semaxinib and Colorectal-Neoplasms

The realization that the growth and spread of tumors are dependent on angiogenesis has created new avenues of research designed to help us to better understand cancer biology and to facilitate the development of new therapeutic strategies. However, the process of angiogenesis consists of multiple sequential and interdependent steps with a myriad of positive and negative regulators of angiogenesis being involved. The survival of tumors and thus their metastases are dependent on the balance of endogenous angiogenic and antiangiogenic factors such that the outcome favors increased angiogenesis. Several growth factors have been identified that regulate angiogenesis in colon cancer; the most important of these is vascular endothelial growth factor. In addition, specific integrins such as alphavbeta3 and alpha5beta1 mediate endothelial cell survival and have been shown to be overexpressed on the endothelium of colon cancer. These angiogenic mediators thus serve as targets for therapy of metastatic colon cancer and have shown promise in preclinical trials.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Colonic Neoplasms; Colorectal Neoplasms; Endothelial Growth Factors; Extracellular Matrix; Humans; Indoles; Integrins; Intercellular Signaling Peptides and Proteins; Lymphokines; Neovascularization, Pathologic; Oxindoles; Propionates; Pyrroles; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Recent trials have established the IFL combination (fluorouracil [5-FU], leucovorin, and irinotecan [CPT-11, Camptosar]) as a new standard first-line therapy for patients with metastatic colorectal cancer. Median survival for such patients treated with IFL still ranges from approximately 14 to 18 months, however, underscoring the need for new agents with novel mechanisms of action. Angiogenesis has become an attractive target for anticancer drug development, based on its important roles in tumor growth, invasion, and metastasis. A potent stimulus of angiogenesis is vascular endothelial growth factor (VEGF); two agents developed to inhibit VEGF activity, bevacizumab (Avastin) and SU5416, are in advanced clinical trials. Based on encouraging results in phase I and II trials with bevacizumab, a randomized trial of IFL with or without this monoclonal antibody is under way. Similarly, a randomized trial of 5-FU and leucovorin with or without the tyrosine kinase inhibitor SU5416 has recently completed accrual and results are pending. SU5416 is also being tested in a phase I/II trial combined with IFL. This article briefly reviews preclinical and clinical data leading to the current trials of these two agents in patients with colorectal cancer.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Disease-Free Survival; Endothelial Growth Factors; Female; Fluorouracil; Humans; Indoles; Irinotecan; Leucovorin; Male; Neovascularization, Pathologic; Prognosis; Pyrroles; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome

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

One of the most studied pro-angiogenic factors involved in the development of colorectal cancer is the vascular endothelial growth factor (VEGF). The small molecule tyrosine kinase inhibitor semaxanib (SU5416) is one of the several agents targeting the VEGF signaling pathway, and its development centered mostly in the treatment of colorectal cancer.. We designed and conducted an NCI-sponsored trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of semaxanib given twice weekly in combination with weekly irinotecan in patients with advanced colorectal cancer who had failed at least one prior treatment. The irinotecan dose was fixed at 125 mg/m(2) given weekly for 4 weeks followed by 2 weeks of rest. Patients with prior pelvic irradiation received a reduced dose of 100 mg/m(2). The semaxanib dose was escalated, going from 85 to 110 mg/m(2) and finally to 145 mg/m(2).. Ten patients were treated in our study and all were evaluable for toxicity. There were no drug-related Grade 4 toxicities. There was one episode of Grade 3 headache and one episode of Grade 3 vomiting. The most common Grades 1 and 2 toxicities included diarrhea, abdominal cramping, anemia and nausea. Nine patients completed at least one 6 week cycle of treatment and were considered evaluable for response. Among those nine, two had a partial response, three had stable disease and four had progressive disease after the first cycle.. Both irinotecan and semaxanib could be given at their full single-agent recommended doses without significant toxicity, and the combination showed signs of clinical activity. However, owing to discouraging results from Phase III trials, it is unlikely that this combination will be further explored.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Indoles; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Protein Kinase Inhibitors; Pyrroles; Treatment Outcome

Determine the toxicity, tolerability, and pharmacokinetics of SU5416, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, coadministered with bolus 5-fluorouracil (5-FU), leucovorin, and irinotecan (IFL) in untreated patients with metastatic colorectal cancer.. SU5416 (85 or 145 mg/m2) was administered twice weekly throughout a 6-week period along with standard IFL (4 weeks on/2 weeks off). Plasma samples were assayed for SU5416, irinotecan, and SN-38 by reverse-phase HPLC. Contrast enhanced, color Doppler sonography was performed on patients at the MTD to identify changes in tumor perfusion.. Eleven patients received treatment with SU5416 85 mg/m2 (n = 5) or 145 mg/m2 (n = 6). At 85 mg/m2, no DLTs were observed. At 145 mg/m2, grade 3 diarrhea and vomiting were observed during cycle 1; other grade 3 toxicities included fatigue, nausea, anorexia, anemia, pain, urinary retention, and hypertension. The pharmacokinetics of irinotecan and SN-38 were not altered by coadministration of SU5416. SU5416 pharmacokinetics were not altered by IFL. Contrast-enhanced, color Doppler sonography was performed on 2 patients and demonstrated reduced tumor perfusion after treatment in a patient who responded to treatment and increased perfusion in a patient who developed progressive disease. Three patients (27%) had confirmed partial responses, 2 patients (18%) had unconfirmed partial responses, and 4 patients (36%) had stable disease.. Twice weekly SU5416 can be administered with bolus IFL without unexpected toxicities or altering the pharmacokinetic behavior of the administered drugs. Changes in tumor blood perfusion can be detected by contrast-enhanced, color Doppler sonography. The further development of SU5416 was halted before this study was completed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Indoles; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pyrroles; Vascular Endothelial Growth Factor Receptor-2

The hypoxia-inducible factor (HIF) is a heterodimeric basic helix-loop-helix transcriptional factor and the activated HIF plays pivotal roles in various pathological conditions, including inflammation and cancer. HIF-1alpha overexpression has been observed in many common human cancers, including brain, breast, colon, lung, ovary, and prostate, and HIF-mediated genes, such as vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and insulin-like growth factor (IGF)-1, are associated with tumor angiogenesis, metastasis, and invasion. Therefore, the pro-oncogenic protein HIF is a novel target of cancer therapy. We examined the effects of VEGFR inhibitors, AAL993, SU5416, and KRN633, on suppression of HIF-1alpha accumulation under the hypoxic condition. We found that VEGFR tyrosine kinase inhibitors, AAL993, SU5416, and KRN633, possess dual functions: inhibition of VEGFR signaling and HIF-1alpha expression under the hypoxic condition. The detailed mechanistic study indicated that SU5416 and KRN633 suppressed HIF-1alpha expression through inhibition of both Akt and ERK phosphorylation signaling pathways, whereas AAL993 suppressed HIF-1alpha expression through ERK inhibition without affecting Akt phosphorylation.

Topics: Angiogenesis Inhibitors; Cell Culture Techniques; Cell Line, Tumor; Colorectal Neoplasms; DNA Primers; DNA-Directed DNA Polymerase; Female; Glyceraldehyde-3-Phosphate Dehydrogenases; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Indoles; Phenylurea Compounds; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Vascular Endothelial Growth Factor A

Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Camptothecin; Cell Proliferation; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Immunoenzyme Techniques; Immunohistochemistry; Indoles; Irinotecan; Male; Mice; Mice, Nude; Microcirculation; Pyrroles; Thrombospondin 1; Transplantation, Heterologous; Vascular Endothelial Growth Factor A

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; Hepatectomy; Humans; Indoles; Liver Neoplasms; Prognosis; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Survival Rate

Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity.. Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration.. Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion.. These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

Topics: Aged; Angiogenesis Inhibitors; Antigens, CD; Biomarkers, Tumor; CD24 Antigen; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Indoles; Lactoferrin; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 9; Membrane Glycoproteins; Middle Aged; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Protein-Tyrosine Kinases; Pyrroles; Reverse Transcriptase Polymerase Chain Reaction

The Authors review the natural history of colorectal cancer from the point of view of molecular biology and genetics from aberrant crypts foci and familiar adenomatous polyposis to hereditary non polyposis colon cancer and sporadic colorectal cancer. They carry out international literature about basis knowledges, experimental trials and personal studies. Up to day traditional colorectal cancer surgical treatments and adjuvant or neoadjuvant pharmacological therapy cannot be modified, nevertheless "new drugs generation" known as signal transduction inhibitor could, in the future, prove to be an effective cancer treatment. The Authors highlight recent experimental clinical trials probably able to prevent sporadic colorectal cancer spreading and precursor evolution.

Topics: Adenomatous Polyposis Coli; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Cetuximab; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; ErbB Receptors; Follow-Up Studies; Gefitinib; Genes, APC; Genes, DCC; Genes, p53; Genes, ras; Humans; Indoles; Mutation; Prognosis; Protein-Tyrosine Kinases; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Research; Time Factors

Topics: Angiogenesis Inhibitors; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Humans; Indoles; Protein-Tyrosine Kinases; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Colorectal Neoplasms; Disease Progression; Extracellular Matrix; Humans; Indoles; Matrix Metalloproteinases; Neoplasm Metastasis; Neovascularization, Pathologic; Pyrroles

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for "go/no go" in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the "go/no go" decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies. Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy). The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Decision Making; Disease Progression; Drug Evaluation; Drug Resistance, Neoplasm; Drugs, Investigational; Endothelial Growth Factors; Enzyme Inhibitors; Humans; Indoles; Lung Neoplasms; Lymphokines; Protein Isoforms; Protein-Tyrosine Kinases; Pyrroles; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors