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Linomide Plus TAMs Inhibit Growth of Prostate Cancer Tumors in Mice
November 10, 1998 Linomide, a drug that failed to pan out for treating multiple sclerosis because it caused heart problems, may prove useful for prostate cancer. Tests on animals have shown intriguing effects of Linomide on tumor-associated macrophages (TAMs) which play a dual role in tumor growth and tumor angiogenesis. Researchers report that Linomide is more powerful than three other anti-angiogenesis drugs, thalidomide, pentoxifylline, and genistein, when used on prostate cancer tumors implanted in mice and rats.
John Isaacs, Ph.D.    "Linomide's unique properties could make it more effective against prostate cancer than other anti-angiogenic agents that we tested," say Drs. Ingrid Joseph and John Isaacs of The Johns Hopkins University School of Medicine, Baltimore, Maryland. Their report is published in the November 4th issue of the Journal of the National Cancer Institute.

Tumor Growth and Macrophage Messengers
Angiogenesis is the process by which solid tumors form new blood vessels. Tumors cannot grow bigger than about 1-3 cubic mm without their own blood supply. Ordinary macrophages (white blood cells) circulating in the patient's blood as part of the immune system are recruited by the tumor site to help the tuimor grow.
    Tumor-associated macrophages (TAMs) play a dual role in angiogenesis. Most macrophages are large cells that "eat" and digest microorganisms. As part of a healthy immune system macrophages eat bacteria and cause inflammation (making wounds get hot and swollen as they heal). They spit out (or secrete) various chemicals including proteins that work as messengers running between cells. These cytokines (from Gk. kytos a hollow vessel [cell] + Gk. kinesis movement) help regulate the immune response. Recruited by tumors, the cytokines help switch phases of tumor growth on or off.
    Some proteins made by TAMs promote angiogenesis, others tell it when to stop. Angiogenesis-promoting proteins include proteases; vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (EGF-1), and tumor necrosis factor-a (TNF-a). Angiogenesis-inhibiting switches include granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates production of an anti-angiogenesis protein called PAI-2.

Linomide Compared with Thalidomide and Genistein
The Johns Hopkins researchers were looking to see if Linomide and three other drugs might act on tumor macrophages to hold back angiogenesis-promoting effects without interfering with secretion of messenger chemicals such as GM-CSF and PAI-2, which themselves impede tumor growth..
    In rats implanted with human prostate cancer, Linomide (roquinimex) reduced the number of macrophages within the tumors (TAMs) while selectively inhibiting macrophage secretion of "TNF-a but not of GM-CSF." Linomide also stimulated PAI-2. This shows, the researchers say, that Linomide is more effective than thalidomide, pentoxifylline, and genistein, which unlike Linomide downregulated both of the two tumor-inhibiting chemicals.
    In rats dosed for three weeks (10mg/ml.), Linomide cut the number of macrophages less dramatically than the rival drugs (Linomide, by 46%; thalidomide, by 94%; pentoxifylline, by 71%; genistein, by 96%). But Linomide "reduced tumor blood vessel density and tumor growth" more than any of the other agents and produced a 69% reduction in prostate cancer tumor growth.
    The researchers are interested in combining Linomide with other drugs. They say chemotherapies including androgen ablation (hormonal therapy) might make it even more effective. Larry Wahl and Hynda Kleinman, in an editorial, see many avenues of further research. This prostate cancer study, they say, "points to a new mechanism of Linomide action." They say that what they found out about how Linomide stimulates PAI-2 is worth following up in view of other evidence of antitumor effects of PAI-2.


SOURCES: Joseph IBJK, Isaacs JT. Macrophage Role in the Anti-Prostate Cancer Response to One Class of Antiangiogenic Agents. Journal of the National Cancer Institute Nov. 4, 1998;90:1648-1653.

Wahl LM, Kleinman HK. Tumor-Associated Macrophages as Targets for Cancer Therapy. Editorial, Journal of the National Cancer Institute Nov. 4, 1998;90: 1583-84

You might like to visit Dr. John Isaacs' abstracts of some earlier articles

For therapeutic perspective see a press-release from Pharmacia, the Swedish company that makes Linomide: Side effects of Linomide in Multiple Sclerosis Phase III trials

Journal of the National Cancer Institute is online with restricted access.

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November 10 1998. Page modified December 26, 1998

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