The <it>in vitro </it>effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours
<p>Abstract</p> <p>Background</p> <p>Activation of the epidermal growth factor receptor (EGFR) triggers downstream signaling pathways that regulate many cellular processes involved in tumour survival and growth. Gefitinib ('Iressa') is an orally active tyrosin...
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| Format: | Article |
| Language: | English |
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BMC
2004-11-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/4/83 |
| _version_ | 1811246938270466048 |
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| author | Knight Louise A Di Nicolantonio Federica Whitehouse Pauline Mercer Stuart Sharma Sanjay Glaysher Sharon Johnson Penny Cree Ian A |
| author_facet | Knight Louise A Di Nicolantonio Federica Whitehouse Pauline Mercer Stuart Sharma Sanjay Glaysher Sharon Johnson Penny Cree Ian A |
| author_sort | Knight Louise A |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Activation of the epidermal growth factor receptor (EGFR) triggers downstream signaling pathways that regulate many cellular processes involved in tumour survival and growth. Gefitinib ('Iressa') is an orally active tyrosine kinase inhibitor (TKI) targeted to the ATP-binding domain of EGFR (HER1; erbB1).</p> <p>Methods</p> <p>In this study we have used a standardised ATP-based tumour chemosensitivity assay (ATP-TCA) to measure the activity of gefitinib alone or in combination with different cytotoxic drugs (cisplatin, gemcitabine, oxaliplatin and treosulfan) against a variety of solid tumours (n = 86), including breast, colorectal, oesophageal and ovarian cancer, carcinoma of unknown primary site, cutaneous and uveal melanoma, non-small cell lung cancer (NSCLC) and sarcoma. The IC50 and IC90 were calculated for each single agent or combination. To allow comparison between samples the Index<sub>SUM </sub>was calculated based on the percentage tumour growth inhibition (TGI) at each test drug concentration (TDC). Gefitinib was tested at concentrations ranging from 0.0625–2 microM (TDC = 0.446 microg/ml). This study represents the first use of a TKI in the assay.</p> <p>Results</p> <p>There was heterogeneity in the degree of TGI observed when tumours were tested against single agent gefitinib. 7% (6/86) of tumours exhibited considerable inhibition, but most showed a more modest response resulting in a low TGI. The median IC50 value for single agent gefitinib in all tumours tested was 3.98 microM. Interestingly, gefitinib had both positive and negative effects when used in combination with different cytotoxics. In 59% (45/76) of tumours tested, the addition of gefitinib appeared to potentiate the effect of the cytotoxic agent or combination (of these, 11% (5/45) had a >50% decrease in their Index<sub>SUM</sub>). In 38% of tumours (29/76), the TGI was decreased when the combination of gefitinib + cytotoxic was used in comparison to the cytotoxic alone. In the remaining 3% (2/76) there was no change observed.</p> <p>Conclusion</p> <p>The <it>in vitro </it>model suggests that gefitinib may have differential effects in response to concomitant cytotoxic chemotherapy with the agents tested during this study. The mechanism involved may relate to the effect of TKIs on growth rate versus their effect on the ability of the cell to survive the stimulus to apoptosis produced by chemotherapy.</p> |
| first_indexed | 2024-04-12T15:00:45Z |
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| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-12T15:00:45Z |
| publishDate | 2004-11-01 |
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| spelling | doaj.art-2f30717cf9cb43fdbd1676ce8017120b2022-12-22T03:28:05ZengBMCBMC Cancer1471-24072004-11-01418310.1186/1471-2407-4-83The <it>in vitro </it>effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumoursKnight Louise ADi Nicolantonio FedericaWhitehouse PaulineMercer StuartSharma SanjayGlaysher SharonJohnson PennyCree Ian A<p>Abstract</p> <p>Background</p> <p>Activation of the epidermal growth factor receptor (EGFR) triggers downstream signaling pathways that regulate many cellular processes involved in tumour survival and growth. Gefitinib ('Iressa') is an orally active tyrosine kinase inhibitor (TKI) targeted to the ATP-binding domain of EGFR (HER1; erbB1).</p> <p>Methods</p> <p>In this study we have used a standardised ATP-based tumour chemosensitivity assay (ATP-TCA) to measure the activity of gefitinib alone or in combination with different cytotoxic drugs (cisplatin, gemcitabine, oxaliplatin and treosulfan) against a variety of solid tumours (n = 86), including breast, colorectal, oesophageal and ovarian cancer, carcinoma of unknown primary site, cutaneous and uveal melanoma, non-small cell lung cancer (NSCLC) and sarcoma. The IC50 and IC90 were calculated for each single agent or combination. To allow comparison between samples the Index<sub>SUM </sub>was calculated based on the percentage tumour growth inhibition (TGI) at each test drug concentration (TDC). Gefitinib was tested at concentrations ranging from 0.0625–2 microM (TDC = 0.446 microg/ml). This study represents the first use of a TKI in the assay.</p> <p>Results</p> <p>There was heterogeneity in the degree of TGI observed when tumours were tested against single agent gefitinib. 7% (6/86) of tumours exhibited considerable inhibition, but most showed a more modest response resulting in a low TGI. The median IC50 value for single agent gefitinib in all tumours tested was 3.98 microM. Interestingly, gefitinib had both positive and negative effects when used in combination with different cytotoxics. In 59% (45/76) of tumours tested, the addition of gefitinib appeared to potentiate the effect of the cytotoxic agent or combination (of these, 11% (5/45) had a >50% decrease in their Index<sub>SUM</sub>). In 38% of tumours (29/76), the TGI was decreased when the combination of gefitinib + cytotoxic was used in comparison to the cytotoxic alone. In the remaining 3% (2/76) there was no change observed.</p> <p>Conclusion</p> <p>The <it>in vitro </it>model suggests that gefitinib may have differential effects in response to concomitant cytotoxic chemotherapy with the agents tested during this study. The mechanism involved may relate to the effect of TKIs on growth rate versus their effect on the ability of the cell to survive the stimulus to apoptosis produced by chemotherapy.</p>http://www.biomedcentral.com/1471-2407/4/83 |
| spellingShingle | Knight Louise A Di Nicolantonio Federica Whitehouse Pauline Mercer Stuart Sharma Sanjay Glaysher Sharon Johnson Penny Cree Ian A The <it>in vitro </it>effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours BMC Cancer |
| title | The <it>in vitro </it>effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours |
| title_full | The <it>in vitro </it>effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours |
| title_fullStr | The <it>in vitro </it>effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours |
| title_full_unstemmed | The <it>in vitro </it>effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours |
| title_short | The <it>in vitro </it>effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours |
| title_sort | it in vitro it effect of gefitinib iressa alone and in combination with cytotoxic chemotherapy on human solid tumours |
| url | http://www.biomedcentral.com/1471-2407/4/83 |
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