semaxinib and Neoplasms

Cancer progression is attained by uncontrolled cell division and metastasis. Increase in tumor size triggers different vascular channel formation to address cell nutritional demands. These channels are responsible for transferring of nutrients and gaseous to the cancer cells. Cancer vascularization is regulated by numerous factors including vascular endothelial growth factors (VEGFs). These factors play an important role during embryonic development. Members included in this group are VEGFA, VEGFB, VEGFC, PIGF and VEGFD which markedly influence cellular growth and apoptosis. Being freely diffusible these proteins act in both autocrine and paracrine fashions. In this review, genetic characterization these molecules and their putative role in cancer staging has been elaborated. Prognostic significance of these molecules along with different stages of cancer has also been summarized. Brief outline of ongoing efforts to target hot spot target sites against these VEGFs and their cognate limitations for therapeutic implications are also highlighted.

Topics: Angiogenesis Inhibitors; Bevacizumab; Humans; Indoles; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Neovascularization, Pathologic; Prognosis; Protein Kinase Inhibitors; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factors

The recent completion of the human genome sequence provided the basis and the tools to better understand the cellular biological complexity in both healthy and disease conditions, such as human cancer. In recent years, the improvement in biological and molecular knowledge enabled us to identify new targets and innovative drugs, allowing the beginning of new therapeutic strategies based on the so called "target oriented therapies".

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Clinical Trials as Topic; ErbB Receptors; Humans; Indoles; Neoplasms; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor

Anti-vascular tumor therapy represents a promising new strategy for cancer treatment. Anti-vascular treatment may be divided in anti-angiogenic and vascular targeting therapy. Whereas anti-angiogenic drugs aim on the inhibition of new vessel formation, vascular targeting compounds are designed to selectively destruct preexisting tumor blood vessels leading to secondary tumor cell death. Both anti-angiogenic drugs and vascular targeting agents have proven effective anti-tumoral activity in numerous preclinical studies over the last decade. In vivo, a combination with anti-vascular tumor therapy enhances the effects of other treatment modalities as chemo- and radiotherapy. Phase I clinical studies revealed a number of well-tolerated candidates. As monotherapy, however, anti-angiogenic treatment lacked efficacy in randomized clinical studies so far. In contrast, combination of anti-angiogenic therapy with chemotherapy was highly effective in an encouraging, large randomized phase III trial on metastatic colorectal cancer. This review will outline recent advances in the preclinical and clinical development of anti-vascular therapy with focus on vascular targeting. Conceptual differences between anti-angiogenic and vascular targeting therapies will be discussed with emphasis on specific problems and pitfalls in the conversion into the clinic.

Topics: Animals; Anti-HIV Agents; Drug Delivery Systems; Humans; Indoles; Neoplasms; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyrroles; Randomized Controlled Trials as Topic; Sunitinib

The institution of combined modality therapy for unresected solid tumors has resulted in significant improvements in tumor control and survival benefit compared with radiotherapy (RT) alone. A number of chemotherapy agents that can enhance the effectiveness of RT, such as cisplatin and 5-fluorouracil, are now considered standard treatment for patients with a number of cancer types. There is growing interest in a number of additional agents that have also been found to have radiosensitizing ability. These include paclitaxel, docetaxel, irinotecan, gemcitabine, and vinorelbine, as well as biologic agents. Other agents may be of value because they act to counter dose-limiting toxicities associated with RT. This article provides an update of some important, recently completed and ongoing clinical trials evaluating novel chemoradiation protocols, with examples taken primarily from studies conducted by the Radiation Therapy Oncology Group (RTOG). Theoretical approaches to the development of new agents and combined modality regimens are also discussed.

Topics: Alkyl and Aryl Transferases; Angiogenesis Inhibitors; Angiostatins; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose Fractionation, Radiation; Drugs, Investigational; Endothelial Growth Factors; Enzyme Inhibitors; Esophageal Neoplasms; Farnesyltranstransferase; Female; Head and Neck Neoplasms; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Isoenzymes; Laryngeal Neoplasms; Lung Neoplasms; Lymphokines; Male; Membrane Proteins; Neoplasms; Peptide Fragments; Plasminogen; Prostaglandin-Endoperoxide Synthases; Prostatic Neoplasms; Pyrroles; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Treatment Outcome; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The inhibitors of VEGF-mediated signaling continue to wind their way through extensive preclinical and clinical development paths. Whereas the first phase III trial did not meet its endpoints, one hopes that the others will. As we learn more about the VEGF pathways in the laboratory and the clinic, we can interpret with greater certainty what role these drugs or their successors will have in the treatment of human cancers.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Clinical Trials as Topic; Colorectal Neoplasms; Drug Design; Drug Screening Assays, Antitumor; Endothelial Growth Factors; Enzyme Inhibitors; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Lymphokines; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Phthalazines; Piperidines; Pyridines; Pyrroles; Quinazolines; Recombinant Proteins; RNA, Catalytic; Treatment Failure; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Activation of the KIT tyrosine kinase by somatic mutation has been documented in a number of human malignancies, including gastrointestinal stromal tumor (GIST), seminoma, acute myelogenous leukemia (AML), and mastocytosis. In addition, paracrine or autocrine activation of this kinase has been postulated in numerous other malignancies, including small-cell lung cancer and ovarian cancer. In this review, we discuss the rationale for and development of KIT tyrosine kinase inhibitors for the treatment of human malignancies.. Studies were identified through a MEDLINE search, review of bibliographies of relevant articles, and review of abstracts from national meetings.. Four tyrosine kinase inhibitors that have activity against KIT are currently being used in clinical trials, and one, STI571, has recently been approved by the United States Food and Drug Administration for treating patients with chronic myelogenous leukemia. The role of KIT inhibitors in treating KIT-positive malignancies is reviewed.. Targeted therapy to inhibit the kinase activity of KIT is a rational approach to the treatment of KIT-positive malignancies. Two key factors are the potency of a given inhibitor and the relative contribution of KIT activation to the growth of the tumor. Given our current understanding of KIT activity in human malignancy, the best candidate diseases for treatment with KIT inhibitors are GIST, mastocytosis, seminoma and possibly some cases of AML. Additionally, KIT inhibitors may play an adjunctive role in diseases such as small-cell lung cancer, in which KIT activation is secondary to ligand binding rather than an acquired mutation.

Topics: Angiogenesis Inhibitors; Benzamides; Enzyme Inhibitors; Humans; Imatinib Mesylate; Indoles; Mutation; Neoplasms; Oxindoles; Piperazines; Propionates; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit; Pyrimidines; Pyrroles

It is important to survey the molecular targets which are involved in tumor angiogenesis for the development of antiangiogenic agents as one of the cancer therapy. This article is meant to review the recent molecular targets of tumor angiogenesis and the molecular mechanism of antiangiogenic agents in human clinical trials.

Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Antigens, CD; Antineoplastic Agents; Cadherins; ErbB Receptors; Gefitinib; Humans; Indoles; Mice; Neoplasms; Oxindoles; Peptide Fragments; Plasminogen; Propionates; Pyrroles; Quinazolines; Vascular Cell Adhesion Molecule-1

This phase I study evaluated the safety of SU5416, a potent and selective inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase Flk-1, in combination with weekly cisplatin and irinotecan in patients with advanced solid tumors.. The patients received cisplatin 30 mg/m² and irinotecan 50 mg/m² weekly from week 1 to week 4, with SU5416 at either 65 mg/m² (dose level (DL)1) or 85 mg/m² (DL2) twice weekly for 6 weeks (1 cycle). Serial ¹⁸fluorodeoxyglucose-positron emission tomography (¹⁸FDG-PET) and ¹⁵O-H₂O-PET scans were obtained.. 13 patients were treated (7 on DL1, 6 on DL2); 7 patients completed at least 1 cycle of treatment. 3 patients experienced dose-limiting toxicity (DLT) at DL2 (grade 3 neutropenia and grade 3 thrombocytopenia causing treatment delay, grade 3 nausea/vomiting). No objective responses were observed at DL1, which was determined to be the maximum tolerated dose (MTD). 1 partial response (PR) was observed at DL2. ¹⁸FDG-PET responses were documented but did not predict response according to the Response Evaluation Criteria in Solid Tumors (RECIST).. SU5416 at 65 mg/m² twice weekly combined with cisplatin and irinotecan weekly for 4 of 6 weeks is well tolerated but without evidence of clinical activity. ¹⁸FDG-PET may be a useful pharmacodynamic marker of SU5416 bioactivity but requires additional development.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy-Induced Febrile Neutropenia; Cisplatin; Dose-Response Relationship, Drug; Female; Humans; Indoles; Irinotecan; Male; Middle Aged; Nausea; Neoplasms; Pyrroles; Thrombocytopenia; Treatment Outcome

Vascular endothelial growth factor (VEGF) is a potent stimulant of angiogenesis. SU5416, is a small molecule tyrosine kinase inhibitor, and a potent inhibitor of VEGF-mediated Flk-1 receptor signaling. Intravenous agent SU5416 has shown evidence of biological activity against a variety of tumor types. The current intravenous dosing regimen is not optimal for long-term administration, which is needed for optimal efficacy. The aim of this study was to evaluate the safety profile and pharmacokinetics of a Nanocrystal Colloidal Dispersion (NCD) SU5416 formulation in humans. Patients with advanced and/or metastatic solid organ tumors were included in the trial; various SU5416 regimens were tested for tolerability, safety and were evaluated concerning pharmacokinetics. The results of this study indicate that induction of clearance after oral dosing of NCD SU5416 in humans occurs and is greater than following i.v. administration. It has been confirmed that SU5416 is a high clearance compound, also as an oral NCD formulation. The NCD formulation was well tolerated, but no effective drug serum levels could be achieved. These data help to understand the ADME (Absorption, Distribution, Metabolism, Excretion) properties of indoline chemical class compounds. The lessons learned should be applied in the development of next generation indoline anti-angiogenic and anti-tumor compounds.

Topics: Administration, Oral; Adult; Drug Administration Schedule; Female; Humans; Indoles; Infusions, Intravenous; Middle Aged; Neoplasm Staging; Neoplasms; Protein Kinase Inhibitors; Pyrroles

SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone; semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR2). A Phase I dose escalation study was performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic assessment tool. In all, 27 patients were recruited. SU5416 was administered twice weekly by fixed rate intravenous infusion. Patients were treated in sequential cohorts of three patients at 48, 65, 85 110 and 145 mg m-2. A further dose level of 190 mg m-2 after a 2-week lead in period at a lower dose was completed; thereafter, the cohort at 145 mg m-2 was expanded. SU5416 showed linear pharmacokinetics to 145 mg m-2 with a large volume of distribution and rapid clearance. A significant degree of interpatient variability was seen. SU5416 was well tolerated, by definition a maximum-tolerated dose was not defined. No reproducible changes were seen in DCE-MRI end points. Serial assessments of VEGF in a cohort of patients treated at 145 mg m-2 did not show a statistically significant treatment-related change. Parallel assessments of the impact of SU5416 on coagulation profiles in six patients showed a transient effect within the fibrinolytic pathway. Clinical experience showed that patients who had breaks of therapy longer than a week could not have treatment reinitiated at a dose of 190 mg m-2 without unacceptable toxicity. The 145 mg m-2 dose level is thus the recommended dose for future study.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Drug Administration Schedule; Endpoint Determination; Female; Humans; Indoles; Infusions, Intravenous; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyrroles

SU5416 is a small molecule antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF) stimulation of the KDR tyrosine kinase receptor. In this Phase I dose escalation trial, a weekly dose schedule of SU5416 was tested whereby an initial 5-day loading dose was followed by weekly maintenance infusions. The start dose was 20 mg/m(2) for the loading dose followed by 65 mg/m(2) for the weekly infusions. Dose escalations occurred at 33% until a final dose of 65 mg/m(2) (loading dose) and 190 mg/m(2) (weekly infusion) was obtained. Twenty-two patients were treated at five dose levels; tumor types included gastrointestinal (8), breast (3), lung (4), sarcoma (2), and other (5). The most common serious drug-related toxicity was headache, often associated with nausea and vomiting. Grade 1 and 2 toxicities included headache, nausea, vomiting, asthenia, pain at the infusion site, phlebitis, change in voice, and fevers. Of 19 evaluable patients, 4 obtained clinical benefit as defined by tumor regression (1) or disease stabilization for at least 12 weeks (3). Pharmacokinetic data revealed that the weekly infusion schedule prevented the reported 50-60% induction in SU5416 clearance observed with either daily or twice weekly dosing. Higher baseline levels of urine VEGF were observed in the 4 patients who gained clinical benefit, suggesting this may be a useful marker for predicting response to anti-VEGF therapies. Our results suggest that a weekly schedule of SU5416 shows signs of biological activity and is well tolerated at doses up to 145 mg/m(2).

Topics: Adult; Aged; Angiogenesis Inhibitors; Combined Modality Therapy; Endothelial Growth Factors; Fatigue; Female; Fibroblast Growth Factor 2; Headache; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Middle Aged; Molecular Structure; Nausea; Neoplasms; Pyrroles; Salvage Therapy; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vomiting

To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416.. Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine.. In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner.. The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Drug Administration Schedule; Female; Gemcitabine; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Pyrroles; Thromboembolism; Treatment Outcome

Angiogenesis, the sprouting of capillaries from preexisting ones, is essential for the sustained growth of solid tumors. In this study, we used SU5416, a hydrophobic molecule with potent tyrosine kinase inhibitor of type 2 receptor for vascular endothelial growth factor (VEGF), as PEGylated emulsion (SU5416-PE), and evaluated the antitumor potency of this formulation in Lewis lung cancer (LLC), Colon-26 (C26), and B16BL6 melanoma (B16) tumor-bearing mice. Intravenous injection of SU5416-PE into tumor-bearing mice significantly suppressed the growth of C26 and B16 tumors, but had no effect on the growth of LLC tumors. MTT assay revealed that SU5416 inhibited the proliferation of human umbilical vein endothelial cells in a concentration-dependent manner but did not show such an inhibitory effect on all types of tumor cells examined, demonstrating the specificity of SU5416 for endothelial cells. Considering that VEGF levels within C26 and B16 tumors were found to be about 10-fold and 20-fold higher than that in LLC tumors, respectively, it was suggested that SU5416-PE would inhibit angiogenesis in certain types of tumor tissue such as C26 and B16 where VEGF plays a major role for promoting angiogenesis, leading to the suppression of in vivo tumor growth.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Emulsions; Endothelium, Vascular; Humans; Indoles; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms; Neovascularization, Pathologic; Pharmaceutical Vehicles; Polyethylene Glycols; Protein Kinase Inhibitors; Pyrroles; Vascular Endothelial Growth Factor A

With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N(4)-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N(4)-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).

Topics: Animals; Binding Sites; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Drug Design; Humans; Indoles; Mice; Mice, Nude; Molecular Dynamics Simulation; Neoplasms; Oxindoles; Propionates; Protein Kinase Inhibitors; Protein Structure, Tertiary; Pyrimidines; Pyrroles; Receptor, Platelet-Derived Growth Factor beta; Transplantation, Heterologous; Vascular Endothelial Growth Factor Receptor-2

Tumor neovascularization is a highly complex process including multiple steps. Understanding this process, especially the initial stage, has been limited by the difficulties of real-time visualizing the neovascularization embedded in tumor tissues in living animal models. In the present study, we have established a xenograft model in zebrafish by implanting mammalian tumor cells into the perivitelline space of 48 hours old Tg(Flk1:EGFP) transgenic zebrafish embryos. With this model, we dynamically visualized the process of tumor neovascularization, with unprecedented high-resolution, including new sprouts from the host vessels and the origination from VEGFR2(+) individual endothelial cells. Moreover, we quantified their contributions during the formation of vascular network in tumor. Real-time observations revealed that angiogenic sprouts in tumors preferred to connect each other to form endothelial loops, and more and more endothelial loops accumulated into the irregular and chaotic vascular network. The over-expression of VEGF165 in tumor cells significantly affected the vascularization in xenografts, not only the number and size of neo-vessels but the abnormalities of tumor vascular architecture. The specific inhibitor of VEGFR2, SU5416, significantly inhibited the vascularization and the growth of melanoma xenografts, but had little affects to normal vessels in zebrafish. Thus, this zebrafish/tumor xenograft model not only provides a unique window to investigate the earliest events of tumoral neoangiogenesis, but is sensitive to be used as an experimental platform to rapidly and visually evaluate functions of angiogenic-related genes. Finally, it also offers an efficient and cost-effective means for the rapid evaluation of anti-angiogenic chemicals.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Humans; Indoles; Mice; Microvessels; Neoplasms; Neovascularization, Pathologic; Pyrroles; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays; Zebrafish

Embryonic stem (ES) cells spontaneously differentiate capillary-like structures as well as leucocytes such as monocytes/macrophages, neutrophils, natural killer (NK) cells and cytototoxic T lymphocytes. The interplay between vasculogenesis and leucocyte differentiation as well as the population of tumour tissues with ES cell-derived leucocytes and endothelial cells is, however, not sufficiently specified. In the present study, gene expression of the cell surface markers CD68 and CD14 (expressed on monocytes and macrophages), Mac-1 (CD11b) (expressed on granulocytes, monocytes and NK cells) and CD16 (expressed on neutrophils) was investigated in murine CGR8 ES cells in relation to the endothelial cell markers CD31 and vascular endothelial (VE)-cadherin. Expression of leucocyte markers increased from day 7-8 of cell culture on. Furthermore, addition of macrophage colony-stimulating factor to the cell culture medium resulted in a threefold increase in the number of CD68(+) monocytes/macrophages. Treatment of embryoid bodies with lipopolysaccharide (LPS) up-regulated CD14 thus suggesting functionality of the CD14 LPS receptor. Differentiation of vascular structures positive for CD31 and VE-cadherin preceded leucocyte differentiation by 2 days (i.e. from day 5-6 on) suggesting that vasculogenesis may be a determinant of leucocyte differentiation. Consequently the Flk-1 antagonist SU5416 which inhibits vasculogenesis of ES cells significantly blunted leucocyte differentiation. Confrontation culture of embryoid bodies with multicellular breast tumour spheroids initiated significant increase of leucocyte cell numbers and invasion of leucocytes into the tumour tissue. In summary our data demonstrate that during ES cell differentiation vasculogenesis precedes leucocyte differentiation, and point towards the direction that leucocyte cell invasion into tumour tissue may initiate the pro-inflammatory microenvironment necessary for tumour vascularization.

Topics: Angiogenesis Inhibitors; Animals; Antigens, CD; Biomarkers; Cell Differentiation; Cell Line; Embryonic Stem Cells; Indoles; Leukocytes; Lipopolysaccharides; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice; Monocytes; Neoplasms; Neovascularization, Physiologic; Pyrroles

Investigations on the combination of radiotherapy with vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) antiangiogenic agents, which has the potential to improve the clinical outcome in cancer patients.. Here, we analyze the combined VEGF (SU5416) and PDGF (SU6668) receptor tyrosine kinase inhibition with irradiation in human endothelium (HUVEC), prostate cancer (PC3), and glioblastoma (U87) in vitro and in vivo.. Combined inhibition of VEGF and PDGF signaling resulted in enhanced apoptosis, reduced cell proliferation, and clonogenic survival as well as reduced endothelial cell migration and tube formation compared with single pathway inhibition. These effects were further enhanced by additional irradiation. Likewise, in PC3 and U87 tumors growing s.c. on BALB/c nu/nu mice, dual inhibition of VEGF and PDGF signaling significantly increased tumor growth delay versus each monotherapy. Interestingly, radiation at approximately 20% of the dose necessary to induce local tumor control exerts similar tumor growth-inhibitory effects as the antiangiogenic drugs given at their maximum effective dose. Addition of radiotherapy to both mono- as well as dual-antiangiogenic treatment markedly increased tumor growth delay. With respect to tumor angiogenesis, radiation further decreased microvessel density (CD31 count) and tumor cell proliferation (Ki-67 index) in all drug-treated groups. Of note, the slowly growing PC3 tumor responded better to the antiangiogenic drug treatments than the faster-growing U87 tumor. In addition to the beneficial effect of abrogating VEGF survival signaling when combined with radiation, we identified here a novel mechanism for the tumor escape from radiation damage. We found that radiation induced up-regulation of all four isoforms of PDGF (A-D) in endothelial cells supporting adjacent smooth muscle cells resulting in a prosurvival effect of radiation. The addition of SU6668 attenuated this undesirable paracrine radiation effect, which may rationalize the combined application of radiation with PDGF signaling inhibition to increase antitumor effects.. A relative low radiation dose markedly enhances local antitumor effects of combined VEGF and PDGF signaling inhibition, suggesting a promising combination regimen for local tumor treatment with radiotherapy remaining an essential element.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Endothelial Cells; Flow Cytometry; Humans; Immunohistochemistry; Indoles; Mice; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Oxindoles; Propionates; Protein Kinase Inhibitors; Pyrroles; Radiation-Sensitizing Agents; Radiotherapy; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; Xenograft Model Antitumor Assays

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells

Destruction of existing tumor blood vessels may be achieved by targeting vascular endothelial growth factor (VEGF) signaling, which mediates not only endothelial cell proliferation but also endothelial cell survival. In this study, however, intravital microscopy failed to demonstrate that targeting of VEGFR-2 (by the tyrosine kinase inhibitor SU5416) induces significant regression of experimental tumor blood vessels. Immunohistochemistry, electron microscopy, expression analyses, and in situ hybridization provide evidence that this resistance of tumor blood vessels to VEGFR-2 targeting is conferred by pericytes that stabilize blood vessels and provide endothelial cell survival signals via the Ang-1/Tie2 pathway. In contrast, targeting VEGFR-2 plus the platelet-derived growth factor receptor (PDGFR)-beta system (PDGFR-beta) signaling (by SU6668) rapidly forced 40% of tumor blood vessels into regression, rendering these tumors hypoxic as shown by phosphorescence quenching. TUNEL staining, electron microscopy, and apoptosis blocking experiments suggest that VEGFR-2 plus PDGFR-beta targeting enforced tumor blood vessel regression by inducing endothelial cell apoptosis. We further show that this is achieved by an interference with pericyte-endothelial cell interaction. This study provides novel insights into the mechanisms of how 1) pericytes may provide escape strategies to anti-angiogenic therapies and 2) novel concepts that target not only endothelial cells but also pericyte-associated pathways involved in vascular stabilization and maturation exert potent anti-vascular effects.

Topics: Animals; Apoptosis; Cell Survival; Hypoxia; Indoles; Microcirculation; Models, Biological; Neoplasms; Neovascularization, Pathologic; Oxindoles; Pericytes; Platelet-Derived Growth Factor; Propionates; Pyrroles; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

The International Conference on Molecular Targets and Therapeutics, jointly sponsored by the American Association for Cancer Research (AACR), National Cancer Institute (NCI) and European Organization for Research and Treatment of Cancer (EORTC), was held in Boston on November 17-21, 2003. It offered updates of the latest developments and emerging trends in anti-cancer research. One of the most exciting areas was the development of molecular target-specific therapeutics that have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells. Signifying the coming of age of tumour-specific targets and agents was the recurring theme, to urgently develop and validate biomarker assays as surrogate endpoints; both for showing that targeted agents act as expected and for providing proof of concept in the scientific rationale of new agents. Given the dominance of protein tyrosine kinase inhibitors in small-molecule drug design, a strong case was made for the implementation of phospho-proteomics or signal transduction signatures and pharmaco-proteomics or chemotherapeutic scans in phase I/II trials--or for the future "Nanolab", eloquently described by Leroy Hood. However, molecular targeted agents-other than imanitib (Gleevec)--have yet to enter broad clinical use and several presentations described efforts for improving classical (cytotoxic) chemotherapeutic agents by targeting them selectively to tumour cells.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Drug Delivery Systems; Enzyme Inhibitors; Gefitinib; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Neoplasms; Proteomics; Pyrroles; Quinazolines; Sunitinib

This is the first preclinical report evaluating a trimodal therapy consisting of irradiation, chemotherapy, and antiangiogenesis in the context of a multimodal anticancer strategy. The combination of the folate antimetabolite pemetrexed, SU5416, a receptor tyrosine kinase inhibitor of VEGFR2, and irradiation was investigated in human endothelial cells and tumor cell lines.. Primary isolated human umbilical vein endothelial cells (HUVEC), human dermal microvascular endothelial cells (HDMEC), and human glioblastoma (U87) and prostate cancer cells (PC3) were exposed to pemetrexed (2 h) alone and in combination with SU5416 (2 h). When combined with irradiation up to 8 Gy, fixed concentrations of pemetrexed (1.06 muM) and SU5416 (1.0 muM) were used. Proliferation and clonogenic assays were conducted with endothelial and tumor cells. The migration/invasion ability of endothelial cells and the ability to produce tubular structures were tested in Matrigel and tube formation assays. Apoptosis was measured by sub-G1 DNA and caspase-3 flow cytometry. To investigate underlying cell signaling, immunocytochemistry was used to detect Akt survival signaling involvement.. Triple combination using only a low-toxicity drug exposure of pemetrexed and SU5416 results in greater response than each treatment alone or than each combination of two modalities in all tested endothelial and tumor cell models. Triple combination substantially inhibits proliferation, migration/invasion, tube formation, and clonogenic survival. Triple combination also induced the highest rate of apoptosis in HDMEC and HUVEC as indicated by sub-1 G1 and caspase-3 assessment. Interestingly, triple combination therapy also reduces proliferation and clonogenic survival significantly in U87 and PC3 tumor cell lines. SU5416 potently inhibited Akt phosphorylation which could be induced by radiation and radiochemotherapy in human endothelial cells.. Our findings demonstrate the high antiendothelial/antitumoral efficacy of the concurrent administration of irradiation, chemotherapy, and angiogenesis inhibition in vitro. A potential explanation for the favorable combination would be that VEGF signaling inhibition downregulates Akt survival signaling upon activation by radiation and/or chemotherapy. The data also suggest that endothelial cell apoptosis may have an important role in the benefits of the presented therapy.

Topics: Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Combined Modality Therapy; Endothelial Cells; Glutamates; Guanine; Humans; Indoles; Neoplasms; Neovascularization, Pathologic; Pemetrexed; Protein-Tyrosine Kinases; Pyrroles; Tumor Stem Cell Assay

The cancer process in a combination of two kinds of events: a multistep cellular genetic defects giving cells independent growth and great adaptation capability, a multistep interactions profiles with what is called the stromal reaction from the original in situ tumor to the invasive metastatic and angiogenic tumor. The immune system plays an important role in the control of the cancer process but always must be seen as a part integrated in the stromal reaction. In order to boost the immune system capability to treat a cancer we must never forget these cellular and tissular dimensions. Interleukins, growth factors and monoclonal antibodies are new agents are able to bring immunotherapy of cancer to reality. Interleukin 2 did not match our dreams of the ideal factor which can stimulate the defective immune system and bring the cancer evolution to an end. The little but real remissions obtained with the IL-2 high dose protocols still sustains our trust of the immune system as a critical barrier to cancer evolution but the numerous side effects reminds us that cytokines are not to be used as antibiotics and hormones. IL-2 is a regulator of the immune system at the microenvironment level, therefore flooding the blood circulation with high IL-2 doses is not appropriate. We have also to understand that IL-2 can interact directly with cancer cells and also with stromal cells (endothelial and fibroblastic cells), the outcome of IL-2 immunotherapy is not restricted to the interactions with immune cells.

Topics: Cytokines; Humans; Immunotherapy; Indoles; Interleukin-2; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oxindoles; Propionates; Protein-Tyrosine Kinases; Pyrroles; Receptors, Interleukin-2

MGI114, ET743, BBR3464, ZD0473, ZD9331, BN80915, J107088, F11782, XR11576, BMS247550, PS341, UCN01, ISIS 3521, STI571, ZD1839, IMC-C225, OSI774, SU5416, DNA minor and major grooves, chimeric proteins, ribonucleotide reductase, topoisomerases, tubuline, proteasome, protein kinase C, bcr-abl, EGF or VEGF tyrosine kinase receptors are code names (somewhat barbarian) and targets for new drugs which will complement the therapeutic arsenal of the twenty-first century oncologist. This review provides a survey their clinical advances.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Boronic Acids; Bortezomib; Dioxoles; Indoles; Isoquinolines; Neoplasms; Organoplatinum Compounds; Protease Inhibitors; Pyrazines; Pyrroles; Quinazolines; Sesquiterpenes; Tetrahydroisoquinolines; Trabectedin

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biomedical Research; Drug Design; Drug Industry; Drugs, Investigational; Endothelial Growth Factors; Erlotinib Hydrochloride; Germany; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Lymphokines; Neoplasms; Pyrroles; Quinazolines; Signal Transduction; United States; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Angiogenesis Inhibitors; Endothelium, Vascular; Humans; Indoles; Neoplasms; Pyrroles; Thromboembolism; Thrombophilia; Treatment Outcome

The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (PC3), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Division; Cell Movement; Cell Survival; Drug Synergism; Endostatins; Endothelium, Vascular; Female; Glioblastoma; Humans; Indoles; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Neoplasms; Neovascularization, Pathologic; Prostatic Neoplasms; Pyrroles; Ultrasonography; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Benzamides; Benzoquinones; Cell Cycle Proteins; DNA-Binding Proteins; E2F Transcription Factors; Gefitinib; Genes, Tumor Suppressor; HSP90 Heat-Shock Proteins; Humans; Imatinib Mesylate; Indoles; Lactams, Macrocyclic; Mutation; Neoplasms; Phosphoric Monoester Hydrolases; Piperazines; PTEN Phosphohydrolase; Pyrimidines; Pyrroles; Quinazolines; Rifabutin; Signal Transduction; Sirolimus; Transcription Factors; Tumor Suppressor Proteins

A study designed to compare the effects on VEGF-induced angiogenesis of a number of known anti-angiogenic agents together with some novel derivatives thereof was undertaken. Thus the isoflavone biochanin A 1[structure: see text], indomethacin 2[structure: see text], the 3-arylquinoxaline SU1433 and its derivatives 3-6[structure: see text], the benzoic acid derivative 7[structure: see text], the oxindoles SU5416 8[structure: see text] and SU6668 11[structure: see text], together with their simple N-benzyl derivatives 9, 10, and 12[structure: see text] were selected for study. Using an in vitro assay the compounds were evaluated for their ability to inhibit VEGF-induced angiogenesis in HUVECs, and the cytotoxicity of representative compounds was also studied in tumour cell lines using 24-h exposure. The results indicate that the SU compounds, SU1433, SU 5416 and SU6668, are more potent inhibitors of VEGF-induced angiogenesis than indomethacin or the naturally occurring biochanin A, presumably because they inhibit VEGF receptor signalling. Blocking one of the phenolic OH groups of SU1433 reduced anti-angiogenic activity, as did blocking the NH groups of SU5416 and SU6668. Cytotoxicity studies indicate that none of the compounds examined exhibited cytotoxicity at anti-angiogenic concentrations.

Topics: Angiogenesis Inhibitors; Endothelium, Vascular; Humans; Indoles; Isoflavones; Neoplasms; Neovascularization, Pathologic; Oxindoles; Propionates; Pyrroles; Quinoxalines

In the setting of target-based anticancer drug development, it is critical to establish that the observed preclinical activity can be attributed to modulation of the intended target in early phase trials in human subjects. This paradigm of target modulation allows us to determine a Phase II or III dose (optimal biochemical/biological modulatory dose) that may not necessarily be the maximum tolerated dose. A major obstacle to target-based (often cytostatic) drug development has been obtaining relevant tumor tissue during clinical trials of these novel agents for laboratory analysis of the putative marker of drug effect.. From 1989 to present, we have completed seven clinical trials in which the end point was a biochemical or biological modulatory dose in human tumor tissues (not surrogate tissue). Eligibility enrollment required that patients have a biopsiable lesion either with computerized tomography (CT) guidance or direct visualization and consent to sequential (pre and posttreatment) biopsies.. A total of 192 biopsies were performed in 107 patients. All but 8 patients had sequential pre and posttreatment biopsies. Seventy-eight (73%) of the 107 patients had liver lesion biopsies. In eight patients, either one or both biopsies contained insufficient viable tumor tissue or no tumor tissue at all for analysis. Of a total of 99 patients in whom we attempted to obtain paired biopsies, a total of 87 (88%) were successful. Reasons for failure included patient refusal for a second biopsy (n = 2), vasovagal reaction with first biopsy precluding a second biopsy (n = 1), subcapsular hepatic bleeding (n = 1), and most commonly obtaining necrotic tumor, fibrous, or normal tissue in one of the two sequential biopsies (n = 8).. This is the first and largest reported series demonstrating that with adequate precautions and experience, sequential tumor biopsies are feasible and safe during early phase clinical trials.

Topics: Animals; Antineoplastic Agents; Biopsy; Carmustine; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Doxorubicin; Fenretinide; Guanine; Humans; Indoles; Neoplasms; O(6)-Methylguanine-DNA Methyltransferase; Paclitaxel; Pyrroles; Tomography, X-Ray Computed; Treatment Outcome; Xenograft Model Antitumor Assays

The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.

Topics: Administration, Oral; Angiogenesis Inhibitors; Aniline Compounds; Animals; Biological Availability; Cell Line; CHO Cells; Cricetinae; Enzyme Inhibitors; Humans; Mice; Models, Molecular; Neoplasms; Neovascularization, Pathologic; Phosphorylation; Phthalazines; Proto-Oncogene Proteins; Pyridines; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Structure-Activity Relationship; Transfection; Vascular Endothelial Growth Factor Receptor-1

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cell Division; Cetuximab; Clinical Trials as Topic; Endothelial Growth Factors; ErbB Receptors; Humans; Indoles; Lymphokines; Neoplasms; Pyrroles; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors