Title: Macrophage Role in the Anti-Prostate Cancer Response to One Class of Antiangiogenic Agent
1Macrophage Role in the Anti-Prostate Cancer
Response to One Class of Antiangiogenic Agent
2Background
- 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).
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. -
4Linomide
- 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.
5Additional antiangiogenic drugs that inhibit
macrophage function
- Thalidomide
- Genistein
- Pentoxifylline
-
6Effects 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.
9Effects 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)
10Effects 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.
11Effects 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.
13Conclusion
- 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.