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A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model.

Towner RA, Ihnat M, Saunders D, Bastian A, Smith N, Pavana RK, Gangjee A - BMC Cancer (2015)

Bottom Line: Tumor volumes (21-31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119 (p < 0.001), anti-VEGF (p < 0.05) and anti-c-Met (p < 0.001) antibody treatments, and TMZ-treated (p < 0.05) mice, compared to untreated controls.Perfusion data indicated that both AG119 and TMZ were able to reduce the effect of decreasing perfusion rates significantly (p < 0.05 for both), when compared to untreated tumors.It was also found that IC50 values for AG119 were much lower than those for TMZ in T98G and U251 cells.

View Article: PubMed Central - PubMed

Affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA. Rheal-Towner@omrf.org.

ABSTRACT

Background: High grade gliomas (HGGs; grades III and IV) are the most common primary brain tumors in adults, and their malignant nature ranks them fourth in incidence of cancer death. Standard treatment for glioblastomas (GBM), involving surgical resection followed by radiation and chemotherapy with temozolomide (TMZ) and the anti-angiogenic therapy bevacizumab, have not substantially improved overall survival. New therapeutic agents are desperately needed for this devastating disease. Here we study the potential therapeutic agent AG119 in a pre-clinical model for gliomas. AG119 possesses both anti-angiogenic (RTK inhibition) and antimicrotubule cytotoxic activity in a single molecule.

Methods: GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice. Animal survival was assessed, and tumor volumes and vascular alterations were monitored with morphological magnetic resonance imaging (MRI) and perfusion-weighted imaging, respectively.

Results: Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p < 0.001) compared to untreated tumors. Tumor volumes (21-31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119 (p < 0.001), anti-VEGF (p < 0.05) and anti-c-Met (p < 0.001) antibody treatments, and TMZ-treated (p < 0.05) mice, compared to untreated controls. Perfusion data indicated that both AG119 and TMZ were able to reduce the effect of decreasing perfusion rates significantly (p < 0.05 for both), when compared to untreated tumors. It was also found that IC50 values for AG119 were much lower than those for TMZ in T98G and U251 cells.

Conclusions: These data support further exploration of the anticancer activity AG119 in HGG, as this compound was able to increase animal survival and decrease tumor volumes in a mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine transferase (MGMT) mediated resistance, as is the case with TMZ, indicating that AG119 may be potentially useful in treating resistant gliomas.

No MeSH data available.


Related in: MedlinePlus

Cytotoxic effect of AG119 on temozolomide (TMZ)-resistant cells. Cells, U251 (TMZ-sensitive; MGMT−) and T98G (TMZ-resistant; MGMT+), were treated with AG119 or TMZ for 48 h and viability determined with Presto Blue. Data are mean IC50 values (μM) ± SEM, n = 4–9 independent experiments
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Fig4: Cytotoxic effect of AG119 on temozolomide (TMZ)-resistant cells. Cells, U251 (TMZ-sensitive; MGMT−) and T98G (TMZ-resistant; MGMT+), were treated with AG119 or TMZ for 48 h and viability determined with Presto Blue. Data are mean IC50 values (μM) ± SEM, n = 4–9 independent experiments

Mentions: Finally, it was determined whether AG119 retained sensitivity in a TMZ resistant glioma cell line. T98G cells overexpress O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair enzyme conferring resistance to a number of alkylating agents, including TMZ [25]. When comparing drug sensitivity of T98G cells to a relatively drug sensitive glioma line, U251, it was found that as expected the T98G cells were significantly less sensitive to TMZ (Fig. 4). It was also found that TMZ-resistant T98G cells were sensitive to AG119, as were the TMZ-sensitive U251 cells (Fig. 4; IC50 comparison).Fig. 4


A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model.

Towner RA, Ihnat M, Saunders D, Bastian A, Smith N, Pavana RK, Gangjee A - BMC Cancer (2015)

Cytotoxic effect of AG119 on temozolomide (TMZ)-resistant cells. Cells, U251 (TMZ-sensitive; MGMT−) and T98G (TMZ-resistant; MGMT+), were treated with AG119 or TMZ for 48 h and viability determined with Presto Blue. Data are mean IC50 values (μM) ± SEM, n = 4–9 independent experiments
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4504175&req=5

Fig4: Cytotoxic effect of AG119 on temozolomide (TMZ)-resistant cells. Cells, U251 (TMZ-sensitive; MGMT−) and T98G (TMZ-resistant; MGMT+), were treated with AG119 or TMZ for 48 h and viability determined with Presto Blue. Data are mean IC50 values (μM) ± SEM, n = 4–9 independent experiments
Mentions: Finally, it was determined whether AG119 retained sensitivity in a TMZ resistant glioma cell line. T98G cells overexpress O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair enzyme conferring resistance to a number of alkylating agents, including TMZ [25]. When comparing drug sensitivity of T98G cells to a relatively drug sensitive glioma line, U251, it was found that as expected the T98G cells were significantly less sensitive to TMZ (Fig. 4). It was also found that TMZ-resistant T98G cells were sensitive to AG119, as were the TMZ-sensitive U251 cells (Fig. 4; IC50 comparison).Fig. 4

Bottom Line: Tumor volumes (21-31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119 (p < 0.001), anti-VEGF (p < 0.05) and anti-c-Met (p < 0.001) antibody treatments, and TMZ-treated (p < 0.05) mice, compared to untreated controls.Perfusion data indicated that both AG119 and TMZ were able to reduce the effect of decreasing perfusion rates significantly (p < 0.05 for both), when compared to untreated tumors.It was also found that IC50 values for AG119 were much lower than those for TMZ in T98G and U251 cells.

View Article: PubMed Central - PubMed

Affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA. Rheal-Towner@omrf.org.

ABSTRACT

Background: High grade gliomas (HGGs; grades III and IV) are the most common primary brain tumors in adults, and their malignant nature ranks them fourth in incidence of cancer death. Standard treatment for glioblastomas (GBM), involving surgical resection followed by radiation and chemotherapy with temozolomide (TMZ) and the anti-angiogenic therapy bevacizumab, have not substantially improved overall survival. New therapeutic agents are desperately needed for this devastating disease. Here we study the potential therapeutic agent AG119 in a pre-clinical model for gliomas. AG119 possesses both anti-angiogenic (RTK inhibition) and antimicrotubule cytotoxic activity in a single molecule.

Methods: GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice. Animal survival was assessed, and tumor volumes and vascular alterations were monitored with morphological magnetic resonance imaging (MRI) and perfusion-weighted imaging, respectively.

Results: Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p < 0.001) compared to untreated tumors. Tumor volumes (21-31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119 (p < 0.001), anti-VEGF (p < 0.05) and anti-c-Met (p < 0.001) antibody treatments, and TMZ-treated (p < 0.05) mice, compared to untreated controls. Perfusion data indicated that both AG119 and TMZ were able to reduce the effect of decreasing perfusion rates significantly (p < 0.05 for both), when compared to untreated tumors. It was also found that IC50 values for AG119 were much lower than those for TMZ in T98G and U251 cells.

Conclusions: These data support further exploration of the anticancer activity AG119 in HGG, as this compound was able to increase animal survival and decrease tumor volumes in a mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine transferase (MGMT) mediated resistance, as is the case with TMZ, indicating that AG119 may be potentially useful in treating resistant gliomas.

No MeSH data available.


Related in: MedlinePlus