zd-6126 and Neoplasms

Vascular disrupting agents (VDAs) have presented a new kind of anti-cancer drug in recent years. VDAs take advantage of the weakness of established tumor endothelial cells and their supporting structures. In contrast to anti-angiogenic therapy, which inhibits the outgrowth of new blood vessels, vascular targeting treatments selectively attack the existing tumor vasculature. Here we summarized the anti-tumor activities, mechanisms and clinical applications of small molecule VDAs.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Bibenzyls; Diphosphates; Endothelial Cells; Humans; Molecular Structure; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Organophosphorus Compounds; Serine; Stilbenes; Tubulin Modulators; Xanthones

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

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

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

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

AstraZeneca is developing ZD-6126, one of the ANG-400 series of vascular-targeting and tubulin-binding agents under license from Angiogene Pharmaceuticals Ltd, for the potential treatment of cancer.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drugs, Investigational; Humans; Neoplasms; Organophosphorus Compounds

ZD6126 is a novel vascular-targeting agent that disrupts the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor necrosis. This Phase I clinical study was conducted to evaluate the dose and administration schedule of ZD6126.. Adult patients with solid tumors refractory to existing treatments received a 10-min, single-dose intravenous infusion of ZD6126 every 14 or 21 days. Subsequent dose escalation was performed, based on the incidence of adverse events (AEs) within the first cycle of drug administration. Blood samples were obtained for pharmacokinetic analysis, and the effects of ZD6126 on tumor vasculature were visualized using DCE-MRI technology.. Forty-four patients received ZD6126 (5-112 mg/m2 in the 21-day schedule, n=35; 40-80 mg/m2 in the 14-day schedule, n=9). Common AEs were similar in both groups and included abdominal pain, nausea and vomiting, which appeared to be dose related. The incidence of abdominal pain at 112 mg/m2 in the 21-day study prevented further dose escalation. Pharmacokinetic studies confirmed that ZD6126 is rapidly hydrolyzed to ZD6126 phenol. There was no difference in the pharmacokinetics of ZD6126 phenol upon repeat administration or between the two dosing regimens. DCE-MRI evaluation has demonstrated the antivascular effects of ZD6126.. This study identified that ZD6126 administered every 2 or 3 weeks at 80 mg/m2 was well tolerated, with mild but manageable gastrointestinal AEs. In approximately 11% (5 out of 44) of patients, ZD6126 was associated with cardiac events categorized as dose limiting toxicities (one patient with asymptomatic decreased left ventricular ejection fraction (LVEF), two with increased troponin concentrations, one with myocardial ischemia, and one with ECG signs of myocardial ischemia).

Topics: Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Humans; Infusions, Intravenous; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms; Organophosphorus Compounds; Tubulin

ZD6126 is a novel vascular-targeting agent that induces selective effects on the morphology of endothelial cells by disrupting the tubulin cytoskeleton. This leads to cell detachment and tumor vessel congestion, resulting in extensive central necrosis in a range of tumor xenograft models. Results from a phase I dose-escalation study of ZD6126 are reported.. Thirty-two patients with advanced cancer received weekly ZD6126 infusion (5 to 28 mg/m2). Assessments for safety and pharmacokinetics were performed. Circulating endothelial cells (CECs) were quantified as a pharmacodynamic marker of vascular damage.. Maximum concentrations of the active species were observed 5 to 25 minutes from the start of infusion, and decayed in a biexponential manner with a half-life of 1 to 3 hours. Maximum serum concentration and area under the time-concentration curve increased with dose in a linear fashion across the dose range of 5 to 28 mg/m2. One patient treated at 10 mg/m2 with a history of ischemic heart disease experienced acute myocardial infarction 2 weeks after drug discontinuation. Four others had asymptomatic creatine phosphokinase-muscle-brain elevation. Maximum-tolerated dose (MTD) was reached at 20 mg/m2/wk. Dose-limiting toxicities at 28 mg/m2 were hypoxia caused by pulmonary embolism and an asymptomatic decrease in left ventricular ejection fraction. No objective antitumor responses were observed. CEC levels increased in the hours after infusion, indicating potential effect of the compound on the vasculature. CONCLUSION ZD6126 administered as a weekly infusion was clinically well tolerated. The MTD was reached at 20 mg/m2.

Topics: Adult; Aged; Antineoplastic Agents; Cell Count; Creatine Kinase; Endothelial Cells; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organophosphorus Compounds; Stroke Volume; Ventricular Function, Left

Vascular-disrupting agents (VDAs) represent a new class of chemotherapeutic agent that targets the existing vasculature in solid tumors. Preclinical and early-phase trials have demonstrated the promising therapeutic benefits of VDAs but have also uncovered a distinctive toxicity profile highlighted by cardiovascular events.. We reviewed all preclinical and prospective phase I-III clinical trials published up to August 2010 in MEDLINE and the American Association of Cancer Research and American Society of Clinical Oncology meeting abstracts of small-molecule VDAs, including combretastatin A4 phosphate (CA4P), combretastatin A1 phosphate (CA1P), MPC-6827, ZD6126, AVE8062, and ASA404.. Phase I and II studies of CA1P, ASA404, MPC-6827, and CA4P all reported cardiovascular toxicities, with the most common cardiac events being National Cancer Institute Common Toxicity Criteria (version 3) grade 1-3 hypertension, tachyarrhythmias and bradyarrhythmias, atrial fibrillation, and myocardial infarction. Cardiac events were dose-limiting toxicities in phase I trials with VDA monotherapy and combination therapy.. Early-phase trials of VDAs have revealed a cardiovascular toxicity profile similar to that of their vascular-targeting counterparts, the angiogenesis inhibitors. As these agents are added to the mainstream chemotherapeutic arsenal, careful identification of baseline cardiovascular risk factors would seem to be a prudent strategy. Close collaboration with cardiology colleagues for early indicators of serious cardiac adverse events will likely minimize toxicity while optimizing the therapeutic potential of VDAs and ultimately enhancing patient outcomes.

Topics: Angiogenesis Inhibitors; Bibenzyls; Cardiovascular System; Clinical Trials as Topic; Humans; Neoplasms; Neovascularization, Pathologic; Organophosphorus Compounds; Quinazolines; Serine; Xanthones

We investigated the influence of two types of vascular damaging agents (VDAs) (DMXAA vs. ZD6126) and sequence of administration (VDA 24 h before HYP vs. HYP 1 h before VDA) to evaluate the effect on hypericin (HYP) accumulation and distribution in necrotic tumors.. Frozen sections of dorsally inoculated RIF-1 tumors were analyzed by fluorescence microscopy and H&E stained for histological evaluation. The localization of HYP was assessed both qualitatively and semi-quantitatively in necrotic tumor, viable tumor, or nontarget host tissue.. Whereas the type of VDA did not influence HYP accumulation and distribution, a clear advantage could be seen when administering VDA 24 h before HYP compared to HYP 1 h before VDA, pointing toward the absence of a "trapping" mechanism. In DMXAA-treated and not in ZD6126-treated tumors, spotty fluorescence was observed which is likely to be a consequence of neutrophil phagocytosis. Dexamethasone treatment neither did influence this phenomenon nor did change HYP uptake in necrotic tumor.. We conclude that HYP accumulation is optimal when it is administered after VDA injection. We also found that HYP accumulation in necrosis is not changed when using VDAs with different working mechanisms. This insight provides a rationale for tumor necrosis therapy (TNT) using iodine-131-labeled hypericin ([(131)I]-HYP) in combination with VDAs.

Topics: Animals; Anthracenes; Antineoplastic Agents; Cell Line, Tumor; Mice; Mice, Inbred C3H; Necrosis; Neoplasms; Neovascularization, Pathologic; Organophosphorus Compounds; Perylene; Telomere-Binding Proteins; Xanthones

The aim of the study was to quantitatively assess tumor microcirculation upon vascular targeting tumor therapy by non-destructive contrast enhanced ultrasonography (CEUS) and to validate this technology by correlation with high-resolution intravital fluorescence microscopy (IVM). Subcutaneous Lewis Lung carcinomas (LLC-1) carcinomas were established in mice. A-MEL-3 melanomas were grown in dorsal skinfold chambers of hamsters to permit bimodal imaging of tumor microcirculation by CEUS and IVM. Animals were treated by i.p. injection of ZD6126 and CEUS imaging after bolus injection of microbubbles was performed. Red blood cell velocity (VRBC), segmental blood flow (Q) and microcirculatory perfusion (PI) of tumors was quantified by IVM. Change in signal intensity (SI) from baseline (ΔSI), rate of SI increase (RSI) and area below intensity time curves (AUC) were calculated in tumors by analysis of CEUS data. Microvessel density was measured by quantitative analysis of CD31 immunohistochemistry. The Mann-Whitney test was used to evaluate differences between groups. Spearman correlation test was used to investigate the relation between CEUS and IVM parameters or histologic CD31 count. ΔSI, RSI and AUC values in ZD6126 treated tumors were lower compared to untreated controls. Comparing central and peripheral tumor regions a vascularized viable rim in the tumor periphery could be detected by CEUS imaging. For the entire cohort ΔSI, RSI and AUC values positively correlated with VRBC, Q and PI quantified by IVM. In LLC-1 carcinomas a positive correlation between ΔSI, RSI and AUC and histological assessment of tumor vascularity was found. In conclusion tumor vascular response to vascular targeting therapy can be quantified non-invasively by CEUS. Bimodal tumor imaging by intravital microscopy and CEUS represents an experimental tool to further develop molecular imaging of tumor microcirculation by CEUS.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Contrast Media; Cricetinae; Male; Mice; Mice, Inbred C57BL; Microcirculation; Microscopy, Fluorescence; Neoplasms; Neovascularization, Pathologic; Organophosphorus Compounds; Ultrasonography, Doppler, Color

A clear definition for vascular targeting agents (VTAs) and vascular disrupting agents (VDAs) has separated the two as distinct methods of cancer treatment. VDAs differ from VTAs (antiangiogenesis drugs) in their mechanism of action. VTAs attempt to keep new blood vessels from forming and do not act on blood vessels that already feed existing tumors. In contrast, VDAs cause the vascular structure inside a solid tumor to collapse, depriving the tumor of blood and oxygen it needs to survive. Therefore, VDAs are an attractive way to approach the cancer problem by combating developed tumors. The following review discusses six small molecule VDAs, namely DMXAA, ZD6126, TZT1027, CA4P, AVE8062, and Oxi4503, their synthesis, biological mechanism of action, and current clinical status.

Topics: Animals; Antineoplastic Agents; Blood Vessels; Cardiovascular Agents; Flavonoids; Humans; Neoplasms; Terminology as Topic; Tubulin

The manner in which cells die is believed to have a major impact on the nature of immune responses to their released Ags. In this study, we present the first direct analysis of tumor-specific immune responses to in vivo occurring tumor cell death through apoptosis or necrosis. Mice bearing thymidine kinase-transfected tumors were treated either with ganciclovir to induce tumor cell apoptosis in vivo or a vascular targeting agent, ZD6126, to induce tumor cell necrosis in vivo. In contrast to tumor apoptosis, induction of necrosis reduced the frequency and impaired the function of tumor-specific CD8(+) T cells. Adoptive transfer of lymphocytes from mice with apoptotic tumors into tumor-challenged mice resulted in a significant tumor protection, which was absent when splenocytes were transferred from mice with necrotic tumors. Anti-CD40 treatment reversed impaired Ag-specific CD8(+) T cell responses in these mice. These observations have not only fundamental importance for the development of immunotherapy protocols but also help to understand the underlying mechanism of in vivo immune responses to tumor cell death.

Topics: Adoptive Transfer; Animals; Antigens, Neoplasm; Apoptosis; CD8-Positive T-Lymphocytes; Female; Ganciclovir; Immunity; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Necrosis; Neoplasms; Organophosphorus Compounds; T-Cell Antigen Receptor Specificity; Thymidine Kinase; Transfection

The effects of the anti-vascular agent ZD6126 were studied in volume matched subcutaneous DU-145 human prostate cancer xenografts in SCID mice using two different MRI techniques, diffusion and vascular imaging. Diffusion weighted MRI was performed before and at 24 h, 48 h and 72 h following a single dose of 200 mg/kg. Tumor vascular volume and permeability surface area product (PSP) were determined 24 h post antivascular therapy following an identical dose using dynamic contrast enhanced MRI of the macromolecular contrast agent albumin-gadolinium diethylenetriaminepentaacetate (albumin-GdDTPA). Consistent with the mechanism of action of ZD6126, significantly lower vascular volume was detected at 24 h whereas diffusion changes were evident at 48 h. Diffusion MRI findings correlated well with histological determination of the necrotic fraction in the tumors by 48 h. Both diffusion and vascular imaging are useful noninvasive techniques to detect response of tumors to antivascular therapy with ZD6126 in the DU-145 human prostate cancer xenograft model.

Topics: Albumins; Animals; Cell Line, Tumor; Contrast Media; Diffusion; Diffusion Magnetic Resonance Imaging; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Mice; Mice, SCID; Necrosis; Neoplasm Transplantation; Neoplasms; Organophosphorus Compounds; Time Factors

Antivascular agents that act by destabilizing microtubules, such as ZD6126 (N-acetylcolchinol-O-phosphate), are associated with adverse cardiovascular effects, including transient hypertension, cardiac ischemia, myocardial infarction, and increases in circulating levels of markers of cardiac damage (e.g., troponins). We investigated mechanisms underlying these effects of ZD6126 in rats by continuously monitoring their heart rate and blood pressure and by assessing heart histopathology and plasma troponin T levels. ZD6126 induced acute transient hemodynamic changes (hypertension and delayed tachycardia), which were associated with statistically significant increases in circulating troponin T levels (median level 3 hours after treatment with vehicle or 12.5 mg/kg ZD6126: <9 pg/mL and 563 pg/mL, respectively; P <.001 [two-sided Wilcoxon rank sum test]) and in the incidence of left ventricular myocardial fiber necrosis (incidence 24 hours after treatment with vehicle or 12.5 mg/kg ZD6126: 0/10 rats and 9/10 rats, respectively; P <.001 [two-sided Wilcoxon rank sum test]). Pretreatment of rats with atenolol and nifedipine ameliorated the acute hemodynamic changes and prevented ZD6126-induced increases in both troponin T and myocardial necrosis but did not prevent ZD6126-induced tumor necrosis in an Hras5 tumor xenograft model in nude rats. Our findings suggest that ZD6126-induced acute hemodynamic changes are a prerequisite for cardiac damage in rats.

Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Antineoplastic Agents; Atenolol; Biomarkers; Calcium Channel Blockers; Disease Models, Animal; Drug Administration Schedule; Female; Heart; Hemodynamics; Hypertension; Myocardium; Neoplasms; Nifedipine; Organophosphorus Compounds; Random Allocation; Rats; Tachycardia; Transplantation, Heterologous; Troponin T; Vasodilator Agents

Topics: Antineoplastic Agents; Endothelial Cells; Heart; Humans; Neoplasms; Organophosphorus Compounds

ZD6126 is a vascular-targeting agent that induces selective effects on the morphology of proliferating and immature endothelial cells by disrupting the tubulin cytoskeleton. The efficacy of ZD6126 was investigated in large vs. small tumors in a variety of animal models.. Three rodent tumor models (KHT, SCCVII, RIF-1) and three human tumor xenografts (Caki-1, KSY-1, SKBR3) were used. Mice bearing leg tumors ranging in size from 0.1-2.0 g were injected intraperitoneally with a single 150 mg/kg dose of ZD6126. The response was assessed by morphologic and morphometric means as well as an in vivo to in vitro clonogenic cell survival assay. To examine the impact of tumor size on the extent of enhancement of radiation efficacy by ZD6126, KHT sarcomas of three different sizes were irradiated locally with a range of radiation doses, and cell survival was determined.. All rodent tumors and human tumor xenografts evaluated showed a strong correlation between increasing tumor size and treatment effect as determined by clonogenic cell survival. Detailed evaluation of KHT sarcomas treated with ZD6126 showed a reduction in patent tumor blood vessels that was approximately 20% in small (<0.3 g) vs. >90% in large (>1.0 g) tumors. Histologic assessment revealed that the extent of tumor necrosis after ZD6126 treatment, although minimal in small KHT sarcomas, became more extensive with increasing tumor size. Clonogenic cell survival after ZD6126 exposure showed a decrease in tumor surviving fraction from approximately 3 x 10(-1) to 1 x 10(-4) with increasing tumor size. When combined with radiotherapy, ZD6126 treatment resulted in little enhancement of the antitumor effect of radiation in small (<0.3 g) tumors but marked increases in cell kill in tumors larger than 1.0 g.. Because bulky neoplastic disease is typically the most difficult to manage, the present findings provide further support for the continued development of vascular disrupting agents such as ZD6126 as a vascular-targeted approach to cancer therapy.

Topics: Angiogenesis Inhibitors; Animals; Benzimidazoles; Drug Screening Assays, Antitumor; Fluorescent Dyes; Humans; Mice; Mice, Inbred C3H; Mice, Nude; Necrosis; Neoplasms; Neovascularization, Pathologic; Organophosphorus Compounds; Sarcoma; Transplantation, Heterologous

The effective magnetic resonance imaging (MRI) transverse relaxation rate R(2)* was investigated as an early acute marker of the response of rat GH3 prolactinomas to the vascular-targeting agent, ZD6126. Multigradient echo (MGRE) MRI was used to quantify R(2)*, which is sensitive to tissue deoxyhemoglobin levels. Tumor R(2)* was measured prior to, and either immediately for up to 35 minutes, or 24 hours following administration of 50 mg/kg ZD6126. Following MRI, tumor perfusion was assessed by Hoechst 33342 uptake. Tumor R(2)* significantly increased to 116 +/- 4% of baseline 35 minutes after challenge, consistent with an ischemic insult induced by vascular collapse. A strong positive correlation between baseline R(2)* and the subsequent increase in R(2)* measured 35 minutes after treatment was obtained, suggesting that the baseline R(2)* is prognostic for the subsequent tumor response to ZD6126. In contrast, a significant decrease in tumor R(2)* was found 24 hours after administration of ZD6126. Both the 35-minute and 24-hour R(2)* responses to ZD6126 were associated with a decrease in Hoechst 33342 uptake. Interpretation of the R(2)* response is complex, yet changes in tumor R(2)* may provide a convenient and early MRI biomarker for detecting the antitumor activity of vascular-targeting agents.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Female; Hemoglobins; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Microscopy, Fluorescence; Neoplasms; Organophosphorus Compounds; Perfusion; Prognosis; Prolactinoma; Rats; Rats, Wistar; Time Factors

ZD6126 is a novel vascular-targeting agent that selectively disrupts the tubulin cytoskeleton of endothelial cells. In the immature vessels characteristic of tumor vasculature, this leads to endothelial cell contraction, blood vessel congestion, and, consequently, tumor cell death. ZD6126 has been shown to delay tumor growth in a range of xenograft models. The antitumor effect of ZD6126 can be increased in combination with cisplatin or radiation therapy, although the precise mechanism of this enhancement has not been demonstrated. ZD6126 treatment has also been shown to inhibit lung metastasis, and the present study has explored the potential to increase the antimetastatic effect of ZD6126 by combining with cisplatin, and the underlining mechanism has been investigated.. Human lung adenocarcinoma PC14PE6 cells were injected into the tail vein of nude mice. Five weeks after injection animals were treated with ZD6126 (200 mg/kg i.p.), cisplatin (6 mg/kg i.v.), or a combination of the two agents. The animals were sacrificed 24 hours later, and the extent of lung metastases and the presence of apoptotic cells were assessed.. Histologic analysis revealed that the ZD6126/cisplatin combination resulted in a 2 to 4-fold increase in the total number of tumor-associated apoptotic cells compared with either treatment alone. ZD6126 alone induced apoptosis of tumor-associated endothelial cells in tumors, and the extent of apoptosis was increased 2-fold in combination with cisplatin. The lung weight was significantly reduced, and the number of metastatic nodules significantly was lower in the combined treatment group than in the control group.. These data suggest that the antimetastatic effect of the vascular-targeting agent ZD6126 can be increased by use in combination with cisplatin, which increases the incidence of endothelial cell apoptosis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Dose-Response Relationship, Drug; Endothelial Cells; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neoplasms; Organophosphorus Compounds; Platelet Endothelial Cell Adhesion Molecule-1; Time Factors