Vascular Disrupting Agents: A Novel Mechanism of Action in the Battle Against Non-Small Cell Lung Cancer

Abstract

1. Explain the molecular mechanism of action of vascular disrupting agents. Evaluate the preclinical results of vascular disrupting agents.3. Assess the preliminary clinical results of vascular disrupting agents in the treatment of patients with NSCLC.This article is available for continuing medical education credit at CME.TheOncologist.com. The aim of this review is to discuss the hypothesized molecular mechanisms of action of VDAs and their early preclinical and clinical results, emphasizing ASA404, combretastatin A-4 disodium phosphate, ABT-751, and NPI-2358, reported in the treatment of non-small cell lung cancer, which is the leading cause of cancer death worldwide, and also to discuss future developments in this cancer population. The Oncologist CME CME ABSTRACT

Detection of Tumor Response to a Vascular Disrupting Agent by Hyperpolarized 13C Magnetic Resonance Spectroscopy

“…Here, we report a preclinical study of the response of lymphoma tumors to the vascular disrupting agent (VDA), combretastatin-A4-phosphate (CA4P), as detected by measuring changes in tumor metabolism of hyperpolarized [1- C]pyruvate and lactate was decreased by 34% within 6 hours of CA4P treatment and remained at this lower level at 24 hours. The rate constant describing production of labeled malate from hyperpolarized [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]fumarate increased 1.6-fold and 2.5-fold at 6 and 24 hours after treatment, respectively, and correlated with the degree of necrosis detected in histologic sections. Although DCE-MRI measurements showed a substantial reduction in perfusion at 6 hours after treatment, which had recovered by 24 hours, DW-MRI showed no change in the apparent diffusion coefficient of tumor water at 6 hours after treatment, although there was a 32% increase at 24 hours (P < 0.02) when regions of extensive necrosis were observed by histology.…”

“…CA4 at 100 mg/kg has been shown to yield rapid and prolonged interruption of blood flow in both human xenograft (MDA-MB-231 breast carcinoma) and murine (CaNT adenocarcinoma) tumor models, resulting in extensive tumor cell necrosis within 24 hours of drug treatment (4). Following successful phase I clinical trials (5), phase II/III trials have been initiated with CA4P as both a single agent in anaplastic thyroid carcinoma (6) and a combination of carboplatin and paclitaxel for ovarian cancer (7) and chemotherapynaive non-small cell lung carcinoma (8).…”

“…Using this technique, both the location of the molecule and, more importantly, the dynamics of its subsequent conversion into other cell metabolites can be imaged in vivo. The rate of conversion of hyperpolarized [1-13 C]pyruvate into [1][2][3][4][5][6][7][8][9][10][11][12][13] C]lactate in a murine model of lymphoma was shown to decrease significantly as early as 24 hours after cytotoxic therapy (21,22), whereas the conversion of hyperpolarized [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]fumarate, a tricarboxylic acid cycle intermediate, into [1,4-13 C 2 ]malate was increased and shown to correlate in vitro with levels of tumor cell necrosis (23).…”

“…We show here that the exchange of hyperpolarized 13 C label between pyruvate and lactate is reduced in murine lymphoma tumors within 24 hours of treatment with CA4P and that the production of [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]malate from hyperpolarized [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]fumarate is increased over the same period. These measurements have been compared directly with DCE-MRI measurements of tumor perfusion and DW-MRI measurements of tumor cell necrosis.…”

“…In a previous study, we presented evidence in vitro that the production of [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]malate from hyperpolarized [1,4-13 C 2 ]fumarate is related to tumor cell necrosis [23]. Because fumarate shows only relatively slow transport across the plasma membrane, the onset of necrosis results in an increased rate of access of the labeled fumarate to intracellular fumarase and hence in the formation of labeled malate within the relatively short lifetime of the hyperpolarized 13 C label.…”