| Summary |
Hematopoietic cells frequently become resistant to the effects of chemotherapeutic drugs and this presents a major problem with current therapeutic approaches. Drug resistant cells are able to overcome the cytotoxic effects of chemotherapeutic drugs rendering treatments less effective. Patients often relapse after treatment only to be diagnosed with a drug resistant form of cancer that has a poor prognosis. Recently it was thought that the drug pumps MRP-1 and MDR-1 were responsible for the drug resistance seen in these resistant cell types. FL5.12 is an early hematopoietic murine cell line derived from BALB/c fetal liver and has germ line immunoglobulin (Ig) and T-cell receptor (TcR) genes. It is an interleukn-3 (IL-3) dependent cell line with a low spontaneous transformation rate to cytokine independence. McCubrey's group at East Carolina University has used parental and drug resistant forms of FL5.12 cells named FL/Doxo, to look for increases in the expression level and activity of the drug pumps MRP-1 and MDR-1. Rhodamine 123 exclusion assay, western blot analysis and mRNA all failed to show any increase or differences in expression in either cytokine dependent FL5.12 or drug resistant FL/Doxo (McCubrey et al, 2008). The mitogen-activated protein kinases (MAPKs) represent a group of signal transduction molecules with oncogenic potential in many cell types. Human malignancies have been shown to occur from the dysřgulation of some members of the MAPKs family (Lee et al., 2002). FL/Doxo express lower levels of the tumor suppressor protein p53, which is often involved in the cellular response to doxorubicin and the downstream target proapoptotic proteins such as Puma and Bok when compared to the parental cell line. FL/Doxo expresses higher levels of MEK, ERiC and Akt implicating the importance of both Raf/MEK/ERK and PI3K/Akt/mTOR pathways in the drug resistance seen in the drug resistant FL/Doxo cell line. Drug resistant and drug sensitive hematopoietic cell lines will be used to investigate the mechanisms which lead to the ineffectiveness of current therapeutic approaches in treating leukemia. |
| General note | Presented to the faculty of the Department of Biology. |
| General note | Advisor: James A. McCubrey |
| Dissertation note | M.S. East Carolina University 2008 |
| Bibliography note | Includes bibliographical references (leaves 115-116). |
| Genre/form | Academic theses. |
| Genre/form | Academic theses. |
| Genre/form | Thèses et écrits académiques. |
