Search Results (12)

This pre-clinical study was designed to demonstrate how vascular disrupting agents (VDAs) should be administered, either alone or when combined with radiation in clinically relevant fractionated radiation schedules, for the optimal anti-tumor effect. CDF1 mice, implanted in the right rear foot with a 200 mm³ murine C3H mammary carcinoma, were injected with various doses of the most potent VDA drug, combretastatin A-1 phosphate (CA1P), under different schedules. Tumors were also locally irradiated with single-dose, or stereotactic (3 × 5–20 Gy) or conventional (30 × 2 Gy) fractionation schedules. Tumor growth and control were the endpoints used. Untreated tumors had a tumor growth time (TGT5; time to grow to 5 times the original treatment volume) of around 6 days. This increased with increasing drug doses (5–100 mg/kg). However, with single-drug treatments, the maximum TGT5 was only 10 days, yet this increased to 19 days when injecting the drug on a weekly basis or as three treatments in one week. CA1P enhanced radiation response regardless of the schedule or interval between the VDA and radiation. There was a dose-dependent increase in radiation response when the combined with a single, stereotactic, or conventional fractionated irradiation, but these enhancements plateaued at around a drug dose of 25 mg/kg. This pre-clinical study demonstrated how VDAs should be combined with clinically applicable fractionated radiation schedules for the optimal anti-tumor effect, thus suggesting the necessary pre-clinical testing required to ultimately establish VDAs in clinical practice. Full article

Vascular-disrupting agents (VDAs) have shown a preliminary anti-cancer effect in extracranial tumors; however, the therapeutic potential of VDAs in intracranial metastatic lesions remains unclear. Simultaneous intracranial and extracranial tumors were induced by the implantation of rhabdomyosarcoma in 15 WAG/Rij rats. Pre-treatment characterizations were performed at a 3.0 T clinical magnet including a T2 relaxation map, T1 relaxation map, diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI). Shortly afterward, a VDA was intravenously given and MRI scans at 1 h, 8 h, and 24 h after treatment were performed. In vivo findings were further confirmed by postmortem angiography and histopathology staining with H&E, Ki67, and CD31. Before VDA treatment, better perfusion (AUC30: 0.067 vs. 0.058, p < 0.05) and AUC300 value (0.193 vs. 0.063, p < 0.001) were observed in extracranial lesions, compared with intracranial lesions. After VDA treatment, more significant and persistent perfusion deficiency measured by PWI (AUC30: 0.067 vs. 0.008, p < 0.0001) and a T1 map (T1 ratio: 0.429 vs. 0.587, p < 0.05) were observed in extracranial tumors, in contrast to the intracranial tumor (AUC30: 0.058 vs. 0.049, p > 0.05, T1 ratio: 0.497 vs. 0.625, p < 0.05). Additionally, significant changes in the T2 value and apparent diffusion coefficient (ADC) value were observed in extracranial lesions, instead of intracranial lesions. Postmortem angiography and pathology showed a significantly larger H&E-stained area of necrosis (86.2% vs. 18.3%, p < 0.0001), lower CD31 level (42.7% vs. 54.3%, p < 0.05), and lower Ki67 level (12.2% vs. 32.3%, p < 0.01) in extracranial tumors, compared with intracranial lesions. The BBB functioned as a barrier against the delivery of VDA into intracranial tumors and multiparametric MRI may predict the efficacy of VDAs on craniofacial tumors. Full article

The vascular disrupting activity of a promising tubulin-binding agent (OXi6196) was demonstrated in mice in MDA-MB-231 human breast tumor xenografts growing orthotopically in mammary fat pad and syngeneic RENCA kidney tumors growing orthotopically in the kidney. To enhance water solubility, OXi6196, was derivatized as its corresponding phosphate prodrug salt OXi6197, facilitating effective delivery. OXi6197 is stable in water, but rapidly releases OXi6196 in the presence of alkaline phosphatase. At low nanomolar concentrations OXi6196 caused G2/M cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells and monolayers of rapidly growing HUVECs underwent concentration-dependent changes in their morphology. Loss of the microtubule structure and increased bundling of filamentous actin into stress fibers followed by cell collapse, rounding and blebbing was observed. OXi6196 (100 nM) disrupted capillary-like endothelial networks pre-established with HUVECs on Matrigel^®. When prodrug OXi6197 was administered to mice bearing orthotopic MDA-MB-231-luc tumors, dynamic bioluminescence imaging (BLI) revealed dose-dependent vascular shutdown with >80% signal loss within 2 h at doses ≥30 mg/kg and >90% shutdown after 6 h for doses ≥35 mg/kg, which remained depressed by at least 70% after 24 h. Twice weekly treatment with prodrug OXi6197 (20 mg/kg) caused a significant tumor growth delay, but no overall survival benefit. Similar efficacy was observed for the first time in orthotopic RENCA-luc tumors, which showed massive hemorrhage and necrosis after 24 h. Twice weekly dosing with prodrug OXi6197 (35 mg/kg) caused tumor growth delay in most orthotopic RENCA tumors. Immunohistochemistry revealed extensive necrosis, though with surviving peripheral tissues. These results demonstrate effective vascular disruption at doses comparable to the most effective vascular-disrupting agents (VDAs) suggesting opportunities for further development. Full article

Specific targeting of the tumoral vasculature by vascular-disrupting agents (VDA), of which combretastatin A-4 (CA-4) is a main representative, has been considered a new therapeutic strategy against multidrug-resistant tumors. In addition, CA-4 and analogs are tubulin-targeting agents and can exert direct antitumor effects by different mechanisms. Herein, we analyzed a series of synthetic CA-4 analogs featuring N-methylimidazole-bridged Z-alkenes with different halo- or amino-substituted aryl rings in vitro and in vivo, focusing on models of colorectal cancer. Combined in vitro/in vivo structure–activity relationship studies using cell lines and xenograft tumors susceptible to VDA-induced vascular damage demonstrated a clear association of cytotoxic and vascular-disrupting activity with the ability to inhibit tubulin polymerization, which was determined by specific substitution constellations. The most active compounds were tested in an extended panel of colorectal cancer (CRC) cell lines and showed activity in CA-4-resistant and chemotherapy-resistant cell lines. The bromo derivative brimamin was then compared with the known fosbretabulin (CA-4P) by activity tests on DLD-1- (multidrug-resistant) and HT29- (CA-4-resistant) derived xenograft tumors. Treatment did not induce pronounced vascular-disrupting effects in these tumors. Histological analyses revealed distinct tumor substructures and vessel compositions of DLD-1/HT29 tumors, which clearly differed from the tumor models susceptible to VDA treatment. Even so, brimamin effectively retarded the growth of DLD-1 tumors, overcoming their resistance to standard treatment, and it inhibited the outgrowth of disseminated HT29 tumor cells in an experimental metastasis model. In conclusion, combretastatin analogous N-methylimidazoles proved capable of inducing vascular-disrupting effects, comparable to those of CA-4P. In addition, they showed antitumor activities in models of drug-resistant colorectal cancer, independent of vascular-disrupting effects. Full article

The selective disruption of tumor-associated vasculature represents an attractive therapeutic approach. We have undertaken the first in vivo evaluation of KGP265, a water-soluble prodrug of a benzosuberene-based tubulin-binding agent, and found promising vascular-disrupting activity in three distinct tumor types. Dose escalation in orthotopic MDA-MB-231-luc breast tumor xenografts in mice indicated that higher doses produced more effective vascular shutdown, as revealed by dynamic bioluminescence imaging (BLI). In syngeneic orthotopic 4T1-luc breast and RENCA-luc kidney tumors, dynamic BLI and oxygen enhanced multispectral optoacoustic tomography (OE-MSOT) were used to compare vascular shutdown following the administration of KGP265 (7.5 mg/kg). The BLI signal and vascular oxygenation response (ΔsO₂) to a gas breathing challenge were both significantly reduced within 2 h, indicating vascular disruption, which continued over 24 h. A correlative histology confirmed increased necrosis and hemorrhage. Twice-weekly doses of KGP265 caused significant growth delay in both MDA-MB-231 and 4T1 breast tumors, with no obvious systemic toxicity. A combination with carboplatin produced significantly greater tumor growth delay than carboplatin alone, though significant carboplatin-associated toxicity was observed (whole-body weight loss). KGP265 was found to be effective at low concentrations, generating long-term vascular shutdown and tumor growth delay, thus providing strong rationale for further development, particularly in combination therapies. Full article

Vascular disrupting agents (VDAs), such as DMXAA, effectively destroy tumor blood vessels and cause the formation of large areas of necrosis in the central parts of the tumors. However, the use of VDAs is associated with hypoxia activation and residues of rim cells on the edge of the tumor that are responsible for tumor regrowth. The aim of the study was to combine DMXAA with radiotherapy (brachytherapy) and find the appropriate administration sequence to obtain the maximum synergistic therapeutic effect. We show that the combination in which tumors were irradiated prior to VDAs administration is more effective in murine melanoma growth inhibition than in either of the agents individually or in reverse combination. For the first time, the significance of immune cells’ activation in such a combination is demonstrated. The inhibition of tumor growth is linked to the reduction of tumor blood vessels, the increased infiltration of CD8⁺ cytotoxic T lymphocytes and NK cells and the polarization of macrophages to the cytotoxic M1 phenotype. The reverse combination of therapeutic agents showed no therapeutic effect and even abolished the effect of DMXAA. The combination of brachytherapy and vascular disrupting agent effectively inhibits the growth of melanoma tumors but requires careful planning of the sequence of administration of the agents. Full article

The fertilised chick egg and particularly its chorioallantoic membrane (CAM) have drawn continuing interest in biomedicine and bioengineering fields, especially for research on vascular study, cancer, drug screening and development, cell factors, stem cells, etc. This literature review systemically introduces the CAM’s structural evolution, functions, vascular features and the circulation system, and cell regulatory factors. It also presents the major and updated applications of the CAM in assays for pharmacokinetics and biodistribution, drug efficacy and toxicology testing/screening in preclinical pharmacological research. The time course of CAM applications for different assays and their advantages and limitations are summarised. Among these applications, two aspects are emphasised: (1) potential utility of the CAM for preclinical studies on vascular-disrupting agents (VDAs), promising for anti-cancer vascular-targeted therapy, and (2) modern imaging technologies, including modalities and their applications for real-time visualisation, monitoring and evaluation of the changes in CAM vasculature as well as the interactions occurring after introducing the tested medical, pharmaceutical and biological agents into the system. The aim of this article is to help those working in the biomedical field to familiarise themselves with the chick embryo CAM as an alternative platform and to utilise it to design and optimise experimental settings for their specific research topics. Full article

Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm³ C3H mammary carcinomas in the right rear foot, were intraperitoneally injected with combretastatin A-4 phosphate (CA4P), its A-1 analogue OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, or CTLA-4 antibodies), administered twice weekly for two weeks. Using the endpoint of tumor growth time (TGT5; time to reach five times the starting volume), we found that none of the checkpoint inhibitors (10 mg/kg) had any effect on TGT5 compared to untreated controls. However, CA4P (100 mg/kg) or OXi4503 (5–50 mg/kg) did significantly increase TGT5. This further significantly increased by combining the VDAs with checkpoint inhibitors, but was dependent on the VDA, drug dose, and inhibitor. For CA4P, a significant increase was found when CA4P (100 mg/kg) was combined with anti-PD-L1, but not with the other two checkpoint inhibitors. With OXi4503 (50 mg/kg), a significant enhancement occurred when combined with anti-PD-L1 or anti-CTLA-4, but not anti-PD-1. We observed no significant improvement with lower OXi4503 doses (5–25 mg/kg) and anti-CTLA-4, although 30% of tumors were controlled at the 25 mg/kg dose. Histological assessment of CD4/CD8 expression actually showed decreased levels up to 10 days after treatment with OXi4503 (50 mg/kg). Thus, the non-immunogenic C3H mammary carcinoma was unresponsive to checkpoint inhibitors, but became responsive in mice treated with VDAs, although the mechanism remains unclear. Full article

Vascular disrupting agents (VDAs) have entered clinical trials for over 15 years. As the leading VDA, combretastatin A4 phosphate (CA4P) has been evaluated in combination with chemotherapy and molecular targeting agents among patients with ovarian cancer, lung cancer and thyroid cancer, but still remains rarely explored in human liver cancers. To overcome tumor residues and regrowth after CA4P monotherapy, a novel dual targeting pan-anticancer theragnostic strategy, i.e., OncoCiDia, has been developed and shown promise previously in secondary liver tumor models. Animal model of primary liver cancer is time consuming to induce, but of value for more closely mimicking human liver cancers in terms of tumor angiogenesis, histopathological heterogeneity, cellular differentiation, tumor components, cancer progression and therapeutic response. Being increasingly adopted in VDA researches, multiparametric magnetic resonance imaging (MRI) provides imaging biomarkers to reflect in vivo tumor responses to drugs. In this article as a chapter of a doctoral thesis, we overview the construction and clinical relevance of primary and secondary liver cancer models in rodents. Target selection for CA4P therapy assisted by enhanced MRI using hepatobiliary contrast agents (CAs), and therapeutic efficacy evaluated by using MRI with a non-specific contrast agent, dynamic contrast enhanced (DCE) imaging, diffusion weighted imaging (DWI) are also described. We then summarize diverse responses among primary hepatocellular carcinomas (HCCs), secondary liver and pancreatic tumors to CA4P, which appeared to be related to tumor size, vascularity, and cellular differentiation. In general, imaging-histopathology correlation studies allow to conclude that CA4P tends to be more effective in secondary liver tumors and in more differentiated HCCs, but less effective in less differentiated HCCs and implanted pancreatic tumor. Notably, cirrhotic liver may be responsive to CA4P as well. All these could be instructive for future clinical trials of VDAs. Full article

Head and neck squamous cell carcinomas (HNSCC) represent a group of epithelial neoplasms that exhibit considerable heterogeneity in clinical behavior. Here, we examined the stromal and vascular heterogeneity in a panel of patient-derived xenograft (PDX) models of HNSCC and the impact on therapeutic response. Tumor sections from established tumors were stained for p16 (surrogate for human papillomavirus (HPV) infection), stromal (Masson’s trichrome) and vascular (CD31) markers. All PDX models retained the HPV/p16 status of the original patient tumor. Immunohistochemical evaluation revealed the presence of multiple vessel phenotypes (tumor, stromal or mixed) in the PDX panel. Vascular phenotypes identified in the PDX models were validated in a tissue microarray of human HNSCC. Treatment with a microtubule targeted vascular disrupting agent (VDA) resulted in a heterogeneous antivascular and antitumor response in PDX models. The PDX with the tumor vessel phenotype that exhibited higher CD31+ vessel counts and leaky vasculature on magnetic resonance imaging (MRI) was sensitive to VDA treatment while the PDX with the stromal vessel phenotype was resistant to therapy. Collectively, our results demonstrate the phenotypic and functional vascular heterogeneity in HNSCC and highlight the impact of this heterogeneity on response to antivascular therapy in PDX models of HNSCC. Full article

Extensive research over the last decade has resulted in a number of highly potent tubulin polymerization inhibitors acting either as microtubule stabilizing agents (MSAs) or microtubule destabilizing agents (MDAs). These inhibitors have potent cytotoxicity against a broad spectrum of human tumor cell lines. In addition to cytotoxicity, a number of these tubulin inhibitors have exhibited abilities to inhibit formation of new blood vessels as well as disrupt existing blood vessels. Tubulin inhibitors as a vascular disrupting agents (VDAs), mainly from the MDA family, induce rapid tumor vessel occlusion and massive tumor necrosis. Thus, tubulin inhibitors have become increasingly popular in the field of tumor vasculature. However, their pharmaceutical application is halted by a number of limitations including poor solubility and toxicity. Thus, recently, there has been considerable interests in the nanoparticle drug delivery of tubulin inhibitors to circumvent those limitations. This article reviews recent advances in nanoparticle based drug delivery for tubulin inhibitors as well as their tumor vasculature disruption properties. Full article

Vascular disrupting agents (VDAs) represent a relatively distinct class of agents that target established blood vessels in tumors. In this study, we examined the preclinical activity of the second-generation VDA OXi4503 against human head and neck squamous cell carcinoma (HNSCC). Studies were performed in subcutaneous and orthotopic FaDu-luc HNSCC xenografts established in immunodeficient mice. In the subcutaneous model, bioluminescence imaging (BLI) along with tumor growth measurements was performed to assess tumor response to therapy. In mice bearing orthotopic tumors, a dual modality imaging approach based on BLI and magnetic resonance imaging (MRI) was utilized. Correlative histologic assessment of tumors was performed to validate imaging data. Dynamic BLI revealed a marked reduction in radiance within a few hours of OXi4503 administration compared to baseline levels. However, this reduction was transient with vascular recovery observed at 24 h post treatment. A single injection of OXi4503 (40 mg/kg) resulted in a significant (p < 0.01) tumor growth inhibition of subcutaneous FaDu-luc xenografts. MRI revealed a significant reduction (p < 0.05) in volume of orthotopic tumors at 10 days post two doses of OXi4503 treatment. Corresponding histologic (H&E) sections of Oxi4503 treated tumors showed extensive areas of necrosis and hemorrhaging compared to untreated controls. To the best of our knowledge, this is the first report, on the activity of Oxi4503 against HNSCC. These results demonstrate the potential of tumor-VDAs in head and neck cancer. Further examination of the antivascular and antitumor activity of Oxi4503 against HNSCC alone and in combination with chemotherapy and radiation is warranted. Full article