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Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro.

Zhang P, Gao WY, Turner S, Ducatman BS - Mol. Cancer (2003)

Bottom Line: Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells.We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology & Cancer Center, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV 26506-9203, USA. pzhang@hsc.wvu.edu

ABSTRACT

Background: Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer.

Results: We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2-3 microM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 microM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor alpha, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR alpha phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-alpha expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.

Conclusion: These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

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Related in: MedlinePlus

Comparison of Gleevec effects on A540 cells with the human 293 kidney cells. A549 cells and human 293 cells were cultured and treated with Gleevec as described above using the concentrations listed. The culture conditions were identical to those described in Figure 1.
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Figure 3: Comparison of Gleevec effects on A540 cells with the human 293 kidney cells. A549 cells and human 293 cells were cultured and treated with Gleevec as described above using the concentrations listed. The culture conditions were identical to those described in Figure 1.

Mentions: We first test to see if Gleevec can inhibit the growth of A549 cells under the culture conditions. We have chosen to perform the experiments under the normal culture condition since we reasoned that the effect of Gleevec on tumor cells, if any, should be under the normal, not serum free condition. Therefore, we chose to add the drug directly into the culture medium containing 5% fetal calf serum. A549 lung cancer cells were plated at two cell densities into the 96 well plates, and Gleevec was added to the culture medium. We used the MTT assays to assess the viability of the tumor cells treated with or without the drug. It was evident that increasing concentrations of Gleevec in the culture medium inhibited the growth of A549 cells in a dose dependent manner. The concentration of Gleevec to inhibit 50% cell growth (IC50) was estimated to be around 2–3 μM (Figure 1), whereas the IC50 of cisplatin on A549 cells was estimated to be 64–70 μM (Figure 2). We have also seen that Gleevec can inhibit the growth of human 293 kidney cells, but at slightly higher concentration (4 μM). The IC50 concentration for A549 cells didn't appear to have inhibitory effects on human 293 cells (Figure 3). These results showed that Gleevec alone can indeed inhibit the growth of A549 lung carcinoma cells. The inhibitory effect of Gleevec on the A549 cells appeared to be in a therapeutic range of the drug as demonstrated in chronic myelogenous leukemia cells from the patients.


Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro.

Zhang P, Gao WY, Turner S, Ducatman BS - Mol. Cancer (2003)

Comparison of Gleevec effects on A540 cells with the human 293 kidney cells. A549 cells and human 293 cells were cultured and treated with Gleevec as described above using the concentrations listed. The culture conditions were identical to those described in Figure 1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC149413&req=5

Figure 3: Comparison of Gleevec effects on A540 cells with the human 293 kidney cells. A549 cells and human 293 cells were cultured and treated with Gleevec as described above using the concentrations listed. The culture conditions were identical to those described in Figure 1.
Mentions: We first test to see if Gleevec can inhibit the growth of A549 cells under the culture conditions. We have chosen to perform the experiments under the normal culture condition since we reasoned that the effect of Gleevec on tumor cells, if any, should be under the normal, not serum free condition. Therefore, we chose to add the drug directly into the culture medium containing 5% fetal calf serum. A549 lung cancer cells were plated at two cell densities into the 96 well plates, and Gleevec was added to the culture medium. We used the MTT assays to assess the viability of the tumor cells treated with or without the drug. It was evident that increasing concentrations of Gleevec in the culture medium inhibited the growth of A549 cells in a dose dependent manner. The concentration of Gleevec to inhibit 50% cell growth (IC50) was estimated to be around 2–3 μM (Figure 1), whereas the IC50 of cisplatin on A549 cells was estimated to be 64–70 μM (Figure 2). We have also seen that Gleevec can inhibit the growth of human 293 kidney cells, but at slightly higher concentration (4 μM). The IC50 concentration for A549 cells didn't appear to have inhibitory effects on human 293 cells (Figure 3). These results showed that Gleevec alone can indeed inhibit the growth of A549 lung carcinoma cells. The inhibitory effect of Gleevec on the A549 cells appeared to be in a therapeutic range of the drug as demonstrated in chronic myelogenous leukemia cells from the patients.

Bottom Line: Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells.We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology & Cancer Center, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV 26506-9203, USA. pzhang@hsc.wvu.edu

ABSTRACT

Background: Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer.

Results: We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2-3 microM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 microM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor alpha, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR alpha phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-alpha expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.

Conclusion: These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

Show MeSH
Related in: MedlinePlus