A combination of E. coli DNA fragments and modified lipopolysaccharides as a cancer immunotherapy

Abstract

The use of Escherichia coli DNA or lipopolysaccharide (LPS) as an immunotherapy is often associated with unacceptable toxicity and insufficient therapeutic effects. In this study, we investigated the efficacy of using a combination of bacterial DNA fragments and LPS as an anticancer agent. LPS was isolated from an E. coli strain expressing short-carbohydrate-chain-containing LPS and subjected to alkaline hydrolysis to remove lipid A. The ability to induce tumor necrosis factor-α (TNF-α) release in human whole blood cells was significantly lower for the LPS devoid of lipid A than for its parent form. The immunostimulating activity of E. coli DNA fragments of various sizes were tested. Those of 0.2-0.5 kb in size exhibited the highest activity in whole blood assays, whereas those of size 0.5-2.0 kb exhibited the highest adjuvant activity in mice. A combination of 0.5-2.0-kb DNA fragments and modified LPS at a ratio of 100:1, designated CIA07, exhibited higher immunostimulating activity than each substance alone, and its antitumor activity was significantly higher than that of Bacillus Calmette-Guerin in a mouse bladder cancer model. An intraperitoneal injection of CIA07 at a dose of 25 mg/kg body weight caused no apparent adverse effects in mice and guinea pigs. Taken together, these data demonstrate that CIA07 exhibits potent immunostimulating activity with no apparent toxicity, and therefore warrant the further development of CIA07 as an immunotherapy for cancer treatment. © 2006 Elsevier Ltd. All rights reserved.