fosbretabulin and Glioblastoma

Long-term survivors of glioblastoma multiforme (GBM) are at high risk of developing second primary neoplasms, including leukemia. For these patients, the use of classic tyrosine kinase inhibitors (TKIs), such as imatinib mesylate, is strongly discouraged, since this treatment causes a tremendous increase of tumor and stem cell migration and invasion. We aimed to develop agents useful for the treatment of patients with GBM and chronic myeloid leukemia (CML) using an alternative mechanism of action from the TKIs, specifically based on the inhibition of tubulin polymerization. Compounds 7 and 25, as planned, not only inhibited tubulin polymerization, but also inhibited the proliferation of both GMB and CML cells, including those expressing the T315I mutation, at nanomolar concentrations. In in vivo experiments in BALB/cnu/nu mice injected subcutaneously with U87MG cells, in vivo, 7 significantly inhibited GBM cancer cell proliferation, in vivo tumorigenesis, and tumor growth, tumorigenesis and angiogenesis. Compound 7 was found to block human topoisomerase II (hTopoII) selectively and completely, at a concentration of 100 μM.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Female; Glioblastoma; Heterocyclic Compounds; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Methane; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Polymerization; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Tumor Cells, Cultured

Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC

Topics: Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glioblastoma; Humans; Microtubules; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship

Mathematical modeling techniques have been widely employed to understand how cancer grows, and, more recently, such approaches have been used to understand how cancer can be controlled. In this manuscript, a previously validated hybrid cellular automaton model of tumor growth in a vascularized environment is used to study the antitumor activity of several vascular-targeting compounds of known efficacy. In particular, this model is used to test the antitumor activity of a clinically used angiogenesis inhibitor (both in isolation, and with a cytotoxic chemotherapeutic) and a vascular disrupting agent currently undergoing clinical trial testing. I demonstrate that the mathematical model can make predictions in agreement with preclinical/clinical data and can also be used to gain more insight into these treatment protocols. The results presented herein suggest that vascular-targeting agents, as currently administered, cannot lead to cancer eradication, although a highly efficacious agent may lead to long-term cancer control.

Topics: Algorithms; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blood Vessels; Computer Simulation; Cytotoxins; Dacarbazine; Glioblastoma; Humans; Models, Biological; Neoplasms; Stilbenes; Temozolomide; Treatment Outcome