semaxinib and Skin-Neoplasms

Kaposi's sarcoma (KS) is the most common neoplasm associated with human immunodeficiency virus-1 (HIV-1) infection. KS involves the skin and mucous membranes as well as other organs and can lead to tumor-associated edema and ulcerations. Despite therapy with highly active antiviral agents, most patients with HIV-1-related KS eventually develop disseminated disease. In the treatment of KS, a strong rationale exists for the use of agents that inhibit vascular endothelial growth factor (VEGF). Angiogenesis appears to be an important feature of this disease, and recent experimental studies have demonstrated the role of VEGF and its receptors in the pathogenesis of KS. Thus, therapeutic agents that target the VEGF pathway may be an effective strategy in reducing the tumor growth and edema associated with KS. Phase I study results with SU5416, a synthetic low molecular-weight inhibitor of the VEGF-Flk-1/KDR receptor tyrosine kinase, demonstrate that this agent is well tolerated. Preliminary results show that in a majority of patients with autoimmune deficiency syndrome (AIDS)-related disease, SU5416 clearly has biological activity (it flattens, shrinks, or dissolves lesions and reduces or resolves edema) or stabilizes the disease. Angiogenesis inhibition with SU5416 is a promising therapeutic approach in treating patients with KS, and further clinical evaluation is currently under way.

Topics: AIDS-Related Opportunistic Infections; Angiogenesis Inhibitors; Antiviral Agents; Endothelial Growth Factors; Enzyme Inhibitors; HIV-1; Humans; Indoles; Lymphokines; Neovascularization, Pathologic; Protein Isoforms; Protein-Tyrosine Kinases; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Mitogen; Receptors, Vascular Endothelial Growth Factor; Sarcoma, Kaposi; Skin Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Vascular endothelial growth factor (VEGF) is a key regulator in angiogenesis. Preclinical and clinical data support the role of VEGF and angiogenesis in renal cell carcinoma (RCC), melanoma (M), and soft tissue sarcoma (STS). The tyrosine kinase inhibitor SU5416 is a potent inhibitor of the VEGF receptors 1 and 2.. We investigated 145 mg/m(2) SU5416 twice weekly in patients with advanced or metastatic RCC, M, and STS. The primary objectives were efficacy and safety. Disease assessments were performed after 4 and 8 weeks of treatment and every 2 months thereafter. Documented stable disease (SD) lasting for > or =3 months was considered an antitumor response.. A group of 29 patients was entered in the RCC trial, 20 patients in the M trial, and 31 patients in the STS trial. Response was observed in 6 (1 minor response and 5 SDs) of 24 evaluable patients (25%) in the RCC group, 6 (1 minor response and 5 SDs) of 26 patients (23%) in the STS group, and none of the patients in the M group. Progression-free survival ranged from 7 to 252 days (median 59 days) in the RCC group, from 7 to 260 days (median 60 days) in the STS group, and from 14 to 139 days (median 41 days) in the M group. Toxicities observed were those reported previously for SU5416.. SU5416 single agent is well tolerated. The antitumor response was low in patients with RCC and STS, whereas no responses were seen in patients with M.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease-Free Survival; Enzyme Inhibitors; Female; Humans; Indoles; Kidney Neoplasms; Male; Melanoma; Middle Aged; Neovascularization, Pathologic; Protein-Tyrosine Kinases; Pyrroles; Sarcoma; Skin Neoplasms; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Angiogenesis Inhibitors; Fatal Outcome; Humans; Indoles; Liver Failure; Male; Middle Aged; Pyrroles; Renal Insufficiency; Sarcoma, Kaposi; Skin Neoplasms

The proto-oncogene c-myc is involved in the regulation of cell proliferation, differentiation, and apoptosis. In this study, we used an inducible transgenic mouse model in which c-Myc was targeted to the epidermis and, after activation, gave rise to hyperplastic and dysplastic skin lesions and to dermal angiogenesis, involving both vascular endothelial growth factor (VEGF) receptor-1 and VEGF receptor-2. After c-Myc activation, VEGF mRNA was expressed in postmitotic keratinocytes where it colocalized with transgene expression and areas of tissue hypoxia, suggesting a role of hypoxia in VEGF induction. In vitro, c-Myc activation alone was able to induce VEGF protein release and in conjunction with hypoxia, c-Myc activation further increased VEGF protein. Blocking VEGF signaling in vivo significantly reduced dermal angiogenesis, demonstrating the importance of VEGF as a mediating factor for the c-Myc-induced angiogenic phenotype.

Topics: Animals; Cell Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Keratinocytes; Mice; Neovascularization, Physiologic; Oxindoles; Papilloma; Precancerous Conditions; Propionates; Proto-Oncogene Proteins c-myc; Pyrroles; RNA, Messenger; Skin; Skin Neoplasms; Tamoxifen; Transcription Factors; Transgenes; Vascular Endothelial Growth Factor A

Vascular endothelial growth factor (VEGF)-Flk-1/KDR tyrosine kinase signaling pathway plays a pivotal role in tumor angiogenesis. Targeting this angiogenic signaling pathway presents a promising alternative for the treatment of neoplasms. However, recent experimental and clinical studies have suggested that VEGF-Flk-1/KDR activity is unevenly distributed throughout the tumor microvasculature. To further evaluate this phenomenon, the regional differences in VEGF-Flk-1/KDR signaling activities in vivo were studied using intravital fluorescence videomicroscopy in an experimental murine brain tumor model. Regional VEGF-Flk-1/KDR was assessed using the small molecule inhibitor SU5416, which selectively inhibits the tyrosine kinase receptor Flk-1. C(6) glioblastoma cells were implanted into the dorsal skinfold chamber preparation of nude mice. The process of tumor vascularization was repeatedly assessed over 22 days. SU5416 treatment resulted in a significant reduction in tumor vascular density (p<0.05). Regional microvascular evaluation indicated that the magnitude of this antiangiogenic effect was pronounced in the more angiogenic and better vascularized peritumoral areas than in the intratumoral areas of the tumor microvasculature. These results demonstrate regional differences in Flk-1 activity in vivo that may have significant impact on the susceptibility of tumors to compounds that target VEGF-Flk-1/KDR. This finding should be considered in upcoming clinical trials targeting individual signal transduction systems in cancer patients.

Topics: Analysis of Variance; Angiogenesis Inhibitors; Animals; Disease Models, Animal; Endothelial Growth Factors; Enzyme Inhibitors; Glioblastoma; Indoles; Lymphokines; Male; Mice; Mice, Nude; Microcirculation; Microscopy, Fluorescence; Microscopy, Video; Neoplasm Transplantation; Neovascularization, Pathologic; Protein Isoforms; Protein-Tyrosine Kinases; Pyrroles; Rats; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Mitogen; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Skin Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors