Eradication of interleukin 5-transfected J558L plasmacytomas in mice by hydrogen peroxide-generating Stealth...

Certain human tumors are extensively infiltrated by eosinophils and contain extracellular deposits of eosinophil peroxidase, which uses hydrogen peroxide as a substrate to produce highly toxic hypohalous acids. We hypothesized that J558L HI, an interleukin 5-transfected murine plasmacytoma that is infiltrated by numerous degranulating eosinophils, would be especially sensitive to killing by hydrogen peroxide generated by glucose oxidase (beta-D-glucose:oxygen-oxido reductase; EC 1.13.4). Here we report that 4 i.v. injections of 0.5 ml of hydrogen peroxide-generating, anionic Stealth liposomes containing 50 micrograms of glucose oxidase eradicated s.c. implants of 10(6) J558L HI plasmacytoma cells in 6 of 13 mice. By contrast, the J558L HI tumors grew rapidly in 13 of 13 untreated mice and in 10 of 10 mice treated with daily i.v. injections of 50 micrograms of unencapsulated (free) glucose oxidase (P = 0.002 by log-rank test of survival curves constructed using the Kaplan-Meier method). Antisense transfected J558L tumors that did not contain eosinophils were not eradicated by the peroxide-generating liposomes in any of the 10 mice that were tested. Treatment with the liposomes was well tolerated for the first three doses (given on days 3, 4, and 5 after tumor inoculation). The fourth dose given on day 10 produced significant allergic toxicity and was, therefore, omitted in a second trial with only minimal reduction in the therapeutic response. We conclude that peroxide-generating, anionic Stealth liposomes can eradicate plasmacytomas infiltrated by eosinophils in mice. Our results, therefore, suggest that peroxide-generating compounds may be a useful experimental approach for treating those human tumors that are naturally infiltrated by eosinophils but resistant to conventional therapies.