fosbretabulin and Neoplasms

CA4 is a potent microtubule polymerization inhibitor and vascular disrupting agent. However, the in vivo efficiency of CA4 is limited owing to its poor pharmacokinetics resulting from its high lipophilicity and low water solubility. To improve the water solubility, CA4 phosphate (CA4P) has been developed and shows potent antivascular and antitumor effects. CA4P had been evaluated as a vascular disrupting agent in previousc linical trials. However, it had been discontinued due to the lack of a meaningful improvement in progression-free survival and unfavorable partial response data. Codrug is a drug design approach to chemically bind two or more drugs to improve therapeutic efficiency or decrease adverse effects. This review describes the progress made over the last twenty years in developing CA4-based codrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues. It also discusses the existing problems and the developmental prospects of CA4 codrugs.

Topics: Antineoplastic Agents, Phytogenic; Drug Design; Humans; Neoplasms; Organophosphates; Stilbenes; Water

Although significant progress over several decades has been evidenced in cancer therapy, there remains a need for the development of novel and effective therapeutic strategies to treat several relapsed and intractable cancers. In this regard, tubulin protein has become one of the efficient and major targets for anticancer drug discovery. Considering the antimitotic ability, several tubulin inhibitors have been developed to act against various cancers. Among various tubulin inhibitors available, combretastatin-A4 (CA-4), a naturally occurring lead molecule, offers exceptional cytotoxicity (including the drugresistant cell lines) and antivascular effects. Although CA-4 offers exceptional therapeutic efficacy, several new advancements have been proposed, in terms of structural modification via A and B rings, as well as cis-olefinic bridging, which provide highly efficient analogs with improved tubulin-binding efficiency to meet the anticancer drug development requirements. This review systematically emphasizes the recent trends and latest developments in the anticancer drug design and discovery using CA-4 analogs as the tubulin inhibiting agents by highlighting their structure-activity relationships (SAR) and resultant pharmacological efficacies.

Topics: Antineoplastic Agents; Bibenzyls; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators

The adverse effects of chemotherapeutic drugs to healthy organs/cells greatly limit their clinical efficacy and patient compliance. The unique behavior of azobenzene photoswitch offers a remarkable tool to address the side effects of chemotherapeutic drugs. The azobenzene moiety has been integrated within some chemotherapeutic drugs to realize photo-triggered activation of drug cytotoxicity. However, the clinical translation of these agents has been facing a few barriers. In this short review, we present our viewpoints on potential solutions to address the following challenges associated with azobenzene-based photoswitchable chemotherapeutic drugs, including poor tissue penetration of light, hypoxia-induced drug degradation in solid tumor and the autonomous cis-trans relaxation.

Topics: Antineoplastic Agents; Azo Compounds; Humans; Isomerism; Neoplasms; Stilbenes

One of the most studied anti-cancer compounds of the last several decades is the microtubule targeting agent and cis-stilbene, combretastatin A4 (CA4). Despite promising results at the pre-clinical level, future clinical use of CA4 as a monotherapy is in question due to metabolic vulnerability and conformational instability.. Thus, medicinal chemists have focused on synthesizing derivatives with improved pharmokinetic profile. One common strategy has been the incorporation of the ethylene linker into a ring system, thus preventing the isomerization of CA4 into the virtually inactive trans-isomer. Although many structurally stable and potent analogues of CA4 have been designed and synthesized, several analogues have been discovered to possess anti-proliferative properties seemingly independent of microtubule targeting. The presence of such analogues suggests that CA4 may also possess nonmicrotubule targets, which reveals the necessity for future structure activity relationship studies and optimization of any non-microtubule targeting. Furthermore, analogues of CA4 not inhibiting microtubule polymerization can no longer be assumed to be inactive.. Future clinical development of the CA4 pharmacophore requires that attention should be paid to abnormal CA4 analogues, which appear to retain cytotoxicity independent of canonical microtubule inhibition.

Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; Microtubules; Molecular Targeted Therapy; Neoplasms; Stilbenes

For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency. The cis-configuration is crucial for its biological activity. To date, many derivatives were synthesized. The attempts to resolve spontaneous isomerization to less active trans-stilbene derivative are still in progress. This issue seems to be overcome by incorporation of the ethene bridge with heterocyclic moiety in combretastatins structure. This modification retains the cis-configuration and prevents isomerization. Nevertheless, combretastatin A4 phosphate disodium is still the most potent compound of this group. The combination therapy, which is the most effective treatment, includes combretastatin A4 phosphate (CA4P) and conventional chemotherapeutics and/or radiotherapy. CA4P is relatively well tolerated giving adverse events of moderate severity, which includes: nausea, vomiting, headache, and tumor pain. The aforementioned effects subside on the day of drug administration or on the following day.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Humans; Nausea; Neoplasms; Stilbenes; Structure-Activity Relationship

Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3'-hydroxy-3,4,4',5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

Topics: Antineoplastic Agents, Phytogenic; Binding, Competitive; Cell Survival; Clinical Trials as Topic; Humans; Models, Molecular; Molecular Structure; Neoplasms; Stilbenes; Tubulin

Tubulin protein is one of several members of a small family of globular proteins. It offers a potential target for anticancer drug design and development. Combretastatin A-4 (CA-4) is a potent anticancer and antiangiogenesis natural substance isolated from Combretum caffrum. Modifications on the CA-4 structure have led to a great number of novel CA-4 derivatives as potent tubulin inhibitors and high cytotoxic anticancer agents is becoming an interesting field, leading to a breakthrough in the treatment of cancer. In this review, the recent developments of novel CA-4 derivatives via the modifications on the A- and B-ring and the double bond as anticancer agents are discussed.

Topics: Antineoplastic Agents; Combretum; Humans; Neoplasms; Stilbenes; Tubulin; Tubulin Modulators

Tumor blood vessels are an important emerging target for anti-cancer therapy. The antimitotic agent combretastatin A-4 (CA-4), a cis-stilbene natural product isolated from the South African tree Combretum caffrum Kuntze, is the lead compound of a new class of anti-cancer drugs that target tumor vasculature. CA-4 inhibits tubulin polymerization by interacting at the colchicine binding site on tubulin. This alters the morphology of endothelial cells and causes vascular shutdown and regression of tumor vasculature. Some tubulin-binding vascular-disrupting agents (VDAs) are currently in clinical trials for cancer therapy. As a consequence of the potential favorable applications of these compounds, several analogs projected to induce rapid and selective vascular shutdown in tumors have been synthesized during the last few years. Many of these molecules have already been tested for their effects on tubulin polymerization as well as for their antiproliferative activity and other biological properties, and possible mechanisms of action have been investigated. The aim of the present review is to offer an overview of most recently developed combretastatin derivatives, focusing on biological effects exerted by these compounds. The published data about new analogs are presented and compared, and a detailed investigation of structure-activity relationships is described.

Topics: Animals; Antineoplastic Agents, Phytogenic; Combretum; Humans; Neoplasms; Neovascularization, Pathologic; Stilbenes; Structure-Activity Relationship

Combretastatin A4 phosphate (CA4P) is the lead compound of a relatively new class of agents termed vascular disrupting agents that target existing tumor blood vessels. Rapid tumor blood flow shutdown has been demonstrated in preclinical models and patients by various techniques such as dynamic contrast-enhanced MRI, perfusion computed tomography and PET scans following CA4P infusion. CA4P typically induces rapid tumor necrosis in the center of the tumor and leaves a rim of viable cells in the periphery. In oncology, CA4P does not appear to be that active by itself, but may be more efficacious when combined with chemotherapy, antiangiogenic therapy and radiation therapy. Studies are currently underway, which combine CA4P with antiangiogenic agents. Side effects have included hypertension, tumor pain and occasional cardiovascular toxicity, without any significant myelosuppression or disabling systemic symptoms. The utility of CA4P for conditions other than cancer, which involves neovascularization such as macular degeneration, is also being explored.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Humans; Neoplasms; Neovascularization, Pathologic; Stilbenes

Microtubule is one of the key components of the cytoskeleton and plays an important role in the maintenance of cell shape and the process of signal transduction and mitosis. Due to the extreme importance of microtubule in the process of mitosis, tubulin becomes one of the most important targets for development of new anticancer drugs and tubulin inhibitors are used for the treatment of cancer nowadays. These inhibitors have antitumor activity by inhibiting or promoting the assembly of tubulin to microtubules and interfering the process of cell mitosis. This review summarized the research progress of the tubulin inhibitors, especially the introduction of the tubulin inhibitors of pharmacological activities and the progress of clinical research. Also, the development trend of these inhibitors is discussed.

Topics: Antineoplastic Agents; Humans; Microtubules; Mitosis; Molecular Structure; Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators

Vascular-disrupting strategies impair a tumor's blood vessel network, which is essential for tumor progression and metastasis. Vascular-disrupting agents (VDAs) cause a rapid and selective vascular shutdown in tumors to produce extensive secondary neoplastic cell death due to ischemia. A lead agent in this therapeutic strategy is the tubulin depolymerizing agent combretastatin-A4 phosphate (CA4P). Used alone, CA4P induces extensive necrosis in a wide variety of preclinical cancer models and significant blood flow reductions in the patient tumors. Preclinical and clinical data further indicate that CA4P can effectively be combined with chemotherapy or radiotherapy. Finally, the potential of combining VDAs with antiangiogenic therapies has shown considerable promise in preclinical models and such combinations are now beginning to be evaluated in patients.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Humans; Neoplasms; Stilbenes

The growth and metastasis of solid tumors critically depends on their ability to develop their own blood supply, a process known as tumor angiogenesis. Over the past decade much work has been performed to understand this process, and modifying this process provides a key point of therapeutic intervention in the fight against cancer. This Review explores the development of anti-VEGF-based antiangiogenic therapies, of which there are currently three licensed for clinical use worldwide. Although originally anticipated to inhibit the growth of tumor vessels, the induction of vascular normalization caused by these approved agents has provided a novel means of effective delivery of known chemotherapeutic agents. The development of small molecules that target VEGF receptors has resulted in the generation of inhibitors with not only vascular activity but antitumor activity in certain cancers. This Review will address the current status of vascular-disrupting strategies, such as therapies designed to induce tumor collapse by selectively destroying existing tumor vessels. These therapies can be broadly divided into small-molecular-weight vascular-disrupting agents and ligand-directed approaches. We discuss the current status of development, drug mechanisms of actions, combination with conventional chemotherapy and radiotherapy, and potential future targets for therapeutic intervention.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Bevacizumab; Clinical Trials as Topic; Humans; Neoplasms; Neovascularization, Pathologic; Regional Blood Flow; Stilbenes; Vascular Endothelial Growth Factor A

Angiogenesis has an essential role in promoting and supporting tumor growth and it is an important therapeutic target. The tumor vascular network is the result of pro-angiogenic and inhibitory factors as well as of the interaction between endothelial cells and extracellular matrix. Different antiangiogenic therapeutics have been developed to improve tumor control through vascular-targeting agents (VTA). VTAs can be divided into two groups: antiangiogenic agents and vascular-disrupting agents (VDAs). VTAs inhibit specific factors required to induce and direct the angiogenic process, with major activity against small tumor masses and at the tumor periphery, encompassing monoclonal antibodies and small molecules inhibitors of the tyrosine kinase domain of the VEGF receptor. VDAs specifically target and destroy well-established tumor vessels with ischemia and destruction of large masses with central hemorrhagic necrosis and survival of a thin peripheral tumor layer. VDAs can be divided into biologics, such as ligand-based, and small-molecule agents; this second group includes small-molecule VDAs like flavonoids, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and microtubule-destabilizing agents. In this review we will discuss the mechanism of action, as well as the preclinical and clinical results, of one of the most promising antitubulin agents: the combretastatin A4-phosphate derivative, AVE8062A.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Neoplasms; Neovascularization, Pathologic; Serine; Stilbenes; Tubulin

A large group of tubulin-binding microtubule-depolymerizing agents act as tumour vascular disrupting agents (VDAs). Several members of this group are now in clinical trials in combination with conventional anticancer drugs and radiotherapy. Here we briefly update on the development of tubulin-binding combretastatins as VDAs, summarize what is known of their mechanisms of action and address issues relating to treatment resistance, using disodium combretastatin A-4 3-O-phosphate (CA-4-P) as an example. Characteristically, VDAs cause a rapid shutdown of blood flow to tumour tissue with much less effect in normal tissues. However, the tumour rim is relatively resistant to treatment. Hypoxia (or hypoxia reoxygenation) induces upregulation of genes associated with angiogenesis and drug resistance. It may be possible to take advantage of treatment-induced hypoxia by combining with drugs that are activated under hypoxic conditions. In summary, VDAs provide a novel approach to cancer treatment, which should effectively complement standard treatments, if treatment resistance is addressed by judicious combination treatment strategies.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Blood Vessels; Combined Modality Therapy; Drug Resistance, Neoplasm; Humans; Mice; Microtubules; Neoplasms; Rats; Stilbenes; Tubulin Modulators

Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.

Topics: Animals; Antineoplastic Agents; Blood Vessels; Humans; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Organophosphorus Compounds; Regional Blood Flow; Stilbenes; Tubulin Modulators; Xanthones

Low molecular weight vascular disrupting agents of the microtubule depolymerizing family cause marked and selective disruption of the established tumour blood vessel network, resulting in tumour cell necrosis. The combretastatins are members of this family and these, together with several other related compounds, have undergone extensive preclinical testing and are now in clinical trials for cancer. Potentially, vascular disrupting agents can also interfere with angiogenesis and constitute a very promising group of novel cancer drugs. In vitro analysis of their signalling activities points to the endothelial cytoskeleton as being their major target and a key player in the events that culminate in vascular collapse. As more of these agents progress into the clinical setting, more research in this area is warranted in order to decipher exact mechanisms responsible for vascular disruption and to understand the reasons for drug selectivity for the tumour vasculature. This information is essential in order to identify new targets within the tumour vasculature and to improve present therapies.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Drug Delivery Systems; Drug Evaluation, Preclinical; Humans; Microtubules; Neoplasms; Neovascularization, Pathologic; Stilbenes

Angiogenesis is critical for a number of physiologic and pathophysiologic processes, and angiogenesis inhibitors are now being used in the treatment of cancer. Although antiangiogenic agents offer great therapeutic potential, preclinical and clinical trial results suggest that these agents will have a delayed onset of activity and may only induce disease stabilization for patients with advanced malignancy. The use of radiation therapy for cancer is also associated with therapeutic challenges that are distinct from those that might be expected with antiangiogenic agents. Thus, the use of angiogenesis inhibitors in combination with radiation therapy should help to overcome the limitations of each leading to enhanced efficacy and diminished toxicity. The goal of this review is to provide an overview and discussion of the combination of angiogenesis inhibitors with radiation therapy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Combined Modality Therapy; Humans; Neoplasms; Organophosphorus Compounds; Stilbenes; Vascular Endothelial Growth Factor A

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

Anthracyclines are a well-known cause of cardiotoxicity, but a number of other drugs used to treat cancer can also result in cardiac and cardiovascular adverse effects. Cardiotoxicity can result in the alteration of cardiac rhythm, changes in blood pressure and ischemia, and can also alter the ability of the heart to contract and/or relax. The clinical spectrum of these toxicities can range from subclinical abnormalities to catastrophic life-threatening, and sometimes fatal, sequelae. These events may occur acutely or may only become apparent months or years following completion of oncological treatment. Ischemia and rhythm abnormalities are treated symptomatically in most cases. Knowledge of these toxicities can aid clinicians to choose the optimal and least toxic regimen suitable for an individual patient.

Topics: Anthracyclines; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cardiovascular Diseases; Heart Diseases; Humans; Interferons; Interleukin-2; Neoplasms; Oxides; Stilbenes; Tretinoin

Novel anticancer compounds are being developed that attempt to exploit the unique properties of the vascular endothelium, which supplies rapidly dividing neoplasms. The goal of these vascular targeting agents (VTAs) or endothelial disrupting agents is to cause rapid shutdown of tumor blood supply with subsequent tumor death from hypoxia and nutrient deprivation. VTAs are classified into two broad categories: biologic therapies or small molecule compounds. A variety of VTAs are in early clinical development. These agents have demonstrated clinical activity in phase I trials and are being evaluated with cytotoxic chemotherapy and radiotherapy.

Topics: Antineoplastic Agents, Phytogenic; Clinical Trials, Phase I as Topic; Endothelium, Vascular; Humans; Neoplasms; Organophosphorus Compounds; Stilbenes; Xanthones

Despite extensive research efforts, effective therapies for refractive cancers have not yet been established, and development of successful treatment strategies remains the most important task in the field of oncology. We recently showed that AVE8062 (formerly AC7700), a derivative of combretastatin A-4, achieved irreversible stasis of tumor blood flow (TBF), thereby causing necrosis of tumor tissue by halting the supply of nutrients. Such effects were unrelated to cancer type. In this review, we summarize our experiments on antivascular and antitumor effects by AVE8062. We maintain that such starvation tactics against solid tumors constitute a new therapeutic strategy for all solid tumors, including refractory cancers.

Topics: Animals; Antineoplastic Agents; Microcirculation; Neoplasms; Rats; Regional Blood Flow; Serine; Stilbenes

Vascular targeting agents (VTAs) for the treatment of cancer are designed to cause a rapid and selective shutdown of the blood vessels of tumors. Unlike antiangiogenic drugs that inhibit the formation of new vessels, VTAs occlude the pre-existing blood vessels of tumors to cause tumor cell death from ischemia and extensive hemorrhagic necrosis. Tumor selectivity is conferred by differences in the pathophysiology of tumor versus normal tissue vessels (e.g., increased proliferation and fragility, and up-regulated proteins). VTAs can kill indirectly the tumor cells that are resistant to conventional antiproliferative cancer therapies, i.e., cells in areas distant from blood vessels where drug penetration is poor, and hypoxia can lead to radiation and drug resistance. VTAs are expected to show the greatest therapeutic benefit as part of combined modality regimens. Preclinical studies have shown VTA-induced enhancement of the effects of conventional chemotherapeutic agents, radiation, hyperthermia, radioimmunotherapy, and antiangiogenic agents. There are broadly two types of VTAs, small molecules and ligand-based, which are grouped together, because they both cause acute vascular shutdown in tumors leading to massive necrosis. The small molecules include the microtubulin destabilizing drugs, combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and Oxi 4503, and the flavonoid, DMXAA. Ligand-based VTAs use antibodies, peptides, or growth factors that bind selectively to tumor versus normal vessels to target tumors with agents that occlude blood vessels. The ligand-based VTAs include fusion proteins (e.g., vascular endothelial growth factor linked to the plant toxin gelonin), immunotoxins (e.g., monoclonal antibodies to endoglin conjugated to ricin A), antibodies linked to cytokines, liposomally encapsulated drugs, and gene therapy approaches. Combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and DMXAA are undergoing clinical evaluation. Phase I monotherapy studies have shown that the agents are tolerated with some demonstration of single agent efficacy. Because efficacy is expected when the agents are used with conventional chemotherapeutic drugs or radiation, the results of Phase II combination studies are eagerly awaited.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Cell Division; Clinical Trials as Topic; Diphosphates; Genetic Therapy; Humans; Hypoxia; Immunotoxins; Ligands; Models, Biological; Necrosis; Neoplasms; Organophosphorus Compounds; Peptides; Radioimmunotherapy; Stilbenes; Time Factors; Up-Regulation; Xanthones

Combretastatin A4 phosphate (CA4P) is a water-soluble prodrug of combretastatin A4 (CA4). The vascular targeting agent CA4 is a microtubule depolymerizing agent. The mechanism of action of the drug is thought to involve the binding of CA4 to tubulin leading to cytoskeletal and then morphological changes in endothelial cells. These changes increase vascular permeability and disrupt tumor blood flow. In experimental tumors, anti-vascular effects are seen within minutes of drug administration and rapidly lead to extensive ischemic necrosis in areas that are often resistant to conventional anti-cancer treatments. Following single-dose administration a viable tumor rim typically remains from which tumor regrowth occurs. When given in combination with therapies targeted at the proliferating viable rim, enhanced tumor responses are seen and in some cases cures. Results from the first clinical trials have shown that CA4P monotherapy is safe and reduces tumor blood flow. There has been some promising demonstration of efficacy. CA4P in combination with cisplatin is also safe. Functional imaging studies have been used to aid the selection of doses for phase II trials. Both dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and positron emission tomography can measure the anti-vascular effects of CA4P in humans. This review describes the background to the development of CA4P, its proposed mechanism of action, the results from the first clinical trials with CA4P and the role of imaging techniques in its clinical development.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Humans; Neoplasms; Neovascularization, Pathologic; Stilbenes; Technology, Pharmaceutical

Combretastatin A4 phosphate (CA4P) represents the lead compound in a group of novel tubulin depolymerising agents being developed as vascular targeting agents (VTAs). VTAs are drugs that induce rapid and selective vascular dysfunction in tumours. CA4P is a water-soluble prodrug of the cis-stilbene CA4 originally isolated from the tree Combretum caffrum. Preclinical studies have shown that CA4P induces blood flow reductions and subsequent tumour cell death in a variety of preclinical models. Moreover, this activity has been linked to its ability to rapidly alter the morphology of immature endothelial cells by disrupting their tubulin cytoskeleton. Phase I clinical trials have established a maximum tolerated dose in the range 60-68 mg/m2 and in addition have established that significant changes to tumour perfusion can be achieved across a wide range of doses. The dose-limiting toxicities include tumour pain, ataxia and cardiovascular changes. The maximum tolerated dose was independent of schedule, indicating the absence of cumulative toxicity. Although unexpected from preclinical studies, some evidence of clinical response was seen using CA4P as a single modality. Based on the Phase I data, combination studies of CA4P with established therapies are in progress and should determine whether the exciting preclinical data obtained when VTAs are used in combination with cytotoxic chemotherapy, radiation, radioimmunotherapy and even antiangiogenic agents, can be translated into man.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Humans; Neoplasms; Neovascularization, Pathologic; Stilbenes

The tumour vasculature is an attractive target for therapy. Combretastatin A-4 (CA-4) and A-1 (CA-1) are tubulin binding agents, structurally related to colchicine, which induce vascular-mediated tumour necrosis in animal models. CA-1 and CA-4 were isolated from the African bush willow, Combretum caffrum, and several synthetic analogues are also now available, such as the Aventis Pharma compound, AVE8062. More soluble, phosphated, forms of CA-4 (CA-4-P) and CA-1 (CA-1-P) are commonly used for in vitro and in vivo studies. These are cleaved to the natural forms by endogenous phosphatases and are taken up into cells. The lead compound, CA-4-P, is currently in clinical trial as a tumour vascular targeting agent. In animal models, CA-4-P causes a prolonged and extensive shut-down of blood flow in established tumour blood vessels, with much less effect in normal tissues. This paper reviews the current understanding of the mechanism of action of the combretastatins and their therapeutic potential.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Endothelium, Vascular; Humans; Neoplasms; Neovascularization, Pathologic; Stilbenes

The requirement for neovascularisation to permit the development of solid tumours beyond a threshold size, has focused attention on the therapeutic potential of agents that prevent angiogenesis. The multistep nature of angiogenesis presents several targets for intervention, including the inhibition of the endothelial-cell migration or proliferation normally associated with developing vessels. Compounds that damage established tumour vasculature are also of potential clinical use. We review the development of one such antivascular drug, combretastatin A4. This tubulin-binding agent was originally isolated from an African shrub, Combretum caffrum. The disodium combretastatin A4 phosphate prodrug is currently undergoing phase I clinical trials in the UK and USA. This review assesses the in vitro and in vivo data for combretastatin and the prodrug, and the preliminary data that have emerged from the phase I clinical trials.

Topics: Antineoplastic Agents, Phytogenic; Cells, Cultured; Clinical Trials as Topic; Humans; Neoplasms; Stilbenes

Topics: Antineoplastic Agents; Benzamides; Benzoquinones; Boronic Acids; Bortezomib; Clinical Trials as Topic; Dioxoles; Enzyme Inhibitors; Humans; Hydroxamic Acids; Imatinib Mesylate; Isoquinolines; Lactams, Macrocyclic; Neoplasms; Piperazines; Pyrazines; Pyrimidines; Rifabutin; Stilbenes; Tetrahydrofolates; Tetrahydroisoquinolines; Trabectedin; Vorinostat

Obstetrical complications affect more than a third of women globally, but are underrepresented in clinical research. Little is known about the comprehensive obstetrical clinical trial landscape, how it compares with other fields, or factors associated with the successful completion of obstetrical trials.. This study aimed to characterize obstetrical clinical trials registered on ClinicalTrials.gov with the primary objective of identifying features associated with early discontinuation and results reporting.. This is a cross-sectional study with descriptive, logistic regression and Cox regression analyses of clinical trials registered on ClinicalTrials.gov. Our primary exposure variables were trial focus (obstetrical or nonobstetrical) and trial funding (industry, United States government, or academic). We conducted additional exploratory analyses of other trial features including design, enrollment, and therapeutic focus. We examined the associations of exposure variables and other trial features with 2 primary outcomes: early discontinuation and results reporting.. Obstetrical trials represent only 1.9% of all clinical trials in ClinicalTrials.gov and have comparatively poor completion. All stakeholders should commit to increasing the number of obstetrical trials and improving their completion and dissemination to ensure clinical research reflects the obstetrical burden of disease and advances maternal health.

Topics: Adipose Tissue, White; Adult; Aged; Air Pollutants; Animals; Anti-Inflammatory Agents; Arginine; bcl-2-Associated X Protein; Biofuels; Biological Products; Blood Glucose; Breast Neoplasms; Caspases; CD36 Antigens; Cell Communication; Cell Proliferation; Cell Survival; Cooking; Cross-Sectional Studies; Databases, Factual; Diabetes Mellitus, Type 2; Diphtheria Toxin; Double-Blind Method; Exenatide; Extracellular Polymeric Substance Matrix; Feasibility Studies; Female; Filgrastim; Fruit; Galactose; Gene Deletion; Gene Knockdown Techniques; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Glucose; Glycated Hemoglobin; Hematopoietic Stem Cell Mobilization; Household Articles; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Lung; Lymphoma; Male; Metals, Heavy; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nanoparticles; Neoplasms; Obesity; Obstetrics; Odds Ratio; Oxygen; Peripheral Blood Stem Cell Transplantation; Photochemotherapy; Plant Extracts; Polyethylene Glycols; Polyglutamic Acid; Porosity; Postprandial Period; Prospective Studies; Quality of Life; Receptors, Glucagon; Receptors, LDL; Receptors, Somatostatin; Registries; Rhodophyta; Rhodotorula; Risk Factors; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Somatostatin; Stilbenes; Terminalia; Treatment Outcome; United States; Venoms

Combretastatin A4 phosphate (CA4P) is a prodrug that selectively destroys tumor blood vessels, and has shown efficacy as a targeted anticancer drug in both animal models and clinical trials. The aims of this single-center, open label, phase I clinical trial were to investigate the safety and tolerability of CA4P administered intravenously to patients aged 18-65 years with advanced solid tumors. Using a dose-escalation protocol, patients were assigned to five groups that received injections with 20 (n=3), 33 (n=3), 50 (n=11), 65 (n=6), or 85 (n=2) mg/m² CA4P. Patients in the 20 and 85 mg/m² groups received a single dose and the other groups received multiple doses. Adverse events (AE), cardiovascular parameters, and biochemical investigations were studied, and the maximum tolerated dose was determined. Of twenty-five patients enrolled, eight were withdrawn/excluded (not because of AE). There were no deaths. A total of 394 AE occurred in the 25 patients, with 89.3% considered related/possibly related to the drug. AE included headache and dizziness (19.8%), tumor-induced pain (14.2%), vascular vagal excitation (10.7%), and vomiting (9.4%). Ninety-five percent of AE were mild (grades 0-II), with only 5% being grade III-IV. Drug administration was associated with biphasic changes in heart rate and blood pressure, and only limited abnormalities in the laboratory investigations performed. The maximum tolerated dose was 65 mg/m². We conclude that CA4P is generally well tolerated, with the vast majority of AE that occurred being of mild severity. Further studies will establish the role of CA4P in cancer therapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Female; Humans; Injections, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prodrugs; Stilbenes; Treatment Outcome; Young Adult

The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.. Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m(2) on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P + bevacizumab.. A total of 63 mg/m(2) CA4P + 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34(+) and CD133(+) bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels.. CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Humans; Male; Middle Aged; Neoplasms; Neovascularization, Pathologic; Stilbenes

• Three pharmacokinetic and safety studies for combretastatin A4 phosphate (CA4P), the first vascular disrupting agent, have been conducted in Western countries. • The maximum tolerated dose (MTD) was approximately 60-68 mg m(-2). • CA4P-related grade 3 or 4 adverse events were tumour pain, dyspnoea, hypoxia and syncope in patients who received doses ≥ 50 mg m(-2).. • This is the first pharmacokinetic and safety study conducted in East Asian patients. • There appeared to be a trend that Chinese patients metabolized CA4 more rapidly and had greater neurotoxicity than patients in Western countries. • We observed favourable clinical responses in patients with refractory nasopharyngeal carcinoma. • CA4P-induced acute renal failure was seen in one dehydrated Chinese patient.. This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours. METHODS Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m(-2) infused intravenously over 30 min.. CA4P was generally well tolerated at ≤ 65 mg m(-2). Transient, moderate increases in the heart rate-corrected QT interval occurred at all doses. CA4P produced a transient dose-dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses ≥65 mg m(-2), including two episodes of reversible ataxia at 85 mg m(-2).For CA4, at 50 mg m(-2),mean (SD) peak plasma concentration (C(max) was 0.99 (0.33) mM, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) mM h and terminal elimination half-life (t(1/2)was 1.81 (0.61) h. At 65 mg m-2,C(max) was 1.73 (0.62) mM,AUC(0,t) was 3.19 (1.47) mM h and t (1/2) was 1.90 (0.61) h [corrected]One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass. CONCLUSION Doses ≤ 65 mg m(-2) given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50-65 mg m(-2) have been selected for further studies.

Topics: Adult; Antineoplastic Agents, Phytogenic; Asian People; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Stilbenes; Treatment Outcome

The vascular disrupting agent combretastatin A4 phosphate (CA4P) causes major regression of animal tumours when given as combination therapy.. Patients with advanced cancer refractory to standard therapy were treated with CA4P as a 10-min infusion, 20 h before carboplatin, paclitaxel, or paclitaxel, followed by carboplatin.. Combretastatin A4 phosphate was escalated from 36 to 54 mg m(-2) with the carboplatin area under the concentration curve (AUC) 4-5, from 27 to 54 mg m(-2) with paclitaxel 135-175 mg m(-2), and from 54 to 72 mg m(-2) with carboplatin AUC 5 and paclitaxel 175 mg m(-2). Grade 3 or 4 neutropenia was seen in 17%, and thrombocytopenia only in 4% of 46 patients. Grade 1-3 hypertension (26% of patients) and grade 1-3 tumour pain (65% of patients) were the most typical non-haematological toxicities. Dose-limiting toxicity of grade 3 hypertension or grade 3 ataxia was seen in two patients at 72 mg m(-2). Responses were seen in 10 of 46 (22%) patients with ovarian, oesophageal, small-cell lung cancer, and melanoma.. The combination of CA4P with carboplatin and paclitaxel was well tolerated in the majority of patients with adequate premedication and had antitumour activity in patients who were heavily pretreated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Ataxia; Carboplatin; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Esophageal Neoplasms; Female; Humans; Infusions, Intravenous; Life Expectancy; Lung Neoplasms; Male; Melanoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Paclitaxel; Patient Selection; Stilbenes

The purpose was to determine the reproducibility of apparent diffusion coefficient (ADC) measurements in a two-centre phase I clinical trial; and to track ADC changes in response to the sequential administration of the vascular disrupting agent, combretastatin A4 phosphate (CA4P), and the anti-angiogenic drug, bevacizumab. Sixteen patients with solid tumours received CA4P and bevacizumab treatment. Echo-planar diffusion-weighted MRI was performed using six b values (b = 0-750 s/mm(2)) before (x2), and at 3 and 72 h after a first dose of CA4P. Bevacizumab was given 4 h after a second dose of CA4P, and imaging performed 3 h post CA4P and 72 h after bevacizumab treatment. The coefficient of repeatability (r) of ADC total (all b values), ADC high (b = 100-750) and ADC low (b = 0-100) was calculated by Bland-Altman analysis. The ADC total and ADC high showed good measurement reproducibility (r% = 13.3, 14.1). There was poor reproducibility of the perfusion-sensitive ADC low (r% = 62.5). Significant increases in the median ADC total and ADC high occurred at 3 h after the second dose of CA4P (p < 0.05). ADC measurements were highly reproducible in a two-centre clinical trial setting and appear promising for evaluating the effects of drugs that target tumour vasculature.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Diffusion Magnetic Resonance Imaging; Dose-Response Relationship, Drug; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms; Phantoms, Imaging; Reproducibility of Results; Stilbenes; Time Factors

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemokine CXCL12; Diphosphates; Endothelial Cells; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Melanoma; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Neoplasms; Prodrugs; Stem Cells; Stilbenes; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin.. Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion.. Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m(2) together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m(2) and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles.. This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nausea; Neoplasms; Neutropenia; Stilbenes; Thrombocytopenia; Treatment Outcome; Vomiting

The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors.. CA4P was administered in a dose-escalating fashion starting at 18 mg/m(2) i.v. every 21 days, and the maximal dosage was 90 mg/m(2). Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett's formula QTc = QT/(R-R interval)(1/2), and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C(max) versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed.. After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion.. CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Blood Pressure; Cardiovascular System; Coronary Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Safety; Stilbenes

Clinical evaluation of novel agents that target tumor blood vessels requires pharmacodynamic end points that measure vascular damage. Positron emission tomography (PET) was used to measure the effects of the vascular targeting agent combretastatin A4 phosphate (CA4P) on tumor and normal tissue perfusion and blood volume.. Patients with advanced solid tumors were enrolled onto part of a phase I, accelerated-titration, dose-escalation study. The effects of 5 to 114 mg/m2 CA4P on tumor, spleen, and kidney were investigated. Tissue perfusion was measured using oxygen-15 (15O)-labeled water and blood volume was measured using 15O-labeled carbon monoxide (C15O). Scans were performed immediately before, and 30 minutes and 24 hours after the first infusion of each dose level of CA4P. All statistical tests were two sided.. PET data were obtained for 13 patients with intrapatient dose escalation. Significant dose-dependent reductions were seen in tumor perfusion 30 minutes after CA4P administration (mean change, -49% at >or= 52 mg/m2; P =.0010). Significant reductions were also seen in tumor blood volume (mean change, -15% at >or= 52 mg/m2; P =.0070). Although by 24 hours there was tumor vascular recovery, for doses >or= 52 mg/m2 the reduction in perfusion remained significant (P =.013). Thirty minutes after CA4P administration borderline significant changes were seen in spleen perfusion (mean change, -35%; P =.018), spleen blood volume (mean change, -18%; P =.022), kidney perfusion (mean change, -6%; P =.026), and kidney blood volume (mean change, -6%; P =.014). No significant changes were seen at 24 hours in spleen or kidney.. CA4P produces rapid changes in the vasculature of human tumors that can be assessed using PET measurements of tumor perfusion.

Topics: Adult; Antineoplastic Agents, Phytogenic; Dose-Response Relationship, Drug; Female; Humans; Image Processing, Computer-Assisted; Infusion Pumps; Kidney; Male; Middle Aged; Neoplasms; Spleen; Statistics, Nonparametric; Stilbenes; Tomography, Emission-Computed; Treatment Outcome

Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer.. Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving >/= 52 mg/m2/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment.. Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m2 to 75 mg/m2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m2. Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles.. Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Area Under Curve; Contrast Media; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms; Neovascularization, Pathologic; Stilbenes; Tomography, Emission-Computed; Treatment Outcome

Combretastatin A-4 phosphate (CA4P) is a novel antitumor vascular targeting agent, the first agent of this class of compounds to enter the clinic. We performed a Phase I trial to determine the maximum-tolerated dose, safety, and pharmacokinetic profile of CA4P on a single-dose i.v. schedule. We also obtained preliminary data on its effect on tumor blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques and cell adhesion molecules at the higher-dose levels. Twenty-five assessable patients with advanced cancer received a total of 107 cycles over the following dose escalation schema: 18, 36, 60, 90 mg/m(2) as a 10-min infusion and 60 mg/m(2) as a 60-min infusion at 3-week intervals. There was no significant myelotoxicity, stomatitis, or alopecia. Tumor pain was a unique side effect, which occurred in 10% of cycles, and there were four episodes of dose-limiting toxicity at dosages > or =60 mg/m(2), including two episodes of acute coronary syndrome. Pharmacokinetics revealed rapid dephosphorylation of the parent compound (CA4P) to combretastatin A4 (CA4), with a short plasma half-life (approximately 30 min). A significant (P < 0.03) decline in gradient peak tumor blood flow by DCE-MRI in six of seven patients treated at 60 mg/m(2) was observed. A patient with anaplastic thyroid cancer had a complete response and is alive 30 months after treatment. The toxicity profile is consistent with a drug that is "vascularly active" and devoid of traditional "cytotoxic" side effects. Dosages < or =60 mg/m(2) as a 10-min infusion define the upper boundary of the maximum-tolerated dose.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Cell Adhesion Molecules; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Magnetic Resonance Angiography; Male; Middle Aged; Neoplasms; Neovascularization, Pathologic; Stilbenes

Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acid–functionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Liberation; Drug Synergism; Folic Acid; Humans; Mice; Nanoparticles; Neoplasms; Platinum; Polymers; Stilbenes; Tumor Microenvironment

Phototheranostics that integrates real-time optical imaging and light-controlled therapy has recently emerged as a promising paradigm for cancer theranostics. Herein, a new small molecule dye DPP-BT-TPA with strong emission above 1000 nm and a redox-responsive prodrug camptothecin-combretastatin A4 (CPT-CA4) were designed and successfully synthesized. A multifunctional phototheranostic nanoplatform was then fabricated by encapsulating them within an amphiphilic polymer. The presence of DPP-BT-TPA enabled high-resolution imaging in the second near-infrared window (NIR-II) and efficient photothermal therapy. The prodrug was cleaved by the overexpressed glutathione (GSH) in the tumor microenvironment to release the chemotherapeutic drug CPT and the angiogenesis inhibitor CA4. Because this process can be accelerated with elevated temperature, laser-induced hyperthermia was utilized to control the drug release and enhance the therapeutic effect. Tumors in living mice were observed through NIR-II imaging after intravenous injection of the obtained nanoparticles. Improved antitumor efficacy by photothermal/chemo/antiangiogenic combination therapy was achieved with a NIR laser both in vitro and in vivo. This work provides a promising strategy for developing tumor microenvironment responsive and light-controlled theranostic platforms. STATEMENT OF SIGNIFICANCE: Fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window and near-infrared light-controlled drug release have been recognized as efficient strategies for cancer theranostics. Herein, we present a phototheranostic platform fabricated with a biocompatible NIR-II emissive dye DPP-BT-TPA and a redox-responsive prodrug camptothecin-combretastatin A4 (CPT-CA4). DPP-BT-TPA not only provides high-resolution NIR-II imaging in vivo but also enables efficient photothermal therapy. In addition, the photothermal effect largely accelerates the release of the chemotherapeutic drug CPT and the angiogenesis inhibitor CA4 in the glutathione-overexpressed tumor microenvironment. Thus, the designed phototheranostic platform can be used for NIR-II imaging-guided photothermal/chemo/antiangiogenic combination therapy for tumors with a single laser.

Topics: Angiogenesis Inhibitors; Animals; Camptothecin; Cell Line, Tumor; Glutathione; Infrared Rays; Lasers; Mice; Nanoparticles; Neoplasms; Optical Imaging; Phototherapy; Photothermal Therapy; Polymers; Prodrugs; Stilbenes; Theranostic Nanomedicine

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Binding Sites; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colchicine; Drug Design; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Neoplasms; Neovascularization, Physiologic; Structure-Activity Relationship; Tubulin; Tubulin Modulators

In this work, a series of cyclic bridged analogs of isocombretastatin A-4 (isoCA-4) with phenyl or pyridine linkers were designed and synthesized. The synthesis of the desired analogs was performed by the formation of nitro-vinyl intermediates, followed by a Cadogan cyclization. Structure activity relationship (SAR) study demonstrates the critical role of the combination of quinaldine as ring A, pyridine as the linker, and indole as ring B in the same molecule, for the cytotoxic activity. Among all tested compounds, compound 42 showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 5.6 nM. Also, compound 42 showed high antiproliferative activity against the MDR1-overexpressing K562R cell line; thus, it was 1.5- and 12-fold more active than the reference compounds, isoCA-4 and CA-4, respectively. Moreover, 42 displayed a strong antiproliferative activity against the colon-carcinoma cells (HT-29), which are resistant to combretastatin A-4 and isoCA-4, and it was found to be 8000-fold more active than natural CA-4. Compound 42 also effectively inhibited tubulin polymerization both in vitro and in cells, and induced cell cycle arrest in G2/M phase. Next, we demonstrated that compound 42 dose-dependently caused caspase-induced apoptosis of K562 cells through mitochondrial dysfunction. Finally, we evaluated the effect of compound 42 in human no cancer cells compared to the reference compound. We demonstrated that 42 was 73 times less cytotoxic than isoCA-4 in quiescent peripheral blood lymphocytes (PBLs). In summary, these results suggest that compound 42 represents a promising tubulin inhibitor worthy of further investigation.

Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclization; Drug Design; Humans; Molecular Docking Simulation; Neoplasms; Stilbenes; Tubulin; Tubulin Modulators

We describe the use of natural product combretastatin A4 (CA4) as a versatile new payload for the construction of antibody-drug conjugates (ADCs). Cetuximab conjugates consisting of CA4 derivatives were site-specially prepared by disulfide re-bridging approach using cleavable and non-cleavable linkers. These ADCs retained antigen binding and internalization efficiency and exhibited high potencies against cancer cell lines in vitro. The conjugates also demonstrated significant antitumor activities in EGFR-positive xenograft models without observed toxicities. CA4 appears to be a viable payload option for ADCs research and development.

Topics: Animals; Cell Line, Tumor; Cell Survival; Cetuximab; Disulfides; Drug Design; Humans; Immunoconjugates; Male; Mice; Mice, Inbred NOD; Neoplasms; Stilbenes; Transplantation, Heterologous

Chemotherapy using vascular targeting agents is an emerging new approach for cancer therapy. Combretastatin A4 (CA4) is a leading vascular-disrupting agent that targets the tumor blood vasculature for clinical tumor elimination. However, the extremely poor water solubility of CA4 hinders its biomedical applications. In this study, nanoparticles composed of novel PEGylated alternating copolymer-CA4 conjugates are designed to improve the therapeutic efficiency of CA4. First, an alternating copolymer with an alkene-pendant is synthesized by mPEG-OH-initiated ring-opening copolymerization. Then, side carboxyl groups are introduced by a thio-ene "click" chemical reaction, followed with CA4 conjugation through the Yamaguchi-reaction, resulting in the target copolymer, mPEG-b-P(PA-alt-GCA4). Interestingly, the polymer-drug conjugates can self-assemble into nanoparticles with an average diameter of 55.6 nm. The in vitro drug release and cytotoxicity of the obtained CA4-NPs toward 4T1 cells are investigated. Finally, the antitumor efficiency is evaluated in a 4T1-tumor bearing murine model. The in vivo test results demonstrate that CA4-NPs inhibited tumor growth much more efficiently at doses of 30 and 60 mg kg

Topics: Animals; Cell Line, Tumor; Mice; Nanoparticles; Neoplasms; Polyethylene Glycols; Polymers; Stilbenes

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Movement; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; G2 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Reactive Oxygen Species; T-Lymphocytes; Tubulin Modulators; Xenograft Model Antitumor Assays

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Azetidines; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Stability; G2 Phase Cell Cycle Checkpoints; Humans; Mice; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Neoplasms; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Design; Humans; K562 Cells; Male; Mice, Inbred ICR; Neoplasms; Organoselenium Compounds; Tubulin; Tubulin Modulators; Vinyl Compounds

Topics: A549 Cells; Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Cell Proliferation; Female; G2 Phase Cell Cycle Checkpoints; HEK293 Cells; Humans; Mice, Inbred BALB C; Molecular Structure; Neoplasms; Protein Binding; Structure-Activity Relationship; Thiadiazines; Triazoles; Tubulin; Tubulin Modulators; Xenograft Model Antitumor Assays

Although the polymeric vascular disrupting agent (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4) nanoparticles (CA4-NPs) has great potential to inhibit cancer growth, it is still a challenge to avert tumor recurrence and metastasis after treatment. It is mainly tightly associated with hypoxia induced by CA4-NPs, which can activate many downstream genes regulating tumor growth and metastasis. Herein, to relieve a tumor hypoxia microenvironment, the mTOR inhibitor temsirolimus was employed to modulate the tumor microenvironment when treated with CA4-NPs. In vitro MTT experiments strongly verified that the combination of temsirolimus with polymeric CA4-NPs exhibited an additive toxicity to 4T1 cells. An in vivo study with the 4T1 mammary adenocarcinoma model revealed that consistent with the proposed scenario, combination therapy with CA4-NPs plus temsirolimus suppressed tumor growth significantly more strongly compared to either CA4-NPs or temsirolimus monotherapy, and the inhibition rate to 4T1 tumor with a volume of 300 mm

Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasm Metastasis; Neoplasms; Polyethylene Glycols; Polyglutamic Acid; Polymers; Sirolimus; Stilbenes; Tumor Microenvironment

Topics: Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Colchicine; Drug Design; Drug Screening Assays, Antitumor; Heterografts; Humans; Indoles; K562 Cells; Neoplasms; Quinolines; Structure-Activity Relationship; Tubulin; Tubulin Modulators

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI

Topics: Amides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Naphthoquinones; Neoplasms; Podophyllotoxin; Pyridines; Quinolines; rho-Associated Kinases; Stilbenes; Structure-Activity Relationship; Topoisomerase II Inhibitors; Tubulin; Tubulin Modulators

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Design; Female; HEK293 Cells; HeLa Cells; Humans; Indoles; Mice, Nude; Mitosis; Models, Molecular; Neoplasms; Pyrazoles; Tubulin Modulators; Uterine Cervical Neoplasms

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Humans; Mice, Nude; Microtubules; Molecular Docking Simulation; Neoplasms; Pyrimidines; Pyrroles; Stereoisomerism; Tubulin; Tubulin Modulators

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

Single walled carbon nanotubes (SWCNT) are currently under intensive investigation by many labs all over the world for being promising candidates for cancer chemotherapy delivery. On the other hand, combretastatin A4 (CA4) is an anticancer drug that induces cell apoptosis by inhibiting tubulin polymerization. However, it has the disadvantage of low water solubility and the non-selective targeting. Therefore, we aim to create nano-drug from the functionalization of SWCNT covalently with CA4 through click reaction in the presence of tetraethylene glycol linker in order to improve its dispersibility. Scanning electron microscopy and transmission electron microscopy showed good dispersibility of the functionalized SWCNT with diameters of 5-15 nm. Moreover, thermogravometric analysis showed that the efficiency of SWCNT functionalization was around 45%. The in vitro release profile of CA4 at physiological conditions showed that approximately 90% of the loaded drug was released over 50 h. After that MTS test was used to determine the suitable concentration range for the in vitro investigation of the SWCNT-CA4. After that the cytotoxic activity of the SWCNT-CA4 was evaluated by flow cytometry using annexin V/propidium iodide (PI) test. In comparison with free CA4, SWCNT-CA4 treatment demonstrated a significant increase in necrotic cells (around 50%) at the expense of the proportion of the apoptotic cells. Moreover, cell cycle PI test demonstrated that free CA4 and SWCNT-CA4 caused G2/M arrest. However with CA4 treatment higher proportion of cells were in the S-phase while with SWCNT-CA4 treatment greater proportion of cells appeared to be in the G1-phase. Taken together, the provided data suggest that the novel SWCNT-CA4 has a significant anticancer activity that might be superior to that of free CA4.

Topics: Apoptosis; Cell Cycle; Cell Survival; Click Chemistry; Drug Liberation; HeLa Cells; Humans; Nanotubes, Carbon; Neoplasms; Stilbenes; Thermogravimetry

Combretastatin A4-phosphate (CA4P) is an anti-tumour vascular targeting agent which selectively blocks tumour blood flow. Research on CA4P in rodent tumour models is extensive; however, knowledge of its effect on spontaneous cancer is scarce. This study was conducted in canine patients with spontaneous solid tumours. The goal was to assess the toxicity and efficacy of CA4P in various spontaneous tumour types. Eight dogs with spontaneous tumours were enrolled and treated with a single dose of 75 mg m

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Cell Count; Dog Diseases; Dogs; Female; Injections, Intravenous; Male; Neoplasms; Neovascularization, Pathologic; Stilbenes; Ultrasonography, Doppler, Pulsed

Several tricyclic compounds inspired by the structure of combretastatin A-4 and bearing group 14 elements have been synthesized by homocoupling lithiated aryl fragments followed by ring-closing metathesis. These tricyclic compounds and their diolefin precursors were evaluated for their antiproliferative action on the tumor cell lines HT-29, MCF-7, HeLa and A-549 and on the non-tumor cell line HEK-293. In addition, their effects on the cell cycle were also measured. The tricyclic compounds show antiproliferative activity similar to that of combretastatin A-4, even though they are not so active in arresting the cell cycle. However, some diolefin precursors are able to cause accumulation of cells in the G2/M phase in a higher percentage than combretastatin A-4 itself. Inhibition of endothelial tube formation and VEGFR-2 phosphorylation of some selected compounds is comparable to that of combretastatin A-4, particularly those of tin-containing compounds 23c and 26c, whose actions exceed those of sorafenib, a clinically used VEGFR-2 inhibitor.

Topics: Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; Neoplasms; Stilbenes; Tubulin; Vascular Endothelial Growth Factor Receptor-2

Topics: Antineoplastic Agents; Bibenzyls; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Neoplasms; Stereoisomerism; Structure-Activity Relationship; Triazoles

5,7-Dihydro-3,9,10,11-tetramethoxybenz[c,e]oxepin-4-ol 1, prepared from a dibenzyl ether precursor via Pd-catalysed intramolecular direct arylation, possesses broad-spectrum in vitro cytotoxicity towards various tumour cell lines, and induces vascular shutdown, necrosis and growth delay in tumour xenografts in mice at sub-toxic doses. The biological properties of 1 and related compounds can be attributed to their ability to inhibit microtubule assembly at the micromolar level, by binding reversibly to the same site of the tubulin αβ-heterodimer as colchicine 2 and the allocolchinol, N-acetylcolchinol 4.

Topics: Animals; Cell Line, Tumor; Dibenzoxepins; Dose-Response Relationship, Drug; Heterografts; Humans; Mice; Molecular Structure; Neoplasms; Tubulin

A series of new butadiene derivatives was synthesized and evaluated as tubulin polymerization inhibitors for the treatment of cancer. The optimal butadiene derivative, 9a, exhibited IC

Topics: Antineoplastic Agents; Apoptosis; Butadienes; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; HeLa Cells; Humans; Neoplasms; Tubulin Modulators

Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Humans; Indoles; Molecular Docking Simulation; Morpholines; Neoplasms; Pyrimidines; Structure-Activity Relationship; Tubulin; Tubulin Modulators

7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2), a promising anticancer lead previously identified by us, inhibited tumor growth by 62% in mice at 1.0 mg/kg without obvious signs of toxicity. Moreover, compound 2 exhibited extremely high antiproliferative activity in the NIH-NCI 60 human tumor cell line panel, with low to sub-nanomolar GI

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Mice, Nude; Molecular Docking Simulation; Neoplasms; Quinazolines; Tubulin; Tubulin Modulators

Topics: Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; G2 Phase; Humans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Rats, Sprague-Dawley; Selenium; Stilbenes

Combretastatin A-4 phosphate (CA4P) selectively blocks tumor blood flow. However, the detailed mechanisms through which CA4P specifically affects tumor blood vessels are not well understood. Recent reports revealed that tumor tissue-derived endothelial cells (TECs) have various specific features in comparison with normal tissue-derived endothelial cells (NECs). Thus, abnormalities in TECs may be involved in the selective vascular blockade mechanism of CA4P. In this study, we evaluated the effects of CA4P on canine NECs and TECs using confocal microscopy. NECs exhibited different susceptibilities at subconfluence and at 100% confluence. In addition, inhibition of vascular endothelial cadherin (VE-cadherin) in NECs increased the sensitivity of the cells to CA4P. TECs seemed to be more susceptible to CA4P than NECs. The expression pattern of VE-cadherin in TECs was abnormal compared with that of NECs, suggesting that VE-cadherin may have functional abnormalities in these cells. Taken together, these results indicate that the tumor-vascular selectivity of CA4P may be related to VE-cadherin dysfunction in TECs.

Topics: Animals; Bibenzyls; Cells, Cultured; Dogs; Endothelial Cells; Endothelium, Vascular; Humans; Neoplasms; Neovascularization, Pathologic; Phosphates; Stilbenes

Combretastatin A4 phosphate (CA4P) is a novel vascular disrupting agent for cancer therapy. However, frequent dosing and negative patient compliance have been encountered over CA4P by injection administration due to its quite short-term action and acute side effects. Therefore, it is significant to develop an oral formulation of CA4P. We established a novel method to prepare CA4P-loaded nanoparticles (CA4P-NPs) for oral administration by combining methoxy poly(ethylene glycol)-b-polylactide (PELA) and poly(d,l-lactic-co-glycolic acid) (PLGA) polymers. Transport study in vitro was evaluated on Madin-Darby canine kidney cell models, and antitumor effect evaluation in vivo was performed on S180 subcutaneous xenotransplanted tumor models in mice. The highest entrapment efficiency of CA4P-NPs was achieved when the weight ratio of PELA to PLGA was optimized to 1:1. The apparent permeability coefficient of CA4P-NPs was found to be 2.08-fold higher than that of free CA4P in transport study. CA4P-NPs reached an absolute bioavailability of 77.6% with the tumor inhibition ratio of 41.2% that was significantly superior to free CA4P. These results suggest a promising application of this composite nanoparticle for the oral delivery of water-soluble drugs.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Cell Line, Tumor; Dogs; Drug Carriers; Lactic Acid; Madin Darby Canine Kidney Cells; Mice; Nanoparticles; Neoplasms; Permeability; Polyesters; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Solubility; Stilbenes; Water

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

Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines. The amino-based parent anticancer agents 7, 8, 32 (also referred to as KGP05) and 33 (also referred to as KGP156) demonstrated potent cytotoxicity (GI50=0.11-40nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50=0.62-1.5μM). The various prodrug conjugates and their corresponding salts were investigated for cleavage by the enzyme leucine aminopeptidase (LAP). Four of the glycine water-soluble AAPCs (16, 18, 44 and 45) showed quantitative cleavage by LAP, resulting in the release of the highly cytotoxic parent drug, whereas partial cleavage (<10-90%) was observed for other prodrugs (15, 17, 24, 38 and 39). Eight of the nineteen AAPCs (13-16, 42-45) showed significant cytotoxicity against selected human cancer cell lines. The previously reported CA1-diamine analog and its corresponding hydrochloride salt (8 and 10, respectively) caused extensive disruption (at a concentration of 1.0μM) of human umbilical vein endothelial cells growing in a two-dimensional tubular network on matrigel. In addition, compound 10 exhibited pronounced reduction in bioluminescence (greater than 95% compared to saline control) in a tumor bearing (MDA-MB-231-luc) SCID mouse model 2h post treatment (80mg/kg), with similar results observed upon treatment (15mg/kg) with the glycine amino-dihydronaphthalene AAPC (compound 44). Collectively, these results support the further pre-clinical development of the most active members of this structurally diverse collection of water-soluble prodrugs as promising anticancer agents functioning through a mechanism involving vascular disruption.

Topics: Amino Acids; Animals; Antineoplastic Agents; Bibenzyls; Breast; Breast Neoplasms; Cell Line, Tumor; Coumarins; Drug Design; Female; Humans; Mice; Mice, SCID; Naphthalenes; Neoplasms; Optical Imaging; Prodrugs; Solubility; Structure-Activity Relationship; Tubulin; Water

A series of 2-aryl-imidazo-pyridines/pyrazines derivatives has been designed, synthesized and evaluated for their biological activities. Among them, several investigated compounds (1a, 3b and 3d) displayed potent antiproliferative activity against HeLa cell, and also displayed comparable tubulin polymerization inhibitory activity to colchicine. These studies provided a new molecular scaffold for the further development of antitumor agents that target tubulin.

Topics: Antineoplastic Agents; Cell Proliferation; Colchicine; Crystallography, X-Ray; HeLa Cells; Humans; Imidazoles; Models, Molecular; Neoplasms; Pyridines; Tubulin; Tubulin Modulators

To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Carriers; Drug Delivery Systems; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Nanoparticles; Neoplasms; Oligopeptides; Silicon Dioxide; Stilbenes; Tissue Distribution; Xenograft Model Antitumor Assays

A series of 12 novel acylhydrazone, chalcone and amide-bridged analogues of combretastatin A-4 were designed and synthesized toward tubulin. All these compounds were determined by elemental analysis, (1)H NMR, and MS. Among them, compound 7 with acylhydrazone-bridge, bearing a benzyl at the indole-N position, was identified as a potent antiproliferative agent against a panel of cancer cell lines with IC50 values ranging from 0.08 to 35.6 μM. In contrast, its cytotoxic effects on three normal human cells were minimal. Cellular studies have revealed that the induction of apoptosis by compound 7 was associated with a collapse of mitochondrial membrane potential, accumulation of reactive oxygen species, alterations in the expression of some cell cycle-related proteins (Cyclin B1, Cdc25c, Cdc2, P21) and some apoptosis-related proteins (Bax, PARP, Bcl-2, Caspase3). The docking mode showed the binding posture of CA-4 and compound 7 are similar in the colchicine-binding pocket of tubulin, as confirmed by colchicine-tubulin competitive binding assay, tubulin polymerization inhibitory activity, extracellular protein expression determination assay and confocal immunofluorescence microscopy. In vivo study, compound 7 effectively inhibited A549 xenograft tumor growth without causing significant loss of body weight suggesting that compound 7 is a promising new antimitotic agent with clinical potential.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Chalcone; Drug Screening Assays, Antitumor; Humans; Hydrazones; Mice; Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Xenograft Model Antitumor Assays

A novel series of tubulin polymerization inhibitors, based on the 1-(3',4',5'-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta- and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3'-chloro-4'-ethoxyphenyl moiety was a good surrogate for the CA-4 B-ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; HeLa Cells; HL-60 Cells; HT29 Cells; Humans; Jurkat Cells; MCF-7 Cells; Mice; Models, Molecular; Molecular Structure; Neoplasms; Stilbenes; Tubulin Modulators; Xenograft Model Antitumor Assays

Tubulin binding agents (TBAs) are commonly used in cancer therapy as antimitotics. It has been described that TBAs, like combretastatin A-4 (CA-4), present also antivascular activity and among its derivatives we identified TR-764 as a new inhibitor of tubulin polymerization, based on the 2-(alkoxycarbonyl)-3-(3',4',5'-trimethoxyanilino)benzo[b]thiophene molecular skeleton. The antiangiogenic activity of TR-764 (1-10 nM) was tested in vitro on human umbilical endothelial cells (HUVECs), and in vivo, on the chick embryo chorioallantoic membrane (CAM) and two murine tumor models. TR-764 binding to tubulin triggers cytoskeleton rearrangement without affecting cell cycle and viability. It leads to capillary tube disruption, increased cell permeability, and cell motility reduction. Moreover it disrupts adherens junctions and focal adhesions, through mechanisms involving VE-cadherin/β-catenin and FAK/Src. Importantly, TR-764 is active in hypoxic conditions significantly reducing HIF-1α. In vivo TR-764 (1-100 pmol/egg) remarkably blocks the bFGF proangiogenic activity on CAM and shows a stronger reduction of tumor mass and microvascular density both in murine syngeneic and xenograft tumor models, compared to the lead compound CA-4P. Altogether, our results indicate that TR-764 is a novel TBA with strong potential as both antivascular and antitumor molecule that could improve the common anticancer therapies, by overcoming hypoxia-induced resistance mechanisms.

Topics: Actin Cytoskeleton; Aniline Compounds; Animals; Antigens, CD; beta Catenin; Cadherins; Cell Adhesion; Cell Membrane Permeability; Cell Movement; Chick Embryo; Chickens; Chorioallantoic Membrane; Fibroblast Growth Factors; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred C57BL; Neoplasms; Neovascularization, Physiologic; Stilbenes; Thiophenes; Tubulin Modulators; Vascular Endothelial Growth Factor A

A potent combretastatin A-4 (CA-4) like tubulin polymerization inhibitor 22b was found with strong antitumor activity previously. However, it easily undergoes cis-trans isomerization under natural light, and the resulting decrease in activity limits its further applications. In this study, we used quantum chemistry calculations to explore the molecular basis of its instability. Aided by the calculations, two rounds of structural optimization of 22b were conducted. Accelerated quantitative light stability testing confirmed that the stability of these designed compounds was significantly improved as predicted. Among them, compounds 1 and 3b displayed more potent inhibitory activity on tumor cell growth than 22b. In addition, the potent in vivo antitumor activity of compound 1 was confirmed. Quantum chemistry calculations were used in the optimization of stilbene-like molecules, providing new insight into stilbenoid optimization and important implications for the future development of novel CA-4-like tubulin polymerization inhibitors.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Cell Proliferation; Female; Humans; Mice; Mice, Inbred BALB C; Models, Molecular; Molecular Structure; Neoplasms; Quantum Theory; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Xenograft Model Antitumor Assays

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer.

Topics: Animals; Cell Division; Cell Line, Tumor; Cytotoxicity, Immunologic; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Indoles; Killer Cells, Natural; Mice; Mitosis; Neoplasms; NIH 3T3 Cells; Tubulin

A strategy for enhancing the treatment efficacy of nanomedicines within the central region of solid tumors is developed by combining nanomedicines and free small-molecule vascular disrupting agents (VDAs). The nanomedicines (cis-diamminedichloroplatinum-loaded nanoparticles) primarily target cells at the tumor periphery whereas the free small-molecule VDA (combretastatin A4 disodium phosphate) efficiently kills the cancer cells within the central regions of the tumor.

Topics: Acoustics; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Drug Therapy, Combination; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nanomedicine; Nanoparticles; Neoplasms; Stilbenes

To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH. This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells. The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control. Comparing with PEG-Phis/DOX/CA4, PEG-Phis/Pasp-DOX/CA4 exhibited enhanced cytotoxicity against DOX-sensitive and DOX-resistant cells (MCF-7 and MCF-7/ADR). Moreover, PEG-Phis/Pasp-DOX/CA4 resulted in enhanced therapeutic efficacy in drug-resistant tumors with reduced toxicity. These results suggested that this site-specific drug-releasing system could be exploited as a promising treatment for cancers with repeated administration.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Resistance; Female; Humans; Hydrogen-Ion Concentration; Mice, Inbred BALB C; Mice, Inbred ICR; Molecular Medicine; Neoplasms; Peptides; Stilbenes

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation; Cell Survival; Colchicine; Drug Screening Assays, Antitumor; Guanidines; Hedgehog Proteins; Humans; M Phase Cell Cycle Checkpoints; Mice; Molecular Docking Simulation; Neoplasms; Polymerization; Protein Binding; Pyrroles; Signal Transduction; Structure-Activity Relationship; Tubulin; Tubulin Modulators

A set of novel selenium-containing heterocyclic analogues of combretastatin A-4 (CA-4) have been designed and synthesised using a rigid 1,2,5-selenadiazole as a linker to fix the cis-orientation of ring-A and ring-B. All of the target compounds were evaluated for their in vitro anti-proliferative activities. Among these compounds, compounds 3a, 3i, 3n and 3q exhibited superior potency against different tumour cell lines with IC50 values at the nanomolar level. Moreover, compound 3n significantly induced cell cycle arrest in the G2/M phase, inhibited tubulin polymerisation into microtubules and caused microtubule destabilisation. A molecular modelling study of compound 3n was performed to elucidate its binding mode at the colchicine site in the tubulin dimer and to provide a basis for the further structure-guided design of novel CA-4 analogues.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Cell Cycle; Cell Proliferation; Drug Screening Assays, Antitumor; Flow Cytometry; Fluorescent Antibody Technique; Heterocyclic Compounds; Humans; Models, Molecular; Molecular Structure; Neoplasms; Selenium; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

We here describe the preparation of a series of hybrid molecules containing a combretastatin A-4 moiety and a pironetin analogue fragment connected through a spacer of variable length which includes a 1,2,3-triazole ring. The cytotoxic activities of these compounds have been measured. Relations between structure and cytotoxicity are discussed. Some of the tested compounds showed cytotoxicity values of the same order of magnitude as combretastatin A-4 and were less toxic than the latter compound for normal cells.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Cell Proliferation; Cells, Cultured; Drug Design; Drug Screening Assays, Antitumor; Flow Cytometry; HEK293 Cells; Humans; Molecular Structure; Neoplasms; Pyrones; Structure-Activity Relationship; Triazoles

A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6-8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9-11. The methoxy-, hydroxyl- and formyl- substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD50 values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Cell Line, Tumor; Coumarins; Drug Screening Assays, Antitumor; Ficusin; Furocoumarins; Humans; Molecular Structure; Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin Modulators

Preliminary biological data on 7-anilino-6-azaindoles (8-11) suggested that hydrophobic substituents at C7 contribute to enhancement of antiproliferative activity. A novel series of 7-aryl-6-azaindole-1-benzenesulfonamides (12-22) were developed and showed improved cytotoxicity compared to ABT751 (5). The conversion of C7 phenyl rings into C7 heterocycles led to a remarkable improvement of antiproliferative activity. Among all the synthetic products, 7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole (21) exhibited the most potent anticancer activity against KB, HT29, MKN45, and H460 cancer cell lines with IC50 values of 21.1, 32.0, 27.5, and 40.0 nM, respectively. Bioassays indicated that 21 not only inhibits tubulin polymerization by binding to tubulin at the colchicine binding site but also arrests the cell cycle at the G2/M phase with slight arrest at the sub-G1 phase. Compound 21 also functions as a vascular disrupting agent and dose-dependently inhibits tumor growth without significant change of body weight in an HT29 xenograft mouse model. Taken together, compound 21 has potential for further development as a novel class of anticancer agents.

Topics: Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Female; Heterocyclic Compounds, 2-Ring; HT29 Cells; Humans; Indoles; Inhibitory Concentration 50; Mice, Nude; Molecular Structure; Neoplasms; Polymerization; Sulfonamides; Tubulin; Xenograft Model Antitumor Assays

Novel 5,6-disubstituted pyridazin-3(2H)-one derivatives were designed and synthesized as combretastatin A-4 analogues. Our objective was to overcome the spontaneous cis to trans isomerization of the compound. We therefore replaced the cis-double bond with a pyridazine ring. The antiproliferative activity of the novel analogues was evaluated against four human cancer cell lines (HL-60, MDAMB- 435, SF-295 and HCT-8). We found that the analogues had little activity either against selected cell lines or against purified tubulin. Molecular modeling studies may account for their inactivity.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Conformation; Neoplasms; Pyridazines; Stilbenes; Tubulin

A series of cinnamic acyl 1,3,4-thiadiazole amide derivatives (6a-10e) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Among all the compounds, 10e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and A549 cell lines with IC(50) values of 0.28 and 0.52μg/mL, respectively. Compound 10e also exhibited significant tubulin polymerization inhibitory activity (IC(50)=1.16μg/mL). Docking simulation was performed to insert compound 10e into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 10e with potent inhibitory activity in tumor growth may be a potential anticancer agent.

Topics: Amides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cinnamates; Humans; Neoplasms; Thiadiazoles; Tubulin; Tubulin Modulators

Twenty-eight new substituted N-phenyl ureidobenzenesulfonate (PUB-SO) and 18 N-phenylureidobenzenesulfonamide (PUB-SA) derivatives were prepared. Several PUB-SOs exhibited antiproliferative activity at the micromolar level against the HT-29, M21, and MCF-7 cell lines and blocked cell cycle progression in S-phase similarly to cisplatin. In addition, PUB-SOs induced histone H2AX (γH2AX) phosphorylation, indicating that these molecules induce DNA double-strand breaks. In contrast, PUB-SAs were less active than PUB-SOs and did not block cell cycle progression in S-phase. Finally, PUB-SOs 4 and 46 exhibited potent antitumor activity in HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membranes, which was similar to cisplatin and combretastatin A-4 and without significant toxicity toward chick embryos. These new compounds are members of a promising new class of anticancer agents.

Topics: Animals; Anticarcinogenic Agents; Benzenesulfonates; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chick Embryo; Chorioallantoic Membrane; Cisplatin; DNA Breaks, Double-Stranded; Histones; HT29 Cells; Humans; Imidazolidines; Jurkat Cells; Neoplasms; Phenylurea Compounds; Phosphorylation; S Phase; Stilbenes; Structure-Activity Relationship

Fluorescein has been used for in vivo imaging to identify tumors. However, this technique presents several limitations, mainly due to its limited targeting efficiency, tissue autofluorescence and poor light penetration in tissue. In the present study, an alternative fluorescence imaging technique to localize tumors has been developed by using up-conversion nanoparticles (UCNs) and enhanced targeting approaches. A folic acid molecule is conjoined with UCNs (NaYF(4): Yb(3+), Er(3+)) to improve the tumor-specificity; the UCN is also loaded with the microtubule inhibitor CA4P, to further improve the local delivery of particles in the tumor. The proposed imaging technique combines several well-established individual concepts into one novel integrated procedure and significantly improves its tumor-imaging capability: the near-infrared excitation for UCNs minimizes tissue autofluorescence and allows imaging into deeper tissue; the improvement in the signal to noise ratio (SNR) is at least a magnitude better than that of a conventional fluorescence imaging technique, and the modification of UCNs with folic acid significantly improves the tumor targeting efficiency by utilizing its affinity for the folic acid receptor that is often over expressed in tumors. The loading of CA4P further helps UCNs to cross blood vessel walls to reach tumor cells by depolymerizing the microtubules of endothelial cells. The integrated nanoparticle possesses the near-infrared-identical optical properties of UCNs alone, thus achieving a highly effective fluorescence imaging probe. The results demonstrated that the proposed method provides an excellent alternative for tumor localization and a potential traceable vehicle for highly efficient drug delivery.

Topics: Animals; Diagnostic Imaging; Erbium; Fluorescent Dyes; Fluorides; Folic Acid; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Nude; Microtubules; Nanoparticles; Neoplasms; Signal-To-Noise Ratio; Stilbenes; Tubulin Modulators; Ytterbium; Yttrium

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

A series of new 4β-acrylamidopodophyllotoxin derivatives (13a-o) were synthesized by coupling of substituted acrylic acids (10a-l and 11m-o) to the 4β-aminopodophyllotoxin. The synthesized derivatives 13a-o were evaluated for their cytotoxicity against five human cancer cell lines (breast, oral, colon, lung and ovarian). These podophyllotoxin conjugates have shown promising activity with GI₅₀ values ranging from <0.1 to 0.29 μM. Some of the compounds 13j, 13k and 13l that showed significant antiproliferative activity were also evaluated for related cytotoxic effects in MCF-7 cells, and compared to etoposide. These compounds (13j, 13k and 13l) showed G2/M cell cycle arrest and the apoptotic event was found to be due to both the single-strand DNA breaks as observed by comet assay as well as double-strand breaks as observed by the large accumulation of gamma H2AX foci.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Comet Assay; DNA; DNA Damage; Drug Screening Assays, Antitumor; Etoposide; Humans; Neoplasms; Podophyllotoxin

(R,S)-1 is a potent antimitotic compound. (R)-1·HCl and (S)-1·HCl were synthesized from (R)- and (S)-3-methyladipic acid. Both enantiomers were potent inhibitors of cell proliferation and caused cellular microtubule loss and mitotic arrest. They inhibited purified tubulin assembly and the binding of [(3)H]colchicine to tubulin, with (S)-1 being about twice as potent. Cytotoxicity against 60 tumor cell lines, however, indicated that the (S)-isomer was 10- to 88-fold more potent than the (R)-isomer.

Topics: Aniline Compounds; Antimitotic Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cytotoxins; Humans; Microtubules; Mitosis; Neoplasms; Pyrimidines; Stereoisomerism; Structure-Activity Relationship; Tubulin Modulators; Tumor Cells, Cultured

A wide variety of small molecules with diverse molecular scaffolds inhibit microtubule formation. In this article we report a one-pot procedure for the preparation of a novel 2-(N-pyrrolidinyl)-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole in which the size of the substituent at the C-2 position of the thiazole ring plays an essential role in compound activity. The most active agent (3f) inhibited at submicromolar concentrations the growth of tumor cell lines. It also inhibited tubulin polymerization with an activity quantitatively similar to that of CA-4, and treatment of HeLa cells resulted in their arrest at the G2-M phase of the cell cycle. Furthermore, 3f was effective against multidrug resistant cancer cells and inhibited the growth of the HT-29 xenograft in a nude mouse model. This indicated that 3f is a promising new antimitotic agent with encouraging preclinical potential.

Topics: Animals; Antineoplastic Agents; Caspase 3; Cell Line, Tumor; Cell Proliferation; Female; G2 Phase; HeLa Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Thiazoles; Tubulin; Tubulin Modulators

In this work we studied the functional differences between the microcirculation of murine tumours that express only single isoforms of vascular endothelial growth factor-A (VEGF), namely VEGF120 and VEGF188, and the effect of VEGF receptor tyrosine kinase (VEGF-R TK) inhibition on their functional response to the vascular disrupting agent, combretastatin A-4 phosphate (CA-4-P), using measurement of red blood cell (RBC) velocity by a 'keyhole' tracking algorithm. RBC velocities in VEGF188 tumours were unaffected by chronic treatment with a VEGF-R tyrosine kinase inhibitor, SU5416, whereas RBC velocities in VEGF120 tumours were significantly increased compared to control VEGF120 tumours. This effect was accompanied by a reduced tumour vascularisation. Pre-treatment of VEGF120 tumours with SU5416 made them much more resistant to CA-4-P treatment, with a RBC velocity response that was very similar to that of the more mature vasculature of the VEGF188 tumours. This study shows that vascular normalisation following anti-angiogenic treatment with a VEGF-R tyrosine kinase inhibitor reduced the response of a previously sensitive tumour line to CA-4-P.

Topics: Animals; Antineoplastic Agents; Blood Vessels; Erythrocytes; Fluorescent Dyes; Gene Expression Regulation, Neoplastic; Hemodynamics; Male; Mice; Neoplasms; Protein Isoforms; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Stilbenes; Vascular Endothelial Growth Factor A

Mathematical modeling techniques have been widely employed to understand how cancer grows, and, more recently, such approaches have been used to understand how cancer can be controlled. In this manuscript, a previously validated hybrid cellular automaton model of tumor growth in a vascularized environment is used to study the antitumor activity of several vascular-targeting compounds of known efficacy. In particular, this model is used to test the antitumor activity of a clinically used angiogenesis inhibitor (both in isolation, and with a cytotoxic chemotherapeutic) and a vascular disrupting agent currently undergoing clinical trial testing. I demonstrate that the mathematical model can make predictions in agreement with preclinical/clinical data and can also be used to gain more insight into these treatment protocols. The results presented herein suggest that vascular-targeting agents, as currently administered, cannot lead to cancer eradication, although a highly efficacious agent may lead to long-term cancer control.

Topics: Algorithms; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blood Vessels; Computer Simulation; Cytotoxins; Dacarbazine; Glioblastoma; Humans; Models, Biological; Neoplasms; Stilbenes; Temozolomide; Treatment Outcome

Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC(50) values from 4.4 to 15 μm against both cell lines. A single-crystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly 'twisted' conformation similar to that of combretastatin A-4. At a concentration of 30 μm, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Cell Line, Tumor; Cell Survival; Chalcones; Drug Design; Humans; Ketones; Mice; Models, Molecular; Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin Modulators

The central role of microtubules in cell division and mitosis makes them a particularly important target for anticancer agents. On our early publication, we found that a series of 2-(3',4',5'-trimethoxybenzoyl)-3-aminobenzo[b]thiophenes exhibited strong antiproliferative activity in the submicromolar range and significantly arrested cells in the G2-M phase of the cell cycle and induced apoptosis. In order to investigate the importance of the amino group at the 3-position of the benzo[b]thiophene skeleton, the corresponding 3-unsubstituted and methyl derivatives were prepared. A novel series of inhibitors of tubulin polymerization, based on the 2-(3,4,5-trimethoxybenzoyl)-benzo[b]thiophene molecular skeleton with a methoxy substituent at the C-4, C-5, C-6 or C-7 position on the benzene ring, was evaluated for antiproliferative activity against a panel of five cancer cell lines, for inhibition of tubulin polymerization and for cell cycle effects. Replacing the methyl group at the C-3 position resulted in increased activity compared with the corresponding 3-unsubstituted counterpart. The structure-activity relationship established that the best activities were obtained with the methoxy group placed at the C-4, C-6 or C-7 position. Most of these compounds exhibited good growth inhibition activity and arrest K562 cells in the G2-M phase via microtubule depolymerization.

Topics: Animals; Anisoles; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Models, Molecular; Neoplasms; Rats; Structure-Activity Relationship; Thiophenes; Tubulin; Tubulin Modulators

A series of novel chalcone linked imidazolones were prepared and evaluated for their anti-cancer activity against a panel of 53 human tumour cell lines derived from nine different cancer types: leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast. Some of these hybrids (6, 7 and 8) showed good anti-cancer activity with GI(50) values ranging from 1.26 to 13.9 microM. When breast carcinoma cells (MCF-7) were treated with 10 microM concentration of compounds TMAC, CA-4, 6 and 8 cell cycle arrest was observed in G2/M phase. Surprisingly, the increased concentration of the same compound to 30 microM caused accumulation of cells in G0/G1 phase of the cell cycle.

Topics: Antineoplastic Agents; Cell Line, Tumor; Chalcone; Drug Screening Assays, Antitumor; Humans; Imidazoles; Neoplasms

The use of peptide receptors as targets for tumor-selective therapies was envisaged years ago with the findings that receptors for different endogenous regulatory peptides are overexpressed in several primary and metastatic human tumors, and can be used as tumor antigens. Branched peptides can retain or even increase, through multivalent binding, the biological activity of a peptide and are very resistant to proteolysis, thus having a markedly higher in vivo activity compared with the corresponding monomeric peptides. Oligo-branched peptides, containing the human regulatory peptide neurotensin (NT) sequence, have been used as tumor-specific targeting agents. These peptides are able to selectively and specifically deliver effector units, for cell imaging or killing, to tumor cells that overexpress NT receptors. Results obtained with branched NT conjugated to different functional units for tumor imaging and therapy indicate that branched peptides are promising novel multifunctional targeting molecules. This study is focused on the role of the releasing pattern of drug-conjugated branched NT peptides. We present results obtained with oligo-branched neurotensin peptides conjugated to 6-mercaptopurin (6-MP), combretastain A-4 (CA4) and monastrol (MON). Drugs were conjugated to oligo-branched neurotensin through different linkers, and the mode-of-release, together with cytotoxicity, was studied in different human cancer cell lines. The results show that branched peptides are very promising pharmacodelivery options. Among our drug-armed branched peptides, NT4-CA4 was identified as a candidate for further development and evaluation in preclinical pharmacokinetic and pharmacodynamic studies. This peptide-drug exhibits significant activity against pancreas and prostate human cancer cells. Consequently, this derivative is of considerable interest due to the high mortality rates of pancreas neuroendocrine tumors and the high incidence of prostate cancer.

Topics: Antineoplastic Agents; Drug Design; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Humans; Mercaptopurine; Neoplasms; Neurotensin; Peptides; Pyrimidines; Receptors, Neurotensin; Stilbenes; Thiones

Nuclear spin hyperpolarization can dramatically increase the sensitivity of the (13)C magnetic resonance experiment, allowing dynamic measurements of the metabolism of hyperpolarized (13)C-labeled substrates in vivo. Here, we report a preclinical study of the response of lymphoma tumors to the vascular disrupting agent (VDA), combretastatin-A4-phosphate (CA4P), as detected by measuring changes in tumor metabolism of hyperpolarized [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate. These measurements were compared with dynamic contrast agent-enhanced magnetic resonance imaging (DCE-MRI) measurements of tumor vascular function and diffusion-weighted MRI (DW-MRI) measurements of the tumor cell necrosis that resulted from subsequent loss of tumor perfusion. The rate constant describing flux of hyperpolarized (13)C label between [1-(13)C]pyruvate and lactate was decreased by 34% within 6 hours of CA4P treatment and remained at this lower level at 24 hours. The rate constant describing production of labeled malate from hyperpolarized [1,4-(13)C(2)]fumarate increased 1.6-fold and 2.5-fold at 6 and 24 hours after treatment, respectively, and correlated with the degree of necrosis detected in histologic sections. Although DCE-MRI measurements showed a substantial reduction in perfusion at 6 hours after treatment, which had recovered by 24 hours, DW-MRI showed no change in the apparent diffusion coefficient of tumor water at 6 hours after treatment, although there was a 32% increase at 24 hours (P < 0.02) when regions of extensive necrosis were observed by histology. Measurements of hyperpolarized [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate metabolism may provide, therefore, a more sustained and sensitive indicator of response to a VDA than DCE-MRI or DW-MRI, respectively.

Topics: Angiogenesis Inhibitors; Animals; Carbon Isotopes; Contrast Media; Diffusion Magnetic Resonance Imaging; Fumarates; Injections, Intravenous; Magnetic Resonance Spectroscopy; Mice; Neoplasms; Neovascularization, Pathologic; Pyruvic Acid; Stilbenes; Time Factors

Highly cytotoxic 1,5-diaryl-1H-imidazoles were studied to clarify the relationship between cytotoxicity and activity as vascular disrupting agents (VDA). All the compounds disorganized the tubulin cytoskeleton, affected endothelial cell morphology and capillary formation in vitro, and caused vessel shutdown and tumor necrosis in vivo, thus confirming their vascular disrupting properties. Nonetheless, the substitution patterns on the imidazole ring, responsible for greater interaction energy with tubulin and higher cytotoxicity, were not associated to greater vascular disrupting activity.

Topics: Animals; Binding Sites; Blood Vessels; Cell Line, Tumor; Endothelial Cells; Humans; Hydrochloric Acid; Imidazoles; Isomerism; Mice; Neoplasms; Tubulin

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

A novel series of dihydronaphthalene and benzosuberene analogs bearing structural similarity to the combretastatins in terms of 1,2-diarylethene, trimethoxyphenyl, and biaryl functionality has been synthesized. The compounds have been evaluated in regard to their ability to inhibit tubulin assembly and for their cytotoxicity against selected human cancer cell lines. From this series of compounds, benzosuberene analogs 2 and 4 inhibited tubulin assembly at concentrations comparable to that of combretastatin A-4 (CA4) and combretastatin A-1 (CA1). Furthermore, analog 4 demonstrated remarkable cytotoxicity against the three human cancer cell lines evaluated (for example GI(50)=0.0000032 microM against DU-145 prostate carcinoma).

Topics: Antineoplastic Agents; Benzocycloheptenes; Bibenzyls; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Structure; Naphthalenes; Neoplasms; Stereoisomerism; Structure-Activity Relationship; Tubulin

A series of aroylnaphthalene derivatives were prepared as bioisosteres of combrestatin A-4 and evaluated for anticancer activity. 2-Amino-1-aroylnaphthalene and 2-hydroxy-1-aroylnaphthalene, 9 and 8, respectively, showed strong antiproliferative activity with IC(50) values of 2.1-26.3 nM against a panel of human cancer cell lines including multiple-drug resistant cell line. Compound 9 demonstrated better antiproliferative activity and has a comparable tubulin binding efficacy as that of colchicine.

Topics: Anisoles; Cell Line, Tumor; Cell Proliferation; Chemistry, Pharmaceutical; Drug Design; Drug Screening Assays, Antitumor; Humans; Indoles; Inhibitory Concentration 50; Models, Chemical; Naphthalenes; Neoplasms; Structure-Activity Relationship; Tubulin; Tubulin Modulators

Combretastatin-A4-phosphate (CA4P) acts most effectively against immature tumour vasculature. We investigated whether histological angiogenic profile can explain the differential sensitivity of human tumours to CA4P, by correlating the kinetic changes demonstrated by dynamic MRI (DCE-MRI) in response to CA4P, with tumour immunohistochemical angiogenic markers. Tissue was received from 24 patients (mean age 59, range 32-73, 18 women, 6 men). An angiogenic profile was performed using standard immunohistochemical techniques. Dynamic MRI data were obtained for the same patients before and 4 h after CA4P. Three patients showed a statistically significant fall in K(trans) following CA4P, and one a statistically significant fall in IAUGC(60). No statistically significant correlations were seen between the continuous or categorical variables and the DCE-MRI kinetic parameters other than between ang-2 and K(trans) (P=0.044). In conclusion, we found no strong relationships between changes in DCE-MRI kinetic variables following CA4P and the immunohistochemical angiogenic profile.

Topics: Actins; Adult; Aged; Angiogenic Proteins; Antigens, CD; Antineoplastic Agents, Phytogenic; Endoglin; Endothelium, Vascular; Female; Gadolinium DTPA; Humans; Immunohistochemistry; Integrin beta3; Magnetic Resonance Angiography; Male; Middle Aged; Neoplasms; Neovascularization, Pathologic; Receptors, Cell Surface; Stilbenes

To investigate the use of the transverse magnetic resonance imaging (MRI) relaxation rate R(2)(*) (s(-1)) as a biomarker of tumor vascular response to monitor vascular disrupting agent (VDA) therapy.. Multigradient echo MRI was used to quantify R(2)(*) in rat GH3 prolactinomas. R(2)(*) is a sensitive index of deoxyhemoglobin in the blood and can therefore be used to give an index of tissue oxygenation. Tumor R(2)(*) was measured before and up to 35 min after treatment, and 24 h after treatment with either 350 mg/kg 5,6-dimethylxanthenone-4-acetic acid (DMXAA) or 100 mg/kg combretastatin-A4-phosphate (CA4P). After acquisition of the MRI data, functional tumor blood vessels remaining after VDA treatment were quantified using fluorescence microscopy of the perfusion marker Hoechst 33342.. DMXAA induced a transient, significant (p < 0.05) increase in tumor R(2)(*) 7 min after treatment, whereas CA4P induced no significant changes in tumor R(2)(*) over the first 35 min. Twenty-four hours after treatment, some DMXAA-treated tumors demonstrated a decrease in R(2)(*), but overall, reduction in R(2)(*) was not significant for this cohort. Tumors treated with CA4P showed a significant (p < 0.05) reduction in R(2)(*) 24 h after treatment. The degree of Hoechst 33342 uptake was associated with the degree of R(2)(*) reduction at 24 h for both agents.. The reduction in tumor R(2)(*) or deoxyhemoglobin levels 24 h after VDA treatment was a result of reduced blood volume caused by prolonged vascular collapse. Our results suggest that DMXAA was less effective than CA4P in this rat tumor model.

Topics: Angiogenesis Inhibitors; Animals; Biomarkers, Tumor; Female; Hemoglobins; Magnetic Resonance Imaging; Neoplasms; Neovascularization, Pathologic; Rats; Rats, Inbred WF; Stilbenes; Xanthones

The diketopiperazine NPI-2358 is a synthetic analog of NPI-2350, a natural product isolated from Aspergillus sp., which depolymerizes microtubules in A549 human lung carcinoma cells. Although structurally different from the colchicine-binding site agents reported to date, NPI-2358 binds to the colchicine-binding site of tubulin. NPI-2358 has potent in-vitro anti-tumor activity against various human tumor cell lines and maintains activity against tumor cell lines with various multidrug-resistant (MDR) profiles. In addition, when evaluated in proliferating human umbilical vein endothelial cells (HUVECs), concentrations as low as 10 nmol/l NPI-2358 induced tubulin depolymerization within 30 min. Furthermore, NPI-2358 dose dependently increases HUVEC monolayer permeability--an in-vitro model of tumor vascular collapse. NPI-2358 was compared with three tubulin-depolymerizing agents with vascular-disrupting activity: colchicine, vincristine and combretastatin A-4 (CA4). Results showed that the activity of NPI-2358 in HUVECs was more potent than either colchicine or vincristine; the profile of CA4 approached that of NPI-2358. Altogether, our data show that NPI-2358 is a potent anti-tumor agent which is active in MDR tumor cell lines, and is able to rapidly induce tubulin depolymerization and monolayer permeability in HUVECs. These data warrant further evaluation of NPI-2358 as a vascular-disrupting agent in vivo. Currently, NPI-2358 is in preclinical development for the treatment of cancer.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Cell Membrane Permeability; Cell Survival; Colchicine; Dextrans; Diketopiperazines; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Endothelial Cells; Endothelium, Vascular; Fluorescein-5-isothiocyanate; HL-60 Cells; HT29 Cells; Humans; Imidazoles; Inhibitory Concentration 50; Jurkat Cells; Microtubules; Neoplasms; Piperazines; Stilbenes; Time Factors; Tubulin; Vincristine

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Blood Vessels; Drug Evaluation; Endothelial Cells; Europe; Humans; Ligands; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic; Stilbenes

Topics: Antineoplastic Agents, Phytogenic; Cardiovascular System; Clinical Trials, Phase I as Topic; Coronary Disease; Electrocardiography; Heart Rate; Humans; Neoplasms; Safety; 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

Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Delivery Systems; Humans; Neoplasms; Stilbenes; Treatment Outcome; Tubulin Modulators

Topics: Antineoplastic Agents; Azetidines; Benzylamines; Blood Coagulation Factors; Clinical Trials as Topic; Endothelium, Vascular; Fibrinolytic Agents; Fondaparinux; Hemostasis; Humans; Neoplasms; Neovascularization, Pathologic; Oligosaccharides; Polysaccharides; Stilbenes; Thrombosis

The most likely clinical application of vascular targeting agents (VTAs) is in combination with more conventional therapies. In this study, we report on preclinical studies in which VTAs were combined with hyperthermia and/or radiation.. A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was treated when at 200 mm3 in size. The VTAs were combretastatin A-4 disodium phosphate (CA4DP, 25 mg/kg), flavone acetic acid (FAA, 150 mg/kg), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, 20 mg/kg), and were all injected i.p. Hyperthermia and radiation were locally administered to tumors of restrained, nonanesthetized mice, and response was assessed using either a tumor growth or tumor control assay.. Heating tumors at 41.5 degrees C gave rise to a linear relationship between the heating time and tumor growth with a slope of 0.02. This slope was increased to 0.06, 0.09, and 0.08, respectively, by injecting the VTAs either 30 min (CA4DP), 3 h (FAA), or 6 h (DMXAA) before heating. The radiation dose (+/-95% confidence interval) that controls 50% of treated tumors (the TCD(50) value) was estimated to be 53 Gy (51-55 Gy) for radiation alone. This was decreased to 48 Gy (46-51 Gy), 45 Gy (41-49 Gy), and 42 Gy (39-45 Gy), respectively, by injecting CA4DP, DMXAA, or FAA 30-60 min after irradiating. These values were further decreased to around 28-33 Gy if the tumors of VTA-treated mice were also heated to 41.5 degrees C for 1 h, starting 4 h after irradiation, and this effect was much larger than the enhancement seen with either 41.5 degrees C or even 43 degrees C alone.. Our preclinical studies and those of others clearly demonstrate that VTAs can enhance tumor response to hyperthermia and/or radiation and support the concept that such combination studies should be undertaken clinically for the full potential of VTAs to be realized.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Dose-Response Relationship, Radiation; Flavonoids; Hyperthermia, Induced; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Stilbenes; Temperature; Time Factors; Tumor Cells, Cultured; X-Rays; Xanthenes; Xanthones

To compare the ability of combretastatin A-4 disodium phosphate (CA4DP) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to change tissue blood perfusion.. The tissues were a C3H mouse mammary carcinoma and various murine normal tissues, with perfusion measured using the 86RbCl extraction technique.. CA4DP (250mg/kg; i.p.) reduced tumour perfusion to 34% of that seen in controls within 1 h of injection. It was maintained at this for at least 6 h, returning to control levels by 24 h. This decrease was dose-dependent. DMXAA (25mg/kg; i.p.) caused a 79% reduction in tumour perfusion 6h after injection; no recovery was observed even after 24 h. DMXAA showed no changes at doses below 10 mg/kg. Both CA4DP and DMXAA increased perfusion in the gut, kidney, bladder and lung, while decreasing splenic perfusion. CA4DP tended to decrease perfusion in muscle, while DMXAA increased liver perfusion. These changes in normal tissue perfusion were generally less than those changes seen in tumours. No significant changes were seen in skin.. CA4DP and DMXAA produced a selective and significant reduction in tumour perfusion, but the pattern of change was different. These results suggest how these vascular targeting drugs should be combined with more conventional therapies.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Blood; Digestive System; Dose-Response Relationship, Drug; Female; Kidney; Liver; Lung; Mice; Mice, Inbred C3H; Muscles; Neoplasm Transplantation; Neoplasms; Perfusion; Skin; Spleen; Stilbenes; Time Factors; Tissue Distribution; Tumor Cells, Cultured; Urinary Bladder; Xanthenes; Xanthones

To investigate the activity of combretastatin A-4 disodium phosphate in a transplanted C3H mouse mammary carcinoma and several murine spontaneous tumors.. The C3H mammary carcinoma was grown in the right rear foot of female CDF1 mice and treated when 200 mm3 in size. Spontaneous tumors (341-1437 mm3 in size) arose at different sites in female CDF1 mice that, 19-21 months earlier, had been irradiated. Oxygen partial pressure (pO2) distributions in the C3H tumors were measured with an Eppendorf oxygen electrode at various times after injecting combretastatin (100 mg/kg, i.p.) in restrained, nonanesthetized mice. Immediately after measurement, tumors were excised and necrotic fraction determined from histological sections. In the spontaneous tumors, pO2 was measured before and 3 h after giving combretastatin. The location of these spontaneous tumors required that measurements be made in anesthetised animals, achieved by injecting a mixture of hypnorm and diazepam.. In untreated C3H tumors, the mean (+/- 1 SE) percentage of pO2 values < or = 2.5 mmHg was 32% (+/- 11). This was significantly (Student's t-test; p < 0.05) increased to 74% (+/- 4) within 1 h after injecting combretastatin, and remained at this level for at least 6 h, although some recovery was seen at 12 and 24 h. The necrotic fraction in control tumors was 1.9% (+/- 0.4) and this was significantly increased to 16.1% (+/- 3.7) 24 h after drug administration. In spontaneous tumors, the pO2 measurements indicated that 5 of 6 showed some response to combretastatin, although the degree of change was variable.. Combretastatin increased tumor hypoxia and necrosis in the C3H mammary carcinoma, consistent with the induction of vascular damage. Drug-induced changes in pO2 were also found in spontaneous tumors, suggesting that the activity of this drug is not restricted to transplanted tumors alone.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Hypoxia; Drug Screening Assays, Antitumor; Female; Mammary Neoplasms, Experimental; Mice; Necrosis; Neoplasms; Oxygen Consumption; Partial Pressure; Stilbenes

Selective induction of vascular damage within tumors represents an emerging approach to cancer treatment. Histological studies have shown that several tubulin-binding agents can induce vascular damage within tumors but only at doses approximating the maximum tolerated dose, which has limited their clinical applicability. In this study, we show that the combretastatin A-4 prodrug induces vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. In vitro studies indicate that a short drug exposure results in profound long-term antiproliferative/cytotoxic effects against proliferating endothelial cells but not cells that are quiescent prior to and during drug exposure. Vascular shutdown, within experimental and human breast cancer models in vivo following systemic drug administration, was demonstrated with a reduction in functional vascular volume of 93% at 6 h following drug administration and persisted over the next 12 h, with corresponding histology consistent with hemorrhagic necrosis resulting from vascular damage. These actions against tumor vasculature and the broad therapeutic window demonstrate the clinical potential of these drugs and warrant further study to elucidate the mechanisms responsible for the antivascular effects of combretastatin A-4.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Endothelium, Vascular; Hindlimb; Humans; Mice; Mice, Inbred CBA; Neoplasms; Neoplasms, Experimental; Neovascularization, Pathologic; Perfusion; Prodrugs; Rats; Stilbenes

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Division; Endothelium, Vascular; Humans; Microtubules; Neoplasms; Phytotherapy; Plants; Protein Binding; Stilbenes; Tubulin

The tubulin-binding natural product combretastatin A-4 (CA-4) was tested for antitumor activity against fresh human tumors in vitro and 2 mouse tumors, both in vitro and in vivo. In colony forming assays using 10% fetal bovine serum, CA-4 was inhibitory in 27/40 human ovary cancers with a mean IC50 of 3.18 micrograms/mL for a 1-hour exposure (n = 35 specimens) and 0.27 microgramf1p4for a continuous exposure to CA-4 for 11-14 days (n = 5 specimens). Murine B-16 melanoma and P-388 leukemia were also highly sensitive to CA-4 in vitro with an identical IC50 value of 0.0007 micrograms/mL for continuous drug exposure for 8 days. Comparable in vitro cell culture studies performed in serum concentrations higher than 10%, revealed a significant loss of cytotoxic potency. Using the same reversed-phase HPLC technique as developed for paclitaxel, CA-4 was shown to bind to serum proteins (> or = 30,000 mw) > 99% and to albumin approximately 70%. CA-4 was only marginally active (25% increased lifespan) in DBA/2 mice bearing P-388 leukemia who were given doses of 100 mg/kg IP on either days, 1, 5 and 9 (p = 0.075 by Wilcoxon analysis) or on consecutive days 1-9 (p = 0.19 compared to control). A higher IP dose of 150 mg/kg on days 1, 5 and 9 did not delay subcutaneous B-16 melanoma tumor growth in C57/B1 mice. These findings demonstrate a substantial loss of antitumor efficacy for CA-4 in physiologic serum concentrations in vitro. No consistent antitumor activity was observed in two murine tumor models in vivo.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cattle; Cell Division; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Proteins; Neoplasms; Phosphates; Protein Binding; Stilbenes; Tubulin; Tubulin Modulators; Tumor Cells, Cultured