Anti-angiogenesis Properties Research Articles

Pigment epithelium-derived factor inhibits angiogenesis and growth of gastric carcinoma by down-regulation of VEGF

Previous studies have shown that pigment epithelium-derived factor (PEDF) is an antitumor candidate with anti-oxidative, anti-inflammatory and anti-angiogenesis properties. However, the effect of PEDF on gastric carcinoma has not been elucidated. MTT assay and Annexin V/PI staining were performed. Immunohistochemistry was applied to detect microvessel density (MVD) of a xenograft model. The protein levels of vascular endothelial growth factor (VEGF) were examined by western blot analysis and hypoxia-inducible factor-1α (HIF-1α) translocation was investigated by immunofluorescence. Results showed that growth and angiogenesis of gastric carcinoma were suppressed after PEDF injection. PEDF could not directly suppress proliferation or induce apoptosis of gastric carcinoma cells. However, the expression of VEGF both in tumor tissues and gastric carcinoma cells was down-regulated by PEDF. The amount and nuclear translocation of HIF-1α, the transcription factor of VEGF, was also inhibited by PEDF. In conclusion, PEDF suppresses angiogenesis and growth of gastric carcinoma by down-regulating HIF-1α and VEGF and may have potential for gastric carcinoma treatment.

Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down‐regulation in vitro

Berberine, an herbal alkaloid, has been reported to have promotion potential of apoptosis and anticancer effect on a variety of human tumor cells. To obtain more specific understanding of those consequences of berberine on hepatocellular carcinoma (HCC) and the tumor microenvironment, we conducted in vitro experiments to investigate the inhibitory effect of berberine on tumor-induced angiogenesis using HCC cells and human umbilical vein endothelial cells (HUVECs). Human umbilical vein endothelial cell growth was quantified with the CCK-8 cell proliferation assay; cell migration was observed with a Boyden chamber (Transwell, Corning, Lowell, MA, USA), and angiogenesis was assessed by endothelial tube formation in Matrigel in vitro. In addition, VEGF level was determined by ELISA and VEGF mRNA expression by RT-PCR. Berberine inhibited the capacity of HCC to stimulate HUVEC's proliferation, migration and endothelial tube formation, suggesting that berberine could influence the cross-talk between the HCC cell and vascular endothelial cells. These results demonstrate berberine's antiangiogenesis property and its clinical potential as an inhibitor of tumor angiogenesis. Subsequently analyses reveal that berberine prevents secretion of VEGF from HCC and down-regulates VEGF mRNA expression. These findings strongly suggest that berberine is a potential antiangiogenic agent and a promising antitumor drug for HCC.

Anti-angiogenic genistein inhibits VEGF-induced endothelial cell activation by decreasing PTK activity and MAPK activation

Genistein (Gen), a soy isoflavone, is considered to exert potent antitumor effect partially through its anti-angiogenesis property. However, the precise molecular mechanism is still unknown. Our previous investigations have demonstrated that genistein down-regulates expression of pro-angiogenic factors via inhibiting protein tyrosine kinase (PTK) activity both in breast cancer cells and in xenograft tumors. In the present experiment, we chose cultured human umbilical vein endothelial cells (HUVECs), which have a considerable role in tumor angiogenesis formation, to explore the influence of genistein on VEGF-stimulated endothelial cell activation and the underlying mechanism. Stimulation of human primary HUVECs by VEGF not only increased endothelial cell protein tyrosine kinase (PTK) activity but also augmented matrix metalloproteinase-2 (MMP-2), -9 secretions and increased MMP-2, -9 activities. Treatment of ECs with genistein induced VEGF-loaded endothelial apoptosis by inhibiting production and activity of matrix metalloproteinases (MMPs). In addition, exposure to genistein decreased activation of JNK and p38, not ERK-1/2, induced by VEGF. Collectively, our findings suggested that the inhibition of PTK activity and MAPK activation and the decrease in MMPs production and activity by genistein interrupt VEGF-stimulated endothelial cell activation, which thereby may represent a mechanism that would explain the anti-angiogenesis effect of genistein and its cancer-protective function.

Triethylenetetramine Pharmacology and Its Clinical Applications

Triethylenetetramine (TETA), a Cu(II)-selective chelator, is commonly used for the treatment of Wilson's disease. Recently, it has been shown that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties. Although TETA has been used in the treatment of Wilson's disease for decades, a comprehensive review on TETA pharmacology does not exist. TETA is poorly absorbed with a bioavailability of 8 to 30%. It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent drug and two acetylated metabolites. It has a relatively short half-life (2 to 4 hours) in humans. The most recent discoveries in TETA pharmacology show that the major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2, the traditionally regarded drug acetylation enzyme, and the TETA-metabolizing enzyme is actually spermidine/spermine acetyltransferase. This review also covers the current preclinical and clinical application of TETA. A much needed overview and up-to-date information on TETA pharmacology is provided for clinicians or cancer researchers who intend to embark on cancer clinical trials using TETA or its close structural analogs.

Radiolabeling, biodistribution and gamma scintigraphy of noscapine hydrochloride in normal and polycystic ovary induced rats.

BackgroundNoscapine, an alkaloid from Papaver somniferum, widely used as an antitussive, is being clinically studied in the treatment of polycystic ovary syndrome (PCOS) and a few other cancers primarily because of its anti-angiogenesis properties. With the advent of diverse application of noscapine, we sought to determine whether the radiolabeling method can be useful in studying uptake and kinetics of the molecule in-vivo. Specific objectives of this study were to radiolabel noscapine with Technetium-99m (Tc-99m), to determine its organ biodistribution in rat model and study its uptake kinetics in PCOS model.MethodsA method for radiolabeling noscapine with Tc-99m was standardized using stannous reduction method and its in vitro and in vivo stability parameters were studied. The radiopharmaceutical was also evaluated for blood kinetics and biodistribution profile. An animal model of PCOS was created by using antiprogesterone RU486 and uptake of 99mTc-noscapine in normal and PCOS ovaries was compared using gamma scintigraphy.ResultsNoscapine hydrochloride was successfully radiolabeled with Tc-99m with high labeling efficiency and in vitro stability. Most of the blood clearance of the drug (80%) took place in first hour after intravascular injection with maximum accumulation being observed in liver, spleen, kidney followed by the ovary. At 4 hours post injection, radiolabeled complex accumulation doubled in PCOS ovaries in rats (0.9 ± 0.03% ID/whole organ) compared to normal cyclic rats (0.53 ± 0.01% ID/whole organ). This observation was further strengthened by scintigraphic images of rats taken at different time intervals (1 h, 2 h, 4 h, and 24 h) where SPECT images suggested discrete accumulation in the PCOS ovaries.ConclusionThrough our study we report direct radiolabeling of noscapine and its biodistribution in various organs and specific uptake in PCOS that may show its utility for imaging ovarian pathology. The increased ovarian uptake in PCOS may be related to its receptor binding suggesting possible role of 99mTc-noscapine in PCOS diagnostics and therapeutics.

Effect of sorafenib on chemotherapy resistance and refractoriness in castration-resistant prostate cancer (CRPC)

e16105 Background: There is no standard for CRPC once chemotherapy fails. In studies employing docetaxel (D), 35–39% of pts did not complete therapy due to progression and only 45–50% had a PSA response. This implies that many pts develop resistance to D. Sorafenib is a multi kinase inhibitor with antiangiogenesis properties. We hypothesized that sorafenib could overcome chemotherapy resistance in these pts. Methods: Eligible pts must have progressed while on either D or mitoxantrone (M). They received sorafenib at 400 mg orally twice/daily in addition to the chemotherapy agent they were on. Sorefinib/chemotherapy combination was given for a maximum of 6 cycles followed by sorafenib monotherapy until progression. Primary end point was safety of the sorafenib/chemotherapy combination. Secondary end points included the overall clinical benefit calculated as the sum of complete response (CR), partial response (PR), and stable disease (SD), toxicity, and time to disease progression (TTP). Results: To date, 15 pts have been enrolled; 14 are evaluable. Eleven pts were on D and 4 on M. Median age was 68 (range 61–83), median PSA was 111.2 ng/ml (13.6–1703.9). Nine pts (60%) had visceral and bone disease. Median PSA-DT pre-study was 2 months (0.5–6) and median time from last chemotherapy to starting study was 4 weeks. Median number of given cycles was 6.5 (2–12). Six pts did not require dose reduction, 2 others were re-escalated to the full dose. Sorafenib was safely combined with chemotherapy with 6 pts experiencing grade 3 fatigue, 3 developing grade 3 hand/foot syndrome, and 1 experiening grade 3 diarrhea. Eleven pts (73%) had SD radiographically that lasted a median of 6.7 months. In all, 6 out of 14 pts (42%) had a PSA decline after adding sorafenib and 3 (21%) had stable PSA. Of these 9 pts (PR+SD), 2 never doubled their PSA. Two pts had PSA decline after withdrawing sorafenib. Median TTP for PSA was 3.75 months. PSA responses did not correlate with radiographic changes or clinical benefit. With a median follow-up of 8 months, 5 pts (33%) remain alive with 1 continuing on therapy without progression. Conclusions: Sorafenib overcomes chemotherapy-refractoriness and failures in CRPC. [Table: see text]

Liposomal honokiol inhibits VEGF‐D‐induced lymphangiogenesis and metastasis in xenograft tumor model

Lymph nodes metastasis of tumor could be a crucial early step in the metastatic process. Induction of tumor lymphangiogenesis by vascular endothelial growth factor-D may play an important role in promoting tumor metastasis to regional lymph nodes and these processes can be inhibited by inactivation of the VEGFR-3 signaling pathway. Honokiol has been reported to possess potent antiangiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor-associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we established lymph node metastasis models by injecting overexpressing VEGF-D Lewis lung carcinoma cells into C57BL/6 mice to explore the effect of honokiol on tumor-associated lymphangiogenesis and related lymph node metastasis. The underlying mechanisms were systematically investigated in vitro and in vivo. In in vivo study, liposomal honokiol significantly inhibited the tumor-associated lymphangiogenesis and metastasis in Lewis lung carcinoma model. A remarkable delay of tumor growth and prolonged life span were also observed. In in vitro study, honokiol inhibited VEGF-D-induced survival, proliferation and tube-formation of both human umbilical vein endothelial cells (HUVECs) and lymphatic vascular endothelial cells (HLECs). Western blotting analysis showed that liposomal honokiol-inhibited Akt and MAPK phosphorylation in 2 endothelial cells, and downregulated expressions of VEGFR-2 of human vascular endothelial cells and VEGFR-3 of lymphatic endothelial cells. Thus, we identified for the first time that honokiol provided therapeutic benefit not only by direct effects on tumor cells and antiangiogenesis but also by inhibiting lymphangiogenesis and metastasis via the VEGFR-3 pathway. The present findings may be of importance to investigate the molecular mechanisms underlying the spread of cancer via the lymphatics and explore the therapeutical strategy of honokiol on antilymphangiogenesis and antimetastasis.

Mda-7/IL-24, novel anticancer cytokine: Focus on bystander antitumor, radiosensitization and antiangiogenic properties and overview of the phase I clinical experience (Review)

Subtraction hybridization applied to a 'differentiation therapy' model of cancer employing human melanoma cells resulted in the cloning of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Initial studies confirm an inverse correlation between mda-7 expression and melanoma development and progression. Forced expression of mda-7 by means of a plasmid or via a replication incompetent adenovirus (Ad.mda-7) promotes growth suppression and induces apoptosis in a broad array of human cancers. In contrast, mda-7 does not induce growth suppressive or toxic effects in normal cells. Based on structure (containing an IL-10 signature motif), secretion by cells (including subsets of T-cells) and location on chromosome 1q (in an area containing IL-10-family genes), mda-7 has now been renamed mda-7/IL-24. Studies by several laboratories have uncovered many of mda-7/IL-24's unique properties, including cancer-specific apoptosis-induction, cell cycle regulation, an ability to inhibit angiogenesis, potent 'bystander antitumor activity' and a capacity to enhance the sensitivity of tumor cells to radiation, chemotherapy and monoclonal antibody therapy. Moreover, based on its profound cancer tropism, substantiated by in vivo human xenograft studies in nude mice, mda-7/IL-24 (administered as Ad.mda-7) was evaluated in a phase I clinical trial in patients with melanomas and solid cancers. These studies document that mda-7/IL-24 is well tolerated and demonstrates evidence of significant clinical activity. In these contexts, mda-7/IL-24 represents a unique cytokine gene with potential for therapy of human cancers. The present review focuses on three unique properties of mda-7/IL-24, namely its potent 'bystander antitumor activity', ability to sensitize tumor cells to radiation, and its antiangiogenesis properties. Additionally, an overview of the phase I clinical trial is provided. These studies affirm that mda-7/IL-24 has promise for the management of diverse cancers.

Thalidomide failed to inhibit angiogenesis and fibrosis in hepatic schistosomiasis of the mouse

The relationship between angiogenesis and fibrosis has been demonstrated in several pathological conditions, one of them being schistosomiasis. To observe whether suppression of angiogenesis would interfere with fibrosis, Thalidomide, an anti-angiogenesis drug, was administered during 30 consecutive days to mice with experimental schistosomiasis. Computerized morphometric measurements of fibrosis, and the counting of blood vessels from hepatic schistosomal lesions did not significantly differ when treated animals and their controls were compared at the end of the experiments. These rather unexpected results are presented under the understanding that they may be of interest during further studies on the anti-angiogenesis properties of thalidomide, and the relationship between angiogenesis and fibrosis.

Intracellular signaling pathways involved in cell growth inhibition of human umbilical vein endothelial cells by melatonin

Melatonin, an indolamine mainly produced in the pineal gland, has received a great deal of attention in the last decade because of its oncostatic effects, which are due to its immunomodulatory, antiproliferative, antioxidant and its possible antiangiogenesis properties. Herein, we document its antiproliferative action on human umbilical vein endothelial cells (HUVECs). Moreover, the possible cell signaling pathways when melatonin inhibited HUVEC proliferation were explored in this study. Primary HUVECs were isolated, cultured, purified and identified before the studies were performed. HUVECs were found to possess G-protein-coupled membrane receptors for melatonin (MT1 and MT2) and also nuclear melatonin receptors (RORalpha and RORbeta, especially RORbeta). No obvious expression of RORgamma was found. We investigated the membrane receptors and several intracellular signaling pathways including mitogen-activated protein kinases (MAPK)/extracellular signal-related kinases (ERK), phosphoinositol-3-kinase (PI3K)/Akt and protein kinases C (PKC) involved in antiproliferative action of melatonin on HUVECs. The blockade of these pathways using special inhibitors decreased cell growth. Furthermore, the constitutive activation of nuclear factor kappa B (NF-kappaB) contributed to the proliferation of HUVECs. High concentrations of melatonin inhibited both NF-kappaB expression and its binding ability to DNA, possibly through inactivation of ERK/Akt /PKC pathways. Taken together, high concentrations of melatonin markedly reduced HUVEC proliferation; the antiproliferative action of melatonin was closely correlated with following pathway: melatonin receptors/ERK/PI3K/Akt/PKC/ NF-kappaB.

The Effect of Combination of CDK Inhibitor (Roscovitine) and Derivatives of Tetracycline on Human Leukemic Cells.

Roscovitine is a 2,6,9- trisubstituted aminopurine analogue that compete with ATP for binding to the active site of Cyclin-dependent kinases (CDKs). It inhibits CDK2/cyclinE, CDK7/cyclinH and CDK9/cyclinT. The cytotoxic effect of roscovitine and its analogues has been reported in several cancer cell lines in vitro and in animal models of cancer xenografts in vivo. The analogues of tetracycline (Doxycycline and Minocycline) possess anti-tumor, anti-metastatic and anti-angiogenesis properties with low toxicity besides acting as antibiotics. The effect of single agent is usually limited in cancer therapy and the use of single agent may mediate drug resistance. We have studied a cytotoxic effect of the CDK inhibitor roscovitine and tetracycline derivatives either alone or in combinations in human leukemia cells lines HL-60 (myeloid), Jurkat (lymphoblastic) and K562 (CML). HL-60, Jurkat and K562 cells were cultured in RPMI 1640 supplemented with 10% FBS. Cells were treated with roscovitine (0.5 – 100 μM), doxycyline (0.5 – 100 μg/ml) or minocycline (0.5 – 100 μg/ml) up to 48 hours alone or in combinations. The cells were examined for viability using AlarmaBlue assay, proliferation using 3H-thymidine incorporation assay, apoptosis using morphological criteria in Giemsa staining, cell cycle using propidium iodide and flow cytometry. Mitochondrial membrane permeabilization was assessed using tetramethylrhodamine ethyl ester. Specific proteins were detected by Western blotting. Incubation with roscovitine, doxycycline or minocycline decreased the cell viability in concentration-dependent manner in all three cell lines. Pretreatment of cells with doxycycline and minocycline for 24 hours followed by roscovitine for 24 hours have shown the additional decrease in cell viability. No such effect was observed when the drugs were used concomitantly. Roscovitine alone decreased proliferation in concentration- and time-dependent way in all three cell lines. Apoptotic morphology was firstly observed at 3 hrs after the treatment with roscovitine and markedly increased at 6 hrs in HL60 and Jurkat cells, but not in K562 cells. In HL60 and Jurkat cells, the cell cycle analysis has shown an increase in sub-G1 cells at 6 hours with maximum at 24h without preceding cell cycle arrest. In K562 cells sub-G1 peak increased subsequently to G2/M arrest. A marked loss of ΔΨm was observed at 2 hrs of exposure to 25uM of roscovitine in Jurkat and HL-60 cell lines, respectively. In HL60 and Jurkat cells, release of cytochrome c, AIF and Smac from mitochondria into cytosol were detected along with activation of caspases and PARP. However in K562, no caspase activation was detected at studied time points. Thus, all three agents have a cytotoxic effect in different types of leukemic cells, however, the additional cytotoxic effect of combination of Roscovitine and derivatives of tetracycline might be a potent therapeutic approach in treatment of leukemia.

Neurotoxicity of Bortezomib Therapy in Multiple Myeloma (MM): A Single Center Experience.

Bortezomib has demonstrated activity in heavily pretreated MM patients. The dose limiting toxicity is peripheral neuropathy (PN) that affects up to 35% of the patients (Richardson et al JCO 2006). We retrospectively reviewed the incidence and severity of PN in 78 patients who received bortezomib at our institution. The median age was 57 years (range: 33–80), 62% were men, and 37% were African Americans (AA). Risk factors for PN included prior use of thalidomide in 53 patients (68%) and vincristine in 31 patients (40%). Seventeen patients (22%) had diabetes mellitus. Before bortezomib treatment 29 patients (37%) reported subjective grade 1–2 PN. Patients received bortezomib alone (n=10) or in combination with dexamethasone (n=36) and thalidomide (n=20) or chemotherapy (n=12). Responses included complete, near complete and partial responses in 5%, 10% and 27%, respectively. Grade 2 and higher PN occurred in 52% of the patients including Grade grades 3 and 4 PN in 15% and 7%, respectively. Twelve patients stopped bortezomib due to side effects that included PN (n=8), diarrhea (n=2) and CMV pneumonia (n=1), and 11 patients had dose reductions because of PN and fatigue. Grade 4 PN affected 6 patients (sensory n=4, and motor/sensory, n=2), 5 of whom were AA and 4 of whom had DM. The onset of grade 4 PN was acute rather than cumulative as noted with lower grades and took a median of 8 months (range: 4–16+) to improve compared to 3–4 months for lower grade PN. Neuropathy grade was not associated with age, sex, race or renal function (10 patients had creatinine > 2 mg/dl, including 2 on dialysis). Factors predictive of PN were baseline neuropathy (p=0.002) in addition to prior thalidomide use (p=0.03) and presence of DM (p=0.03). Responses were independent of neuropathy grade and whether bortezomib was combined with chemotherapy or thalidomide. The duration of therapy in responding patients was longer in patients receiving bortezomib in combination with thalidomide with a median of 5 cycles (range: 2–36) versus those who received other bortezomib combinations 3 cycles (range 1–19). Two of four patients with grade 4 sensory PN had their best response ever after 3 cycles of bortezomib; both had failed transplant and thalidomide based therapies; one remains in continuous complete remission for 24 months. PN therapy was mostly supportive including combinations of analgesics duloxetine, gabapentin, and pregabalin. Interestingly, 6 of 9 patients with PN who received lenalidomide as salvage therapy after progression on bortezomib had significant improvement in their symptoms; 3 of them stopped analgesics. In conclusion, the highest risk and grade of bortezomib neurotoxicity was seen in patients with baseline PN secondary to prior thalidomide use and DM. On the other hand, responding patients who received bortezomib in combination with thalidomide remained longer on therapy with minimal dose reductions. Although this may represent a section bias it is possible that thalidomide's known anti-inflammatory and anti-angiogenesis properties protect against bortezomib-induced PN. Similar effects may explain the unexpected symptomatic improvement of PN on lenalidomide.

Dendritic Cells: Emerging Roles in Tumor Immunotherapy

The purpose of this article is to examine the use of myeloid dendritic cells (DCs) as immunotherapy in the treatment of cancer. DCs can be stimulated either from circulating blood or bone marrow progenitor cells using cytokines, particularly granulocyte macrophage-colony-stimulating factor (GM-CSF) (e.g., sargramostim, Leukine). GM-CSF has been shown to promote maturation, mobilization, and antigen presentation of DCs in vivo or ex vivo as a therapeutic cancer vaccine. Once stimulated, DCs can present tumor antigen to naive T cells to initiate an immune response. In addition to myeloid-related DC stimulation, antitumor properties of GM-CSF include direct cytotoxicity, antiangiogenesis properties, and potential upregulation of antibody-dependent cellular cytotoxicity. Oncology nurses need to be knowledgeable regarding new therapies. Using knowledge gained through reading professional journals and self-education, nurses can inform patients of new therapies, which may increase patients' hope.

Synthesis of 3-substituted-2-oxoindole analogues and their evaluation as kinase inhibitors, anticancer and antiangiogenic agents

Several analogues of the 3-substituted-2-oxoindole chemotype were synthesized by condensing isatin or the appropriate haloisatin with some amino acids or histamine under neutral conditions. All the imino derivatives produced were tested for kinase inhibitory properties against three serine/threonine kinases, namely CDK1/cyclin B, CDK5/p25 and GSK3α/β. Most of the histidine derivatives showed inhibitory properties to the three kinases in the low micromolar range. The histamine derivatives were less potent against CDK1/cyclin B and CDK5/p25 and totally inactive against GSK3α/β. So, the management of the carboxyl function may be a tool to impart selectivity in such family of kinases. Docking of 2-{[-5-bromo-2-oxoindolin-3-ylidene]amino}-3-(1 H-imidazol2-yl)propanoic acid 14 to CDK5/p25 indicates that this compound can interact with the enzyme through four hydrogen bonds; for GSK/3β, the ligand poses itself in another orientation, also four hydrogen bonds can be formed between the ligand and the receptor, otherwise hydrophobic interactions seem to predominate. Also, all the final compounds were tested for their in vitro antitumor properties against MCF7 (breast), NCI-H460 (lung) and SF268 (CNS) cancer cell lines. None of the synthesized compounds was cytotoxic at 10 –4 molar concentration. Moreover, compounds 13 and 14 were tested for potential antiangiogenic properties by testing their ability to inhibit the proliferation of human umbilical vein endothelial cells (HUVECs), cord formation and migration in response to chemoattractant. Only compound 14 showed moderate inhibitory properties to HUVECs proliferation and cord formation while its non-brominated derivative 13 did not. Thus, the antiangiogenesis properties are not apparently caused by inhibition of any of the tested kinases.

Roles of platelet factor 4 in hematopoiesis and angiogenesis

Platelet factor 4 (PF4) has been recognized as a physiological inhibitor of megakaryocytopoiesis and angiogenesis for two decades. Structure–function studies have shown that the DLQ determinant in position 54–56 is necessary for megakaryocytic inhibition whereas mutations of these residues into ELR sequence and more importantly, into DLR sequence, induce a stronger inhibitory activity of peptide p47-70 on angiogenesis. The α-helix region of peptides may participate in the fixation of the effector to its cellular receptor and the other important structural domains would activate the receptor. In vivo, PF4 and its related peptides can protect hematopoiesis from chemotherapy by enhancing cell viability and suppress tumor growth through anti-angiogenic pathway. Several PF4 fragments and modified molecules exhibit antiangiogenesis properties and may become an alternative for further therapeutic angiogenesis.

Phase II study of CC-4047 in patients (pts) with metastatic hormone-refractory prostate cancer (HRPC)

4629 Background: CC-4047 is a new analog of thalidomide with potent immunomodulatory and anti-angiogenesis properties. similar to thalidomide. This study investigates whether single agent CC-4047 can induce PSA responses and increase time to progression in HRPC. Eligibility included: histologically confirmed HRPC, 2 consecutive rises in prostate-specific antigen (PSA) with an absolute change of at least 1ng/ml separated by 28 days, with or without radiographic evidence of disease, castrate levels of serum testosterone (≤50 ng/dL), failure to androgen withdrawal, ≤1 prior chemotherapy regimen, ECOG performance status of ≤1, life expectancy ≥3 months, and normal organ/marrow function. Methods: CC-4047 was administered orally in doses of 1 or 2mg/day without interruption. Pts. are followed every 4 weeks with re-evaluation at week 12. Forty-four pts have been enrolled. Pt characteristics: 1mg dose level: 22 pts enrolled, median age 69 years (range 58–82). Fourteen pts with bone involvement only. Four pts with bone and nodal involvement. Four pts with nodal or visceral tumor involvement only. Median PSA 157 (0.8–313). 2mg dose level: 22 pts enrolled, median age 68 years (range 44–84). Seven pts with bone involvement only. Two pts with bone and nodal involvement. Five pts with bone and visceral involvement. Three pts with nodal or visceral tumor involvement. Four pts with prostate intact. Median PSA: 70 (0.6–139). Results: Of the 22 pts at 1mg, 20 pts have completed 12 weeks of therapy. One pt remains on study for 60+ weeks. PSA decreased in 6 pts, 3 pts with >50% decrease. Of the 22 pts at 2mg, 19 completed 12 weeks of therapy. Nine pts remain on study. PSA decreased in 9 pts, with 2 pts having a >50% reduction. Grade 1–2 toxicity included: constipation, nausea, vomiting, and fatigue. One Grade 3 toxicity consisting of nausea. One pt expired secondary to a CNS bleed while on therapeutic doses of coumadin. Of the 22 pts at 2mg, 16 completed 12 weeks of therapy. Nine pts remain on study. PSA decreased in 9 pts, with 2 pts having a >50% reduction. Conclusion: CC-4047 shows promising activity in pts with HRPCa, with an acceptable tolerability. Response, progression-free survival and toxicity data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene Celgene, Chiron Celgene, Chiron, Endocyte

The effect of mizolastine on expression of vascular endothelial cell growth factor, tumour necrosis factor-alpha and keratinocyte-derived chemokine in murine mast cells, compared with dexamethasone and loratadine

It has been shown that many antihistamines may have anti-inflammatory activity in addition to being H1 antagonists. Mizolastine (MIZ), a novel antihistamine, might also have anti-angiogenesis properties. In this study, we investigated the influence of MIZ on proangiogenesis factors, vascular endothelial cell growth factor (VEGF), tumour necrosis factor (TNF)-alpha and keratinocyte-derived chemokine (KC) in murine mast cells by using ELISA and RT-PCR, as compared with dexamethasone (DEX) and loratadine (LOR). Our results show that MIZ is effective in the inhibition of KC, VEGF and TNF-alpha release induced by an IgE-dependent mechanism, in a time- and dose-dependent manner. The differences between the inhibitory effects of the three drugs on these proangiogenic factors were rather subtle. Semiquantitative analysis using RT-PCR showed that the three drugs significantly reduced VEGF165, VEGF120, TNF-alpha and KC mRNA expression. Statistical results revealed that the effect of DEX on VEGF165 mRNA was different from that of MIZ or LOR (P < 0.01) and the differences between the three drugs on VEGF120, TNF-alpha and KC mRNA were not statistically significant (P > 0.05). These findings raise the possibility that MIZ can mediate anti-angiogenesis activity and that the effect may depend not only on the inhibition on the levels of cytokine proteins but also at the mRNA level.

Platelet factor 4: an inhibitor of angiogenesis.

Platelet factor 4 (PF4) is an antiangiogenic ELR-negative chemokine. PF4 inhibits endothelial cell proliferation and migration and angiogenesis in vitro and in vivo. Three different mechanisms have been proposed to explain PF4's antiangiogenic effects. First, PF4 may bind proteoglycans and interfere with the proteoglycan-bystander effect on growth factor activity. Second, PF4 is able to interact directly with angiogenesis growth factors such as fibroblast growth factors or vascular endothelial growth factors and inhibits their interaction with cell surface receptors. Third, PF4 may activate cell surface receptors on endothelial cells and induce inhibitory signals. Recently, one such receptor, CXCR3-B, was identified. In cardiovascular disease, PF4 may possibly intervene in collateral vessel formation, plaque neovascularization, heparin-induced thrombocytopenia and stent endothelialization. Several PF4 fragments such as PF4-CTF and modified molecules have been made that exhibit antiangiogenesis properties and may serve as leads for further therapeutic development.

Thalidomide use in general oncology practice: A single institution experience

3161 Background:Since the approval of thalidomide by the FDA in 1998, there has been wide off-label use in oncology based on its purported cytokine modulating and anti-angiogenesis properties. We conducted a retrospective review on the use of thalidomide in a single institution to evaluate its role in cancer treatment and palliation. Methods: From Dec 1, 1999 to July 31, 2003, an estimated 110 patients have been enrolled in the thalidomide education (STEPS Program) database. Patients enrolled but did not take thalidomide were excluded. 45 patients have been evaluated so far. All cancer diagnoses are included. Clinical response is recorded by using a 1–4 ranking (1-responsive, 2-stable, 3-progressive, 4-death). A 1 or 2 ranking is considered a positive response to thalidomide. Patients are further divided into two groups: treated with thalidomide alone or treated with any concurrent chemotherapy agents. Results: 38 of the 45 reviewed charts contained adequate information to evaluate tumor response. All had prior chemotherapy before starting thalidomide (median 2 regimens, range 1–4). Mean dose of thalidomide is 169 mg/day (50–500 mg/day). 23/38 (60.5%) had a 1 or 2 tumor response to thalidomide. No complete responder. Eighteen patients were treated with thalidomide alone and had a 17% response rate (3/18). Twenty patients were treated concurrently with other agents and had a 65% response rate (13/20). Excluding myeloma diagnosis the tumor response rate is 50% (13/26) and the average response duration is 11 months (2- >24). The table lists the responding tumor types. Weight changes data available in 12 responders with a mean weight gain of 1.9 kg. Conclusions: Unpredictable but some long-term disease control was seen with relatively low dose thalidomide alone or in combination with other agent(s). Objective weight gain as a surrogate marker for improved functional status is noted among the majority of responders. No significant financial relationships to disclose.

Thalidomide use in general oncology practice: A single institution experience

3161 Background:Since the approval of thalidomide by the FDA in 1998, there has been wide off-label use in oncology based on its purported cytokine modulating and anti-angiogenesis properties. We conducted a retrospective review on the use of thalidomide in a single institution to evaluate its role in cancer treatment and palliation. Methods: From Dec 1, 1999 to July 31, 2003, an estimated 110 patients have been enrolled in the thalidomide education (STEPS Program) database. Patients enrolled but did not take thalidomide were excluded. 45 patients have been evaluated so far. All cancer diagnoses are included. Clinical response is recorded by using a 1–4 ranking (1-responsive, 2-stable, 3-progressive, 4-death). A 1 or 2 ranking is considered a positive response to thalidomide. Patients are further divided into two groups: treated with thalidomide alone or treated with any concurrent chemotherapy agents. Results: 38 of the 45 reviewed charts contained adequate information to evaluate tumor response. All had prior chemotherapy before starting thalidomide (median 2 regimens, range 1–4). Mean dose of thalidomide is 169 mg/day (50–500 mg/day). 23/38 (60.5%) had a 1 or 2 tumor response to thalidomide. No complete responder. Eighteen patients were treated with thalidomide alone and had a 17% response rate (3/18). Twenty patients were treated concurrently with other agents and had a 65% response rate (13/20). Excluding myeloma diagnosis the tumor response rate is 50% (13/26) and the average response duration is 11 months (2- >24). The table lists the responding tumor types. Weight changes data available in 12 responders with a mean weight gain of 1.9 kg. Conclusions: Unpredictable but some long-term disease control was seen with relatively low dose thalidomide alone or in combination with other agent(s). Objective weight gain as a surrogate marker for improved functional status is noted among the majority of responders. No significant financial relationships to disclose.