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

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

• By Ezra Kassin

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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-? (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).

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• 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.

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Linomide

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

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Additional antiangiogenic drugs that inhibit
macrophage function

• Thalidomide
• Genistein
• Pentoxifylline

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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)

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• 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.

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

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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)

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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.

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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.

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

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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).

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