The selective epidermal growth factor receptor tyrosine kinase inhibitor PD153035 suppresses expression of prometastasis phenotypes in malignant pleural mesothelioma cells in vitro
Sunday, May 1st, 2005.
The Journal of Thorscic Cardiovascular Surgery. 2005 May;129 (5):1010-7. [Link]
Cole GW Jr, Alleva AM, Reddy RM, Maxhimer JB, Zuo J, Schrump DS, Nguyen DM.
Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA
Abstract
Objective: Malignant pleural mesothelioma is notoriously refractory to aggressive multimodality therapy. Epidermal growth factor receptor expression has been observed on malignant pleural mesothelioma cells. Epidermal growth factor receptor-mediated signaling promotes tumorigenesis and metastasis of cancer cells. The purpose of this study is to evaluate the ability of the epidermal growth factor receptor tyrosine kinase inhibitor PD153035 to abrogate the expression of prometastasis phenotypes in malignant pleural mesothelioma cells in vitro.
Methods: Epidermal growth factor receptor expression of malignant pleural mesothelioma cells and primary normal cells was quantitated by means of flow cytometry. PD153035-mediated growth inhibition was determined by means of 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan and clonogenic assays. Cell motility and invasion of extracellular matrix was evaluated with in vitro wound-healing and Matrigel invasion assays, respectively. Vascular epidermal growth factor levels in conditioned media were measured by using enzyme-linked immunosorbent assay.
Results: Epidermal growth factor receptor expression was detected on all 6 cultured malignant pleural mesothelioma cells, with 4 of 6 having normal receptor expression and 2 of 6 overexpressing the receptor. PD153035 suppressed cell motility and cell invasion through a Matrigel membrane, regardless of the baseline epidermal growth factor receptor expression. Decreased vascular epidermal growth factor production and significant inhibition of growth only occurred in malignant pleural mesothelioma cells that overexpress epidermal growth factor receptor.
Conclusions: Epidermal growth factor receptor tyrosine kinase inhibitor PD153035 significantly inhibited motility and invasion in malignant pleural mesothelioma cells in vitro, regardless of their epidermal growth factor receptor expression levels. Inhibition of epidermal growth factor receptor-dependent signaling might be a useful strategy to diminish malignant pleural mesothelioma recurrence after aggressive cytoreductive surgery.
Glossary
- therapy
- any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.
- recurrence
- cancer that has come back after treatment. Local recurrence is when the cancer comes back at the same place as the original cancer. Regional recurrence is when the cancer appears in the lymph nodes near the first site. Distant recurrence is when it appears in organs or tissues (such as the lungs, liver, bone marrow, or brain) farther from the original site than the regional lymph nodes. Metastasis means that the disease has recurred at a distant site.
- oncology
- (on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.
- metastasis
- (meh-tas-teh-sis) the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream.
- flow cytometry
- (flow cy-tom-uh-tree) a test of tumor tissue to see how fast the tumor cells are reproducing and whether the tumor cells contain a normal or abnormal amount of DNA. This test is used to help predict how aggressive a cancer is likely to be. (See also ploidy, DNA, S-phase fraction.)
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- cancer
- malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
- multimodality therapy
- an approach to therapy which utilizes a variety of treatments at once as opposed to following only one mode of treatment.
- tumorigenesis
- production or formation of tumors.
- epidermal growth factor receptor
- The process of cell division, growth, differentiation and death is a highly regulated process. Several class of trans membrane receptors play a pivot role in this process, of these, epidermal growth factor receptor (EGFR) a member of Receptor Tyrosine Kinase (RTK) family are best known. These comprises of four receptors Erb B1/HER 1, Erb B2 / HER 2, Erb B3/ HER 3, and Erb B4 / HER 4. Of these HER 2 is the most favoured target. (Source: Manoj Pandey and K Chandramohan)
