Macrophage Role in the Anti-Prostate Cancer Response to One Class of Antiangiogenic Agent

1. Macrophage Role in the Anti-Prostate Cancer Response to One Class of Antiangiogenic Agent By Ezra Kassin

2. Background • Tumor-associated macrophages (TAMs) are immune cells which play a positive or negative role in tumor angiogenesis. • Can either promote angiogenesis in tumors by secreting tumor necrosis factor-ά (TNF). • Or inhibit angiogenesis by producing granulocyte-macrophage colony stimulating factor (GM-CSF). • GM-CSF stimulates production of antiangiogenic protein plasminogen activator inhibitor type-2 (PAI-2).

3. TAMs can have both positive and negative effects on tumor angiogenesis. • Any drug that attempts to inhibit angiogenesis by means of affecting TAMs within the cancer should do so without inhibiting the positive effects.

4. Linomide • An antiangiogenic drug used to inhibit growth of prostate cancer in vivo (rodents and humans). • Reduces the number of TAMs withinprostate cancer tumors. • Linomide has been shown to work well in combination with other chemotherapeutic drugs.

5. Additional antiangiogenic drugs that inhibit macrophage function • Thalidomide • Genistein • Pentoxifylline

6. Effects of Different antiangiogenic agents on TAM Function and Growth of Cancer Cells in Vitro • Inhibition of TAM was tested by exposing mouse macrophage cells to different concentrations of each drug in an in vitro system. • All the antiangiogenic agents inhibited the cells ability to secrete TNF. • Thalidomide, Pentoxifylline and genistein all inhibited the secretion of GM-CSF. • Linomide, even at higher concentrations, did not inhibit GM-CSF. (Table1)

7. To test whether the agents could directly inhibit growth of prostate cancer cells, MAT-Lu rat prostate cancer cells were used as a model. • MAT-Lu cells are highly metastatic cancer cells, mimicking the most lethal form of prostate cancer. • The cells were exposed to the antiangiogenic agents and a cell count was performed. • Neither Thalidomide nor Pentoxifylline significantly decreased cell growth.

8. Linomide and Genistein each decreased the growth of the cells significantly.

9. Effects of Antiangiogenic Agents on Tumor Blood Vessel Density, and on Growth of MAT-Lu Cancer Cells in Vivo. • To determine whether the antiangiogenic agents functioned in vivo, rats infected with the MAT-Lu prostate cancer were treated every day with the drugs for three weeks. • Autopsies were performed to determine TAM numbers, tumor blood vessel density and reduction of tumor growth. (Table2)

10. Effects of Combinations of Linomide and other Antiangiogenic agents in vivo. • The rats exposed to the MAT-Lu cell were treated daily with combinations of Linomide and the other agents. • There was no combination that demonstrated additional suppression of cell growth. • Combinations of Linomide and either Thalidomide or Pentoxifylline, significantly reduced the effect of Linomide alone.

11. Effects of Linomide, Thalidomide or Pentoxifylline on PAI-2 Production by Macrophages • The results in table 2 show that treatment with Pentoxifylline, genistein or Thalidomide decreased TAMs to a greater extent than Linomide, but Linomide showed greater overall antitumor activity. • This could be due to the inhibition of GM-CSF by Thalidomide,Genistein and pentoxifylline and not by Linomide. • GM-CSF stimulates production of Plasminogen activator inhibitor type-2(PAI-2) which is an antiangiogenic protein produced by the body.

12. Linomide stimulates macrophages to produce PAI-2 reducing the infiltration and migration of the tumor.

13. Conclusion • All four antiangiogenic agents tested had an affect on tumor associated macrophages (TAM) function. • They all inhibit the secretion of tumor necrosis factor (TNF), which is an angiogenic substance. • In contrast to the other three agents Linomide has no effect on granulocyte macrophage colony stimulating factor (GM-CSF), leading to production of plasminogen activator inhibitor-2 (PAI-2).

14. Linomide is shown to be the most effective against prostate cancer.