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Cancer-killers from macrophages.

Cancer-killers from macrophages

Many cancer deaths occur not from theprimary tumor, but from the secondary growths, called metastases, spawned by that primary cancer. Although oncologists try to hunt down and eliminate metastases, even with today's sophisticated diagnostic tools, "it is not likely that we will diagnose metastases or tumors in internal organs that are smaller than a centimeter cubed' (clusters of roughly 1 billion cells), says Isaiah Fidler of the M.D. Anderson Hospital and Tumor Institute in Houston. But he and others are pioneering a strategy to seek and destroy those unseen metastases--one that employs the body's own defense system.

Potentially less toxic than existingchemotherapies, this treatment may also prove more effective, Fidler's studies indicate. The cancer researcher recently described preliminary animal studies suggesting its promise at the Second International Conference on Anticarcinogenesis and Radiation Protection last month in Gaithersburg, Md.

The strategy uses liposomes, microscopiclipid-based, laboratory-made containers, to carry drugs that "activate' macrophages--scavenging cells that ordinarily hunt down, swallow up and degrade foreign particles such as viruses. Though, in the 1970s, researchers demonstrated that these cells could also be activated to attack tumor cells, a problem developed over how to deliver the activators so that they wouldn't cause undue toxicity or degrade too quickly. Fidler's work now suggests that liposomes provide an ideal controlled-release system for delivering activators.

He fashions his liposomes from thesame lipoproteins found in all cell membranes, including those of red blood cells. A thin ribbon of the lipoproteins is wound into a microscopic, onion-like roll. Then he chemically sandwiches macrophage-activating chemicals between layers of the "onion.' As they encounter liposomes, macrophages gobble them up --just as they would aging red cells. Digesting the liposomes releases the activators.

In studies where malignant melanomahad been surgically removed from mouse footpads, metastases to the lymph nodes and lungs killed animals within 80 days. But eight to 12 intravenous injections of liposomes, containing the macrophage activators gamma-interferon, muramyl tripeptide or both, saved 75 percent of Fidler's treated animals.

Similar results were recently observedin a study at the University of Wisconsin in Madison with 18 dogs following their surgery for osteogenic sacromas. By the time this canine disease is initially diagnosed, metastases have almost always implanted in the lungs, leading to death-- despite surgery--within three months. But six of the nine dogs treated with liposomes carrying muramyl tripeptide are still alive more than 200 days after surgery, notes E. Gregory MacEwen, head of the study. As for the three treated animals that died, MacEwen believes their tumor burden was already too high for the activated macrophages to counter.

Since macrophages naturally home inon inflammation, Fidler notes, he tried pretreating the site of fibrosarcoma metastases in mice with low-dose irradiation to induce inflammation. The result: three-fold better mouse survival than with radiation or liposomes only.

And in the April JOURNAL OF THE NATIONALCANCER INSTITUTE, researchers at the Roswell Park Memorial Institute in Buffalo report better survival and less toxicity in mice whose metastases of colon cancer were treated with liposometrapped doxorubicin, rather than just the cancer drug alone. Though macrophage activation was not examined here, Eric G. Mayhew says other work by his group suggests "liposomal doxorubicin can potentiate the host defense--similar to what the people at M.D. Anderson have shown with other drugs.'
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Author:Raloff, Janet
Publication:Science News
Date:Apr 4, 1987
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