Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-dose therapy with stem cell rescue is a treatment option for patients with advanced solid tumors. Although this approach has promise for some pediatric cancers, especially neuroblastoma, it is limited by the risk of relapse posttransplant as well as concern about possible reinfused tumor cells in autologous stem cell products. Antiangiogenic agents given during and after recovery from high-dose therapy with stem cell rescue may decrease the risk of relapse. TNP-470 is an antiangiogenic agent now in clinical trials. Although it inhibits the growth of bone marrow (BM) colony-forming cells in vitro, no significant hematological toxicity has been seen in Phase I trials. To assess the feasibility of using antiangiogenic agents during the period of posttransplant hematopoietic engraftment, we have developed a model of stem cell transplant in mice. Mice were lethally irradiated and then rescued with stem cells containing a transgene expressed in the hematopoietic lineage. Mice were then treated with TNP-470 or placebo, and assessed for survival, successful engraftment, and kinetics of engraftment. Both treated and control mice demonstrated reliable multilineage engraftment as well as normal lymphoid maturation with no excess mortality in the treated group. WBCs were lower but still within the normal range at d+28 in mice treated with bolus TNP-470, but not in those treated with continuous infusion TNP-470, compared with controls. These data indicate that inhibitors of angiogenesis do not adversely impact engraftment after stem cell transplantation.
 ...
PMID:Angiogenesis inhibitor TNP-470 during bone marrow transplant: safety in a preclinical model. 1130 54

We have previously reported that combretastatin-A4 prodrug (CA4P), anantitubulin/antiangiogenic agent isolated from the South African willow tree Combretum caffrum, induced cell death primarily through mitotic catastrophe in a panel of human B-lymphoid tumors. In this study, we investigated the molecular aspects of the mitotic catastrophe and whether or not it shares the same pathways of apoptosis. For this we studied the effect of CA4P on selected markers of apoptosis [caspases 9 and 3, poly(ADP-ribose) polymerase (PARP), bcl-2, and bax] and G2-M protein regulators (p53, MDM2, 14-3-3sigma, GADD45, cdc2, cdc25, chk1, wee1, p21, and cyclin B1). The chronic lymphocytic leukemia cell line WSU-CLL was used for this purpose. Western blot analysis showed that 24 h of CA4P (5 nM) exposure induces caspase 9 activation and PARP cleavage. However, the addition of Z-Val-Ala-Asp-fluoromethylketone (a general caspase inhibitor) or Z-Leu-Glu(OMe)-His-Asp(OMe)-CH2F (a caspase 9 inhibitor) before CA4P treatment did not block cell death. No change in bcl-2 or bax protein expression was observed. Exposure of WSU-CLL cells to 4 and 5 nM CA4P was associated with overproduction of total p53 and no dramatic change in MDM2, 14-3-3sigma, GADD45, the cyclin-dependent kinase cdc2, its inhibitory phosphorylation, the cdc2-inhibitory kinase (wee1), chk1, or cdc25 hyperphosphorylation. The overaccumulation of p21 and cyclin B1 protein was obvious at 24 h. Furthermore, CA4P treatment showed an increase in the expression of a marker of mitosis (mitotic protein monoclonal-2 antibody) and an overaccumulation of the cyclin B in the nucleus. Our findings suggest that CA4P induces mitotic catastrophe and arrest of WSU-CLL cells mostly in the M phase independent of p53 and independent of chk1 and cdc2 phosphorylation pathways. Apoptosis is a secondary mechanism of death in a small proportion of cells through activation of caspase 9 and PARP cleavage. The two mechanisms of cell death, i.e., mitotic catastrophe and apoptosis, are independent of each other in our model.
 ...
PMID:Combretastatin-A4 prodrug induces mitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspase activation and poly(ADP-ribose) polymerase cleavage. 1217 7

Syndecan-1 (CD138) is a transmembrane heparin sulfate proteoglycan expressed on distinct stages of differentiation of B-lymphoid cells. Its prognostic value in B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated so far. The serum concentration of sCD138 and some angiogenesis-involved cytokines: vascular endothelial growth factor (VEGF), basis fibroblast growth factor (bFGF), and endostatin were studied in 52 previously untreated patients with B-CLL. We found that bFGF and sCD138 levels were significantly higher in B-CLL patients than in controls. In patients with sCD138 level or endostatin level below the median value the lymphocyte count was higher than in patients with serum level of those cytokines above the median value. In patients with progressive disease bFGF level was significantly higher and sCD138 level significantly lower than in patients with stable one. Moreover, high sCD138 level was associated with longer lymphocyte doubling-free survival, and, on the limit of statistical significance, a high endostatin level was associated with shorter progression-free survival. We conclude that serum sCD138 level is increased in early stage B-CLL patients and may have a positive prognostic value as to the dynamics of the disease.
 ...
PMID:Circulating sCD138 and some angiogenesis-involved cytokines help to anticipate the disease progression of early-stage B-cell chronic lymphocytic leukemia. 1695 90

A better understanding of the biology and pathogenesis of hematological malignancies has led to the development of immunotherapeutic and immunoregulatory drugs. Many of these agents have revolutionized the current treatment modalities, while others are under investigation. Rituximab (anti-CD20 antibody) has been established as the gold standard of treatment for aggressive B-cell lymphomas in combination with CHOP and has shown significant activity as monotherapy in the treatment of indolent B-cell lymphomas. In follicular lymphomas the combination of Rituximab with chemotherapy improves the outcome compared to chemotherapy alone. CD 20-based radioimmunotherapy, with the advantage of the bystander effect, represents an additional therapeutic alternative in B-cell lymphomas and may produce tumor regression in Rituximab resistant patients. The anti-CD52 monoclonal antibody, alemtuzumab, further expands the armamentarium against lymphoid malignancies producing high response rates in these entities. Antibody-targeted chemotherapy such as gemtuzumab ozogamicin, consisting of an anti-CD33 antibody combined to calicheamicin, has shown efficacy in the treatment of refractory acute myeloid leukemia; exact indications, timing and dosing schedule for optimized efficacy remain to be determined. Interferons have proven significant activity in cutaneous lymphomas, hairy cell leukemia and chronic myelogenous leukemia by mechanisms that are not fully elucidated. Thalidomide, by acting as an immunomodulatory and antiangiogenic agent can modulate neoplastic cells microenvironment and lead to disease control in multiple myeloma as well as in numerous other hematological malignancies. Bortezomib, a proteasome inhibitor, displays significant anti-tumor activity, especially in multiple myeloma and lymphoproliferative disorders. The addition of these agents in therapeutic regimens has improved considerably the treatment of hematological malignancies.
 ...
PMID:Immunotherapeutic and immunoregulatory drugs in haematologic malignancies. 1701 50