Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature:Implications for Cancer Treatment

Abstract

Anticancer agents that interfere with tubulin functions are widely used in the clinic and have a broad spectrum of activity against both haematological malignancies and solid tumours. These Microtubule-Targeting Agents (MTAs), such as the taxanes and Vinca alkaloids, bind to the beta subunit of alpha/beta tubulin and disrupt microtubule dynamics in tumour cells, ultimately leading to mitotic block and subsequent cell death. Recently, MTAs have received considerable interest as potential tumour-selective anti-angiogenic and vascular-disrupting agents. Angiogenesis is a keystone of tumour progression and metastasis and targeting the formation of new blood vessels within the tumour is therefore regarded as a promising strategy for cancer therapy. In this regard, conventional MTAs can be given on daily schedules at non-toxic doses (metronomic dosing) to disturb tumour angiogenesis. Some MTAs can also act as vascular-disrupting agents. After briefly reviewing the classical mechanisms involved in the anti-tumour action of MTAs, we will focus on the latest studies investigating the molecular and cellular processes underlying the anti-angiogenic and the vascular-disrupting properties of these agents. We will also review and discuss the potential clinical development and the limitations of MTAs used as tumour-specific anti-vascular molecules.

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

“…To confirm and further substantiate these findings, we evaluated this dosing regimen using a larger number of animals bearing tumors that varied in size between 200 and 600 mm 3 . Animals were treated with two 28-day cycles of BNC105P at 40 mg/kg.…”

“…The dose level of 40 mg/kg produced an average 52% regression in tumor size in the first 2 weeks posttreatment and a prolongation in suppression of tumor growth up to day 95 (mean of 544.19 mm 3 , SD ± 921.37 mm 3 ) versus saline control (mean of 1745.68 mm 3 , SD ± 1,444.97 mm 3 at day 51 when these animals were euthanized). A subsequent study investigated the effect of a 28-day dosing cycle with BNC105P administration at 40 mg/kg on day 1 and day 8 of each cycle.…”

“…Many of the colchicinesite binding agents that exhibit VDA capability were based on natural products such as combretastatins (CA4P, OXi-4503, and AVE-8062), colchicines (ZD6126), and phenylahistin (NPI-2358), whereas others were discovered independently (MN-029 and EPC2407; refs. 3,4).…”

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

“…Microtubules play a crucial role in biological processes such as motility, cell division and mitotic spindle formation, and are therefore an important target for anticancer drugs. Treatment of cells with microtubule targeting agents has been shown to result in cell cycle arrest, and induction of apoptosis, which accounts for the extensive use of microtubule-interfering agents in tumor chemotherapy [35][36][37]. Indeed, collapsed cytoskeleton was accompanied with strong induction of G2/M or G0/ G1 arrest in cucurbitacin treated cells.…”

The use of the orthotopic model to validate antivascular therapies for cancer

“…The ligand-based therapies include (1) biological response modifiers or cytokines, such as tumour necrosis factor (TNF) (Corti and Ponzoni, 2004), (2) certain chemotherapeutic drugs, such as vinka alkaloids and arsenic trioxide (Griffin, 2005;Pasquier, 2007), and (3) a variety of strategies that use either antibodies, peptides, or growth factors for binding selectively to tumour vessels (Chaplin, 2006;Pastorino, 2006;Pero, 1999;Siemann, 2004a;Siemann, 2004b;Thorpe, 2004). Moreover, different approaches based on linking antibodies or peptides recognizing tumour-associated Orthotopic tumour models and antivascular therapy 549 vasculature, to toxins, pro-coagulant, and pro-apoptotic effector molecules to induce endothelial cell damage have also been explored (Siemann, 2004b;Thorpe, 2004).…”