatment. This reduction in the mechanical properties was shown to correlate with tissue reorganization, particularly, fibrosis and necrosis, assessed by histology.

Topics: Animals; Antineoplastic Agents, Phytogenic; Colon; Colonic Neoplasms; Disease Models, Animal; Elasticity Imaging Techniques; Female; Mice; Mice, Inbred BALB C; Stilbenes; Treatment Outcome

Aggressive, desmoplastic tumors are notoriously difficult to treat because of their extensive stroma, high interstitial pressure, and resistant tumor microenvironment. We have developed a combination therapy that can significantly slow the growth of large, stroma-rich tumors by causing massive apoptosis in the tumor center while simultaneously increasing nanoparticle uptake through a treatment-induced increase in the accumulation and retention of nanoparticles in the tumor. The vascular disrupting agent Combretastatin A-4 Phosphate (CA4P) is able to increase the accumulation of radiation-containing nanoparticles for internal radiation therapy, and the retention of these delivered radioisotopes is maintained over several days. We use ultrasound to measure the effect of CA4P in live tumor-bearing mice, and we encapsulate the radio-theranostic isotope

Topics: Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Drug Therapy, Combination; Lutetium; Mice; Nanoparticles; Neoplasms; Radioisotopes; Stilbenes; Treatment Outcome

Nanocarrier-based anti-tumor drugs hold great promise for reducing side effects and improving tumor-site drug retention in the treatment of solid tumors. However, therapeutic outcomes are still limited, primarily due to a lack of drug penetration within most tumor tissues. Herein, we propose a strategy using a nanocarrier-based combination of vascular disrupting agents (VDAs) and cytotoxic drugs for solid tumor therapy. Specifically, combretastatin A-4 (CA4) serves as a "cannon" by eradicating tumor cells at a distance from blood vessels; concomitantly, doxorubicin (DOX) serves as a "pawn" by killing tumor cells in close proximity to blood vessels. This "cannon and pawn" combination strategy acts without a need to penetrate every tumor cell and is expected to eliminate all tumor cells in a solid tumor. In a murine C26 colon tumor model, this strategy proved effective in eradicating greater than 94% of tumor cells and efficiently inhibited tumor growth with a weekly injection. In large solid tumor models (C26 and 4T1 tumors with volumes of approximately 250 mm(3)), this strategy also proved effective for inhibiting tumor growth. These results showing remarkable inhibition of tumor growth provide a valuable therapeutic choice for solid tumor therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Colonic Neoplasms; Disease Models, Animal; Doxorubicin; Drug Carriers; Drug Therapy, Combination; Mice; Nanoparticles; Stilbenes; Treatment Outcome

Purpose To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with ethiodized oil for improved photothermal ablation (PTA)-chemoembolization therapy (CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods Animal experiments were approved by the institutional animal care and use committee and performed from February 2014 to April 2015. Male Sprague-Dawley rats (n = 45; age, 12 weeks) were inoculated with N1S1 HCC cells in the liver, and 8 days later, were randomly divided into two groups of 10 rats. Group 1 rats received intrahepatic arterial injection of PEG-HAuNS and ethiodized oil alone; group 2 received pretreatment with CA4P and injection of PEG-HAuNS and ethiodized oil 5 minutes later. The gold content of tumor and liver tissue at 1 hour or 24 hours after injection was quantified by using neutron activation analysis (n = 5 per time point). Five rats received pretreatment CA4P, PEG-copper 64-HAuNS, and ethiodized oil and underwent micro-positron emission tomography (PET)/computed tomography (CT). In a separate study, three groups of six rats with HCC were injected with saline solution (control group); CA4P, Dox-loaded PEG-coated HAuNS (Dox@PEG-HAuNS), and ethiodized oil (CET group); or CA4P, Dox@PEG-HAuNS, ethiodized oil, and near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified at postmortem histopathologic and/or autoradiographic examination. Wilcoxon rank-sum test and Pearson correlation analyses were performed. Results PEG-HAuNS uptake in CA4P-pretreated HCC tumors was significantly higher than that in non-CA4P-pretreated tumors at both 1 hour (P < .03) and 24 hours (P < .01). Mean ± standard deviation of tumor-to-liver PEG-HAuNS uptake ratios at 1 hour and 24 hours, respectively, were 5.63 ± 3.09 and 1.68 ± 0.77 in the CA4P-treated group and 1.29 ± 2.40 and 0.14 ± 0.11 in the non-CA4P-treated group. Micro-PET/CT allowed clear delineation of tumors, enabling quantitative imaging analysis. Laser irradiation increased temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Mean HCC tumor volumes 10 days after therapy were 1.68 cm

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Chemoembolization, Therapeutic; Disease Models, Animal; Doxorubicin; Drug Carriers; Ethiodized Oil; Gold; Hyperthermia, Induced; Liver Neoplasms; Male; Nanospheres; Polyethylene Glycols; Positron Emission Tomography Computed Tomography; Random Allocation; Rats; Rats, Sprague-Dawley; Stilbenes

The aim of the present study is to verify the trapping effect of combretastatin A-4-phosphate (CA4P) on small molecular drugs in rodent tumors. Mice with H22 hepatocarcinoma were randomized into groups A and B. Magnetic resonance imaging (MRI) of T1WI, T2WI, and DWI was performed as baseline. Mice in group A were injected with Gd-DTPA and PBS. Mice in group B were injected with Gd-DTPA and CA4P. All mice undergo CE-T1WI at 0 h, 3 h, 6 h, 12 h, and 24 h. Enhancing efficacy of the two groups on CE-T1WI was compared with the signal-to-noise ratio (SNR) calculated. Concentrations of gadolinium measured by ICP-AES in the tumor were compared between groups. On the early CE-T1WI, tumors were equally enhanced in both groups. On the delayed CE-T1WI, the enhancing effect of group A was weaker than that of group B. The SNR and the concentration of gadolinium within the tumor of group A were lower than that of group B at 6 h, 12 h, and 24 h after administration. This study indicates that CA4P could improve the retention of Gd-DTPA in the tumor and MRI allowed dynamically monitoring trapping effects of CA4P on local retention of Gd-DTPA as a small molecular drug.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Liver Neoplasms; Magnetic Resonance Imaging; Male; Mice; Spectrophotometry, Atomic; Stilbenes; Time Factors; Tissue Distribution

Lung cancer is the leading cause of cancer-related death. About 80% of lung cancers are non-small cell lung cancers (NSCLC). Radiotherapy is widely used in treatment of NSCLC. However, the outcome of NSCLC remains unsatisfactory. In this study, a vascular disrupting agent (VDA) combretastatin-A4-phosphate (CA4P) was used to provide massive necrosis targets. (131)I labeled necrosis-avid agent protohypericin ((131)I-prohy) was explored for therapy of NSCLC using tumor necrosis targeted radiotherapy (TNTR). Gamma counting, autoradiography, fluorescence microscopy and histopathology were used for biodistribution analysis. Magnetic resonance imaging (MRI) was used to monitor tumor volume, ratios of necrosis and tumor doubling time (DT). The biodistribution data revealed 131I-prohy was delivered efficiently to tumors. Tracer uptake peaked at 24 h in necrotic tumor of (131)I-prohy with and without combined CA4P (3.87 ± 0.38 and 2.96 ± 0.34%ID/g). (131)I-prohy + CA4P enhanced the uptake of (131)I-prohy in necrotic tumor compared to (131)I-prohy alone. The TNTR combined with CA4P prolonged survival of tumor bearing mice relative to vehicle control group, CA4P control group and (131)I-prohy control group with median survival of 35, 20, 22 and 27 days respectively. In conclusion, TNTR appeared to be effective for the treatment of NSCLC.

Topics: Animals; Antineoplastic Agents; Autoradiography; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Chemoradiotherapy; Disease Models, Animal; Humans; Iodine Radioisotopes; Lung Neoplasms; Magnetic Resonance Imaging; Male; Mice, Inbred BALB C; Mice, Nude; Necrosis; Perylene; Radiography; Radiopharmaceuticals; Stilbenes; Tissue Distribution; Tumor Burden; Xenograft Model Antitumor Assays

Residual cancer cells and subsequent tumor relapse is an obstacle for curative cancer treatment. Tumor necrosis therapy (TNT) has recently been developed to cause residual tumor regression or destruction. Here, we exploited the avidity of the sennidin A (SA) tracer and radioiodinated SA (¹³¹I-SA) to necrotic tumors in order to further empower TNT. We showed high uptake and prolonged retention of SA in necrotic tumors and a quick clearance in other non-targeted tissues including the liver. On SPECT-CT images, tumor mass appeared persistently as a hotspot. Based on the prominent targetability of ¹³¹I-SA to the tumor necrosis, we designed a combinational theragnostic modality. The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) was used to cause massive tumor necrosis, which formed the target of ¹³¹I-SA that subsequently killed the residual tumor cells by cross-fire irradiation of beta particles. Consequently, ¹³¹I-SA combined with CA4P significantly inhibited tumor growth, extended tumor doubling time and prolonged mean animal survival. In conclusion, ¹³¹I-SA in combination with necrosis inducing drugs/therapies may generate synergetic tumoricidal effects on solid malignancies by means of primary debulking and secondary cleansing process.

Topics: Animals; Anthracenes; Antineoplastic Combined Chemotherapy Protocols; Autoradiography; Disease Models, Animal; Iodine Radioisotopes; Magnetic Resonance Imaging; Mice; Necrosis; Neoplasms, Experimental; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Stilbenes

The effect of vascular disrupting agents in tumour therapy depends on both the immediate vascular shutdown, and on the following re-vascularization of the tumour. The aim of this study was to use a tumour model to investigate whether endothelial outgrowth cells (EOCs) influenced the short term treatment efficiency of combretastatin A-4 disodium phosphate (CA4P) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by increasing EOC tumour recruitment.. In order to visualize the recruitment of EOCs to the tumours, umbilical cord blood derived human EOCs were labelled with 111Indium-tropolone in a dose of 0.37 MBq pr 3×106 cells and were injected intravenously into mice carrying a C3H mammary carcinoma on their right rear foot. DMXAA and CA4P in different concentrations and at different exposure times were used to create a hypoxic environment in the C3H mammary carcinoma in the mice. Three different mice strains with various degrees of functional immune system were used to study the homing capability of EOCs.. Our data showed that approximately 4% of the total injected radioactive dose per gram of tissue was found in the tumour after treatment with CA4P and DMXAA. Regardless of the concentration and the treatment duration, CA4P did not increase EOC recruitment to the tumour in comparison to EOC recruitment in control tumours in any of the 3 mice strains studied.. Our data showed that regardless of the grade of the immune system, ranging from a fully working to a fully compromised immune system, treatment with CA4P did not increase recruitment of xenotransplanted EOCs to tumour tissue.

Topics: Angiogenesis Inhibitors; Animals; Breast Neoplasms; Carcinoma; Cell Movement; Cell Survival; Cell Tracking; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Female; Fetal Blood; Humans; Indium Radioisotopes; Mice; Mice, Nude; Stilbenes; Xanthones

Based on the soil-to-seeds principle, we explored the small-molecular sequential dual-targeting theranostic strategy (SMSDTTS) for prolonged survival and imaging detectability in a xenograft tumor model.. Thirty severe combined immunodeficiency (SCID) mice bearing bilateral radiation-induced fibrosarcoma-1 (RIF-1) subcutaneously were divided into group A of SMSDTTS with sequential intravenous injections of combretastatin A4 phosphate (CA4P) and (131)I-iodohypericin ((131)I-Hyp) at a 24 h interval; group B of single targeting control with CA4P and vehicle of (131)I-Hyp; and group C of vehicle control (10 mice per group). Tumoricidal events were monitored by in vivo magnetic resonance imaging (MRI) and planar gamma scintiscan, and validated by ex vivo autoradiography and histopathology. Besides, 9 mice received sequential intravenous injections of CA4P and (131)I-Hyp were subjected to biodistribution analysis at 24, 72 and 120 h.. Gamma counting revealed fast clearance of (131)I-Hyp from normal organs but intense accumulation in necrotic tumor over 120 h. After only one treatment, significantly prolonged survival (p<0.001) was found in group A compared to group B and C with median survival of 33, 22, and 21 days respectively. Tumor volume on day 15 was 2.0 ± 0.89, 5.66 ± 1.66, and 5.02 ± 1.0 cm(3) with tumor doubling time 7.8 ± 2.8, 4.4 ± 0.67, and 4.5 ± 0.5 days respectively. SMSDTTS treated tumors were visualized as hot spots on gamma scintiscans, and necrosis over tumor ratio remained consistently high on MRI, autoradiography and histology.. The synergistic antitumor effects, multifocal targetability, simultaneous theranostic property, and good tolerance of the SMSDTTS were evident in this experiment, which warrants further development for preclinical and clinical applications.

Topics: Administration, Intravenous; Animals; Anthracenes; Antineoplastic Agents; Disease Models, Animal; Fibrosarcoma; Histocytochemistry; Humans; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Mice; Mice, SCID; Perylene; Radiography; Radionuclide Imaging; Stilbenes; Survival Analysis; Transplantation, Heterologous; Treatment Outcome

To study the effect of combretastatin A4 phosphate (CA4P) on the vascularization of endometriotic lesions.. Intravital microscopic, histologic, and immunohistochemical study.. University institute.. BALB/c mice.. Murine endometriotic lesions were induced by syngeneic transplantation of endometrium into dorsal skinfold chambers. After 6 days, the mice received an intraperitoneal injection of 80 mg/kg CA4P or vehicle.. Vascularization of the lesions and the surrounding tissue was analyzed by intravital fluorescence microscopy over 8 days. Lesion morphology, vessel maturation, viability, and proliferation of endometrial glands and stroma were assessed by histology and immunohistochemistry.. All lesions were initially well vascularized, containing immature and mature microvessels. Injection of CA4P induced a selective vessel collapse in the lesions without affecting the surrounding microvasculature. This resulted in a decreased functional capillary density and blood perfusion of CA4P-treated lesions after 2 hours when compared with controls. However, the vascularization of the lesions progressively normalized, and their numbers of proliferating and apoptotic cells did not differ from those of controls.. This study demonstrates a selective vascular disrupting effect of CA4P on endometriotic lesions, indicating that vascular disrupting agents may be suitable for endometriosis therapy.

Topics: Animals; Apoptosis; Capillaries; Cell Proliferation; Disease Models, Animal; Endometriosis; Endometrium; Female; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Stilbenes; Time Factors; Tissue Survival

To investigate the 12-day dynamic characteristics of tumor response to intravenous administration of CA4P in rabbit VX2 tumor models.. Study protocol was approved by local ethical committee for animal care and use. Sixteen rabbits with 32 tumors on bilateral legs were randomly divided into treated and control groups. Conventional and DWI images were acquired before and 24 h, 4 days, 8 days and 12 days after treatment. The dynamic changes of tumor on images were correlated with histological results. ADCs were compared among and between groups at different time points.. The tumors in treated group grew slower than those in control group. In treaded group, the mean ADC decreased slightly at 24 h point due to cell edema caused by ischemia. Then, it increased significantly at 4 days and 8 days because of progressive central necrosis. Finally, peripheral tumor proliferation caused a second decrease of ADC at 12 days. The significant difference of ΔADC% between the two groups at 24 h, 4 days and 8 days indicated that the change of ADC in treated group was really caused by CA4P.. The dynamic histological changes of tumor caused by CA4P as reflected exactly by diffusion-weighted MR imaging indicate a noninvasive measure for monitoring tumor vascular targeting treatment.

Topics: Animals; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Hindlimb; Infusions, Intravenous; Neoplasms, Experimental; Rabbits; Random Allocation; Stilbenes

Combretastatin A-4 disodium phosphate (CA4P) is a promising vascular disrupting agent (VDA) in clinical trials. As CA4P acts on dividing endothelial cells, we hypothesize that CA4P affects vessels of certain sizes. The aim of this study was to evaluate the effect of CA4P by the MRI-based vessel size imaging (VSI).. C3H mammary carcinomas were grown to 200 mm(3) in the right rear foot of female CDF(1) mice. A control group of mice received no treatment, and a treatment group had CA4P administered intraperitoneally at a dose of 250 mg/kg. VSI was conducted on a 3 Tesla MR scanner to estimate the tumor blood volume (ζ(0)) and mean vessel radius (R). Vascularization was also estimated histologically by endothelial and Hoechst 33342 staining.. ζ(0) and R showed different spatial heterogeneity. Tumor median and quartile values of ζ(0) were all significantly reduced by about 35% in the CA4P-treated group as compared with the control group, and the median and upper quartile of R were significantly increased. Histograms of ζ(0) and R showed a general decrease in ζ(0) following treatment, and values of R in a certain range (≈20-30 μm) were decreased in the treatment group. The drug-induced change in ζ(0) was in agreement with histology and our previous dynamic contrast enhanced MRI (DCE-MRI) data.. Tumor blood volume and mean vessel radius showed a clear response following treatment with CA4P. VSI may prove valuable in estimation of tumor angiogenesis and prediction of response to VDAs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Vessels; Disease Models, Animal; Female; Magnetic Resonance Imaging; Mice; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Stilbenes

The efficacy of the vascular disrupting agent combretastatin A-4 phosphate (CA4P) depends on several factors including tumor size, nitric oxide level, interstitial fluid pressure, and vascular permeability. These factors vary among tumor types. The aim of this study was to investigate all these factors in two tumor models that respond differently to CA4P.. Mice bearing C3H mammary carcinomas or KHT sarcomas (200 to 800 mm(3)) were intraperitoneally injected with CA4P (100 mg/kg). Tumor size and the effect of a nitric oxide inhibitor nitro-L-arginine (NLA) administered intravenously were evaluated by necrotic fraction histologically assessed at 24 hours. Interstitial fluid pressure (IFP) was measured using the wick-in-needle technique, and vascular characteristics were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).. Initial necrotic fraction was about 10% in both tumor models at 200 mm(3), but only increased significantly with tumor size in the C3H mammary carcinoma. In this tumor, CA4P significantly induced further necrosis by about 15% at all sizes, but in the KHT tumor, the induced necrotic fraction depended on tumor size. For both tumor types, NLA with CA4P significantly increased necrotic fraction above that for each drug alone. CA4P significantly decreased IFP in all tumors except in the 800 mm(3) C3H tumor, which had an initially non-significant lower value. Interstitial volume estimated by DCE-MRI increased in all groups, except the 800 mm(3) C3H tumors. DCE-MRI vascular parameters showed different initial characteristics and general significant reductions following CA4P treatment.. Both tumor models showed differences in all factors before treatment, and in their response to CA4P. Perfusion and permeability as estimated by DCE-MRI play a central role in the CA4P response, and interstitial volume and IFP seemed related. These factors may be of clinical value in the planning of CA4P treatments.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma; Cell Line, Tumor; Contrast Media; Diagnostic Imaging; Disease Models, Animal; Female; Magnetic Resonance Imaging; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Nitric Oxide; Sarcoma; Statistics as Topic; Stilbenes; Treatment Outcome; Tumor Burden

The effects of the tubulin-binding vascular-disrupting agents (VDAs), combretastatin A4 phosphate (CA4P), OXi4503/CA1P and OXi8007, in subcutaneous mouse models of the Ewing's sarcoma family of tumours (ESFTs) have been investigated alone and in combination with doxorubicin. Delay in subcutaneous tumour growth was observed following treatment of mice with multiple doses of OXi4503/CA1P but not with CA4P or OXi8007. A single dose of OXi4503/CA1P caused complete shutdown of vasculature by 24h and extensive haemorrhagic necrosis by 48h. However, a viable rim of proliferating cells remained, which repopulated the tumour within 10 days following the withdrawal of treatment. Combined treatment with doxorubicin 1h prior to administration of OXi4503/CA1P enhanced the effects of OXi4503/CA1P causing a synergistic delay in tumour growth (p<0.001). This study demonstrates that OXi4503/CA1P is a potent VDA in ESFT and in combination with conventional cytotoxic agents represents a promising treatment strategy for this tumour group.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bibenzyls; Bone Neoplasms; Cell Proliferation; Diphosphates; Disease Models, Animal; Doxorubicin; Drug Evaluation, Preclinical; Mice; Mice, Nude; Necrosis; Neoplasm Transplantation; Neovascularization, Pathologic; Sarcoma, Ewing; Stilbenes

To determine the feasibility of in vivo diffusion-weighted imaging (DWI) to distinguish between normal liver, viable tumor and necrosis compared to postmortem DWI in a rat model with vascular-targeting treatment.. Fifteen rats with liver implantation of 30 rhabdomyosarcomas were treated with combretastatin A-4-phosphate (CA4P) at 10 mg/kg. Two days after treatment, T2-weighted imaging, precontrast T1-weighted imaging, postcontrast T1-weighted imaging, and DWI were performed in vivo and postmortem with a 1.5T scanner. Apparent diffusion coefficients (ADCs) calculated from DWIs with b values of 0, 50, and 100 seconds/mm2 (ADClow), 500, 750, and 1000 seconds/mm2 (ADChigh), 0, 500, and 1000 seconds/mm2 (ADC3b), and 0-1000 seconds/mm2 (ADC10b) for tumor, liver, therapeutic necrosis, and phantoms were compared and validated with ex vivo microangiographic and histopathologic findings.. Except ADClow between tumor and necrosis, in vivo ADCs successfully differentiated liver, viable tumor, and necrosis (P<0.05). Compared to in vivo outcomes, postmortem ADCs significantly dropped in tumor and liver (P<0.05) except ADChigh of tumor, but not in necrosis and phantoms. Compared to ADClow, ADChigh was less affected by vital status.. Advantageous over postmortem DWI, in vivo DWI provides a noninvasive easy-performing tool for distinguishing between liver, viable tumor, and necrosis. ADClow and ADChigh better reflect tissue perfusion and water diffusion, respectively.

Topics: Animals; Antineoplastic Agents, Phytogenic; Contrast Media; Diagnosis; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Feasibility Studies; Image Enhancement; Image Processing, Computer-Assisted; Liver; Liver Neoplasms, Experimental; Male; Necrosis; Phantoms, Imaging; Rats; Rats, Wistar; Rhabdomyosarcoma; Stilbenes

Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI 50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC 50 = 2.8 microM). In addition, a single dose (10 mg/kg) of compound 17 caused a 40% tumor-selective blood flow shutdown in tumor-bearing SCID mice at 24 h, thus suggesting the potential value of this compound and its corresponding salt formulations as new vascular-disrupting agents.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Disease Models, Animal; Drug Design; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Leukemia P388; Mice; Molecular Structure; Neoplasms; Regional Blood Flow; Stilbenes; Tubulin

Combretastatin A-4 (CA-4) is a vascular targeting agent known to rapidly shut off blood flow in new vessels and, as a result, regress neovascularization. In this pilot study, the ability of CA-4 to modify retinal neovascularization, which results in altered retinal vessel blood flow and retinal permeability, was evaluated in aphakic long-term galactose-fed beagles, an animal model that develops diabetes-like retinal neovascularization.. Two (2) groups of aphakic dogs, each group comprised of 4 galactose-fed dogs and 2 age-matched controls dogs, were utilized. Each group initially received the combretastatin A-4-phosphate prodrug (CA-4P) as either sub-Tenon's injections, administered at the corneoscleral junction, or intravitreal injections. Six (6) weeks after this treatment, all dogs also received systemic (intravenous) injections of CA-4P. Retinal vascular changes were monitored at 2-week intervals by fluorescein angiography.. All galactose-fed dogs demonstrated the presence of retinal neovascular lesions by fluorescein angiograms. Fluorescein leakage or perfusion through neovascular vessels was not altered by either sub-Tenon's, intravitreal, or systemic CA-4P administration. Whereas CA-4P was well tolerated by the healthy eyes of the control animals, its administration to some galactose-fed dogs was associated with corneal edema and increases in intraocular pressure following sub-Tenon's and intraocular injections.. Neovascularization in the galactose-fed dog progresses over a period of years, similar to that observed with clinical diabetic retinopathy. The failure of CA-4P to ameliorate neovascularization suggests that chronic, long-term administration may be required to destroy the slowly growing retinal endothelial cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Aphakia; Diabetic Retinopathy; Disease Models, Animal; Dogs; Fluorescein Angiography; Galactose; Injections; Intraocular Pressure; Prodrugs; Retinal Neovascularization; Retinal Vessels; Stilbenes

To evaluate the mechanism and timing of retinal tumor cell death in the LH(BETA)T(AG) mouse model of retinoblastoma after treatment with vascular targeting therapies and conventional therapies (focal chemotherapy and radiation).. For vascular targeting therapy, 12- or 16-week-old mice were treated with a single subconjunctival injection of either anecortave acetate (300 microg) or combretastatin A4 (1.5 mg). Eyes were analyzed at 1 day and 1 week after treatment. Tumor cell death was evaluated using TUNEL assays or immunofluorescence analysis of activated caspase 3 to detect apoptosis. Histopathologic analysis was performed to identify areas of necrosis. For conventional therapy, LH(BETA)T(AG) mice were treated with six serial subconjunctival injections of focally delivered carboplatin chemotherapy (100 microg/delivery) or hyperfractionated external beam radiotherapy (EBRT; 15 Gy total dose). Cell death was analyzed by TUNEL assay.. The highest levels of apoptotic cell death were seen 1 day after treatment in all treatment groups compared with vehicle controls. At 1 week after treatment, apoptotic cell death remained significantly elevated in the EBRT and carboplatin groups, but not after vessel targeting therapy. No significant necrosis was detected by histology in tumors of treated or of control eyes.. Conventional therapies (focal carboplatin chemotherapy and EBRT) and vascular targeting agents significantly increase cell death through apoptosis, while not having a significant effect on necrosis in this murine model of retinoblastoma. These studies will aid in the optimization of delivery schemes of combined treatment modalities.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Carboplatin; Caspase 3; Disease Models, Animal; Endothelium, Vascular; In Situ Nick-End Labeling; Mice; Mice, Transgenic; Neovascularization, Pathologic; Pregnadienediols; Radiotherapy, Conformal; Retinal Neoplasms; Retinoblastoma; Stilbenes; Time Factors

As first-generation small-molecule vascular disrupting agents (VDA) have begun to enter clinical trials, second-generation agents are under active development. One such agent is the combretastatin A4 disodium phosphate (CA4P) analogue OXi4503 (CA1P).. C3H/HeJ mice bearing KHT sarcomas were treated with CA4P and OXi4503 and the effect on tumor vasculature was determined by evaluating the extent of vascular shutdown (Hoechst-33342 vessel staining) and tumor perfusion inhibition (dynamic contrast-enhanced magnetic resonance imaging). Dynamic contrast-enhanced magnetic resonance imaging and tumor necrosis end points also were used to examine the pathophysiologic tumor effects following repeated exposures to these agents.. Single doses of either agent (CA4P, 100 mg/kg; OXi4503, 25 mg/kg) resulted in an 80% to 90% reduction in tumor perfusion 4 hours after treatment. Whereas recovery in tumor perfusion was observed 48 hours posttreatment, this recovery was significantly slower in mice treated with OXi4503. Tumors re-treated with either VDA 72 hours after the first drug exposure showed a similar reduction and recovery in tumor perfusion. Histologic evidence showed the presence of a smaller viable rim after exposure to OXi4503 than that observed after CA4P treatment. Furthermore, the extent of recovery of tumor necrosis 72 hours after drug treatment was less for OXi4053.. The present studies show that the second-generation VDA OXi4503 possesses significant antivascular effects in solid tumors. Importantly, the vasculature of tumors of mice that had received an initial dose this agent was as responsive to a subsequent treatment.

Topics: Animals; Cell Survival; Diphosphates; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Injections, Intraperitoneal; Magnetic Resonance Imaging; Mice; Mice, Inbred C3H; Neovascularization, Pathologic; Radiography; Sarcoma, Experimental; Stilbenes; Time Factors; Transplantation, Heterologous; Xenograft Model Antitumor Assays

To evaluate the effect of subconjunctival injections of combretastatin A-4 phosphate (CA-4P) prodrug treatment on tumor vasculature and growth in an animal model of hereditary retinoblastoma.. Twenty-four, 12-week-old simian virus-40 T-antigen-positive mice received six subconjunctival CA-4P injections at doses of 0.5, 1.0, 1.5, and 2.0 mg delivered at 72-hour intervals to the right eye only. Six control animals received placebo treatment. All animals underwent serial ophthalmic evaluations and were euthanatized at 16 weeks of age, and eyes were obtained for histopathologic examination. Eyes were graded for presence or absence of tumor, delay of tumor growth, and intratumoral vascularity.. The use of subconjunctivally injected CA-4P prodrug induced an extensive, dose-dependent decrease in microvessel density and led to significant tumor reduction in treated eyes compared with the placebo control (P <0.001). No evidence of corneal, lenticular, choroidal, or retinal toxicity was observed by histopathologic evaluation.. Subconjunctival delivery of CA-4P is associated with extensive dose-dependent reduction in blood vessel count in this murine model of retinoblastoma. A combination treatment of retinoblastoma incorporating CA-4P may allow enhanced tumor reduction enabling a decrease in standard treatment doses of both chemotherapy and external beam radiotherapy.

Topics: Animals; Antigens, Polyomavirus Transforming; Antineoplastic Agents; Conjunctiva; Disease Models, Animal; Dose-Response Relationship, Drug; Injections; Mice; Mice, Transgenic; Neovascularization, Pathologic; Prodrugs; Retinal Neoplasms; Retinoblastoma; Stilbenes

Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment.. Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2.. A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at >or= 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium-diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data.. CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

Topics: Animals; Antineoplastic Agents, Phytogenic; Area Under Curve; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Humans; Infusion Pumps; Magnetic Resonance Imaging; Male; Neoplasms; Neoplasms, Experimental; Rats; Stilbenes; Treatment Outcome

Combretastatin A-4 (CA-4) is a naturally occurring agent that binds tubulin and causes necrosis and shrinkage of tumors by damaging their blood vessels. In this study the effect of a CA-4 prodrug, combretastatin A-4-phosphate (CA-4-P), was tested in two models of ocular neovascularization.. The effect of CA-4-P was quantitatively assessed in transgenic mice with overexpression of vascular endothelial growth factor in the retina (rho/VEGF mice) and mice with choroidal neovascularization (CNV) due to laser-induced rupture of Bruch's membrane.. In rho/VEGF mice, daily intraperitoneal injections of 4.0 mg/kg CA-4-P starting at postnatal day (P)7, the time of onset of transgene expression, resulted in a significant reduction in the number of neovascular lesions and total area of neovascularization per retina at P21, compared with vehicle-injected mice. In mice with laser-induced rupture of Bruch's membrane, daily intraperitoneal injections of 75 or 100 mg/kg CA-4-P resulted in a significant reduction in the area of CNV at rupture sites compared with vehicle-injected mice. In mice with established CNV, daily intraperitoneal injections of 100 mg/kg CA-4-P for 1 week resulted in a significant reduction in CNV area at rupture sites compared with the baseline area before treatment or the area of CNV in vehicle-treated mice.. These data indicate that CA-4-P suppresses the development of VEGF-induced neovascularization in the retina and both blocks development and promotes regression of CNV. Therefore, CA-4-P shows potential for both prevention and treatment of ocular neovascularization.

Topics: Animals; Antineoplastic Agents, Phytogenic; Choroidal Neovascularization; Disease Models, Animal; Endothelial Growth Factors; Female; Intercellular Signaling Peptides and Proteins; Lymphokines; Mice; Mice, Inbred C57BL; Mice, Transgenic; Prodrugs; Remission Induction; Rhodopsin; Stilbenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Previous studies have demonstrated the feasibility of using apathogenic clostridia as a promising strategy for hypoxia-specific tumour targeting. The present study shows that the use of the vascular targeting compound combretastatin A-4 phosphate could significantly (P<0.001) increase the number of Clostridium vegetative cells in rat rhabdomyosarcomas with sizes between 0.2 cm(2) and 3 cm(2). Furthermore, this study showed that administration of metronidazole for a 9-day period was sufficient to eliminate systemically administered Clostridium from the tumour. Moreover, previous Clostridium spore administration did not effect tumour colonisation, regardless of the immune response status of the host.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bacterial; Clostridium; Clostridium Infections; Colony Count, Microbial; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Humans; Metronidazole; Rats; Rhabdomyosarcoma; Spores, Bacterial; Stilbenes

Combretastatin A4P (CA4P) is a prodrug that, in active form, binds to tubulin microtubules of capillary endothelial cells. Studies to date indicate it has significant activity as a specific tumor vascular targeting agent. The goals were to assess the effects of CA4P on tumor growth and microvasculature of colorectal liver metastases in the mouse model, using stereological and histological methods to measure tumor growth, and vascular corrosion casting and laser doppler flowmetry to assess effect on the microvasculature. Continuous s.c. infusion of CA4P produced a major reduction in tumor growth. The percentage of the liver occupied by metastases decreased from 20.55 +/- 13.3% in controls to 7.46 +/- 5.99% in treated animals (P = 0.03). Ultrastructural study of tumor microvasculature after a single dose of CA4P revealed marked effects 1 h after treatment. There was loss of patent microvessels at the normal liver-tumor interface. Central microvascular density was reduced, with constriction and tapering of vessels. CA4P appeared to cause no damage to normal liver tissue or vasculature. Tumor blood flow decreased from 37.6 +/- 13.9% in controls to 24.4 +/- 6.1% in tumors >5 mm in diameter, 1 h after treatment with CA4P (P < 0.03). Quantitative histology of tissue at 6 and 24 h after CA4P treatment showed a significant increase in tumor necrosis (48.7 +/- 21% and 55.5 +/- 19% compared with controls, 20.6 +/- 8%; P = 0.01). Continuous infusion with CA4P causes marked reduction in tumor volume. A single dose of CA4P causes major changes of the tumor microvasculature, reduction of tumor blood flow, and increase in tumor necrosis. CA4P has a potential role in the management of patients with liver metastases.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Division; Colorectal Neoplasms; Disease Models, Animal; Laser-Doppler Flowmetry; Liver Neoplasms; Male; Mice; Mice, Inbred CBA; Neovascularization, Pathologic; Stilbenes

AC-7700, a novel combretastatin A-4 derivative, suppresses the growth of solid tumors by inhibiting tumor perfusion. We evaluated the antitumor activity of AC-7700 on solid tumors in two experimental models, an advanced tumor model (murine colon 26 (c26) adenocarcinoma, colon 38 (c38) adenocarcinoma, MethA fibrosarcoma, Sarcoma 180 (S180), Lewis lung carcinoma (3LL), human LS180 adenocarcinoma) and an orthotopically transplanted tumor model (c26), compared with that of cisplatin (CDDP). The maximum tolerable dose (MTD) of CDDP suppressed early-stage c26 and c38 tumor growth when treatment was started after the tumor volume (TV) reached 0.2-0.5 cm3, but it showed reduced activity against the same tumors at an advanced growth stage when TV exceeded 2 cm3. At its MTD, AC-7700 was active against all tumors tested except 3LL in both early and advanced growth stages, reducing the tumor mass and having a curative effect in advanced c38 tumors. AC-7700 was also effective on orthotopically transplanted c26 tumors, showing a comparable activity to that on subcutaneous tumors. Unlike flavon acetic acid, which damages tumor vasculature by inducing endogenous tumor necrosis factor-alpha production, AC-7700 potently suppressed the growth of advanced c26 tumors in athymic as well as euthymic mice. These results suggest that AC-7700 is a novel antivascular agent that may have potent activity against advanced-stage cancer in the clinical setting.

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Drug Screening Assays, Antitumor; Female; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Inbred ICR; Neoplasm Transplantation; Neoplasms, Experimental; Serine; Stilbenes; Survival Analysis; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

The relation between tumor tissue blood flow (tBF) reduction and antitumor effects was investigated. Changes in tBF of normal tissues (liver, kidney cortex, bone marrow and brain cortex) and tumors (Yoshida sarcoma subline, LY80 and Sato lung carcinoma, SLC) due to i.v. administration of AC7700 (1, 3, 10 mg/kg), one of the combretastatin A-4 derivatives, were measured with the hydrogen clearance method. The change in blood flow in tumor microfoci was also observed directly using a rat transparent chamber. Chemotherapy against the solid tumors (LY80, SLC) was performed by administering AC7700 7 times at intervals of 3 days and the effect on the tumor growth, the histological effect, the effect on lymph node metastasis and the survival rate were investigated. Tumor tBF showed a dose-dependent response to AC7700. Although tumor tBF decreased markedly at a dose of 1 mg/kg, it tended to recover partly within several hours. At 10 mg/kg, however, tumor tBF completely stopped within approximately 30 min and never recovered in many regions. The irreversible stoppage of tumor tBF was observed in large s.c. tumors and in microfoci as well. On the other hand, in normal tissues, tBF changes due to AC7700 were not uniform. In the liver, although tBF decreased by approximately 50% at 10 mg/kg AC7700, it recovered within 8 h. In the brain, although the mean maximum reduction was 35%, the blood flow recovered to the original level within 24 h. The blood flow in the kidney cortex did not change at all. In the bone marrow, tBF decreased by approximately 80%. Generally, the blood flow reduction in normal tissues tended to be reversible. The effect on tumor growth and the histological effect were also dependent on the dose of AC7700. The tumor growth was markedly inhibited by 10 mg/ kg AC7700 and extensive necrosis was induced. Lymph node metastases were significantly inhibited and survival was prolonged significantly. In the control group, all 8 SLC tumor-bearing rats died of cancer, the presence of which was verified by gross and microscopic evaluation, within 45 days after tumor implantation. On the other hand, in the treated group, 2 of 8 rats recovered completely and survived. No obvious side effects such as body weight loss, anemia or diarrhea were observed at the dose used in this experiment. From these results, we conclude that strong antitumor effects are obtained by stopping tumor tBF irreversibly and by shutting off the nutritional supply into tumor tissue. AC7700

Topics: Animals; Antineoplastic Agents; Blood Pressure; Body Weight; Disease Models, Animal; Drug Screening Assays, Antitumor; Lymphatic Metastasis; Male; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Regional Blood Flow; Serine; Stilbenes; Survival Rate