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Rapid screening of novel agents for combination therapy in sarcomas.

Cubitt CL, Menth J, Dawson J, Martinez GV, Foroutan P, Morse DL, Bui MM, Letson GD, Sullivan DM, Reed DR - Sarcoma (2013)

Bottom Line: Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984).We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines.Sorafenib and topotecan demonstrated a mixed response.

View Article: PubMed Central - PubMed

Affiliation: Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA ; Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

ABSTRACT
For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies.

No MeSH data available.


Related in: MedlinePlus

MRI imaging response to combination therapy in Ewing sarcoma. T2-weighted fast spin-echo images (TE/TR = 72/2400 ms) with a resolution of 312 mm demonstrating the tumor sizes in dasatinib (a), combination (b), triciribine (c), and untreated (d) at day 6. Representative datasets were chosen to reflect the overall trend of tumor size and growth. Lesions are indicated by arrows.
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fig3: MRI imaging response to combination therapy in Ewing sarcoma. T2-weighted fast spin-echo images (TE/TR = 72/2400 ms) with a resolution of 312 mm demonstrating the tumor sizes in dasatinib (a), combination (b), triciribine (c), and untreated (d) at day 6. Representative datasets were chosen to reflect the overall trend of tumor size and growth. Lesions are indicated by arrows.

Mentions: Cells were treated continuously with dasatinib and triciribine for 72 hours at a constant 2 : 1 molar ratio. All six tested cell lines indicated a synergistic interaction, with CI values for the pediatric cell lines ranging from 0.06 to 0.39 with a mean value of 0.24 (Table 2). The CI values for the two leiomyosarcoma cell lines were 0.24 and 0.27. The concurrent treatment of dasatinib with either MK-2206 or triciribine resulted in more than additive activity, and caspase 3/7 activation was also readily detected, indicating that effects on viability are at least partially mediated through apoptosis (Figure 3).


Rapid screening of novel agents for combination therapy in sarcomas.

Cubitt CL, Menth J, Dawson J, Martinez GV, Foroutan P, Morse DL, Bui MM, Letson GD, Sullivan DM, Reed DR - Sarcoma (2013)

MRI imaging response to combination therapy in Ewing sarcoma. T2-weighted fast spin-echo images (TE/TR = 72/2400 ms) with a resolution of 312 mm demonstrating the tumor sizes in dasatinib (a), combination (b), triciribine (c), and untreated (d) at day 6. Representative datasets were chosen to reflect the overall trend of tumor size and growth. Lesions are indicated by arrows.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824404&req=5

fig3: MRI imaging response to combination therapy in Ewing sarcoma. T2-weighted fast spin-echo images (TE/TR = 72/2400 ms) with a resolution of 312 mm demonstrating the tumor sizes in dasatinib (a), combination (b), triciribine (c), and untreated (d) at day 6. Representative datasets were chosen to reflect the overall trend of tumor size and growth. Lesions are indicated by arrows.
Mentions: Cells were treated continuously with dasatinib and triciribine for 72 hours at a constant 2 : 1 molar ratio. All six tested cell lines indicated a synergistic interaction, with CI values for the pediatric cell lines ranging from 0.06 to 0.39 with a mean value of 0.24 (Table 2). The CI values for the two leiomyosarcoma cell lines were 0.24 and 0.27. The concurrent treatment of dasatinib with either MK-2206 or triciribine resulted in more than additive activity, and caspase 3/7 activation was also readily detected, indicating that effects on viability are at least partially mediated through apoptosis (Figure 3).

Bottom Line: Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984).We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines.Sorafenib and topotecan demonstrated a mixed response.

View Article: PubMed Central - PubMed

Affiliation: Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA ; Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

ABSTRACT
For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies.

No MeSH data available.


Related in: MedlinePlus