In this proposal, we will study the role of glutathione (GSH) and the selenium dependent GSH-peroxidase (Se-GPx) in multidrug resistance (MDR). BACKGROUND: MDR describes a clinically important form of drug resistance in which tumors that become refractory to one drug develop cross resistance to structurally unrelated agents. A common feature of MDR cells is decreased drug accumulation that is due to the increased expression of a membrane glycoprotein (P170). However, it has been suggested that unique patterns of MDR, involving multiple mechanisms, may emerge depending upon the selecting agent used to establish resistance. Clinical MDR is probably accompanied by cellular changes, in addition to P170, that combine to form a """"""""mixed MDR phenotype"""""""" that ultimately effects the tumor response to chemotherapy. LONG TERM GOAL: is to define what these other (i.e., non P-170) mechanisms of resistance are, and study how they interrelate with the P170 for the full expression of clinical drug resistance. PRELIMINARY RESULTS: we demonstrate that resistance to adriamycin (Adr) in several different MDR and de novo resistant colorectal cell lines was due to alterations in both drug accumulation i.e., P170) and in SH and Se-GPx, key components of a free radical detoxification pathway (Kramer et al., Science 241; 694, 1988). THIS PROPOSAL HAS THE FOLLOWING GOALS: 1) to establish whether the alterations in GSH and Se_GPx are a primary component of MDR cells (i.e., cells that express P170), or whether this mechanism of resistance is limited to only those tumor cell lines that acquired the MDR phenotype by selection with Adr; 2) to establish whether a mixed MDR phenotype involving alterations in both GS and P170 contribute to the intrinsic mechanisms of resistance in human colon cancer; 3) to study how the P170 and GSH-dependent mechanisms interrelate to fully express a """"""""mixed MDR phenotype""""""""; 4) to study the role of topoisomerase and free radical mediated mechanism of Adr cytoxicity in MDR cells; 5) to develop more selective inhibitors of the GSH free radical detoxification pathway as potential pharmacologic modifiers of drug resistance.
| Kramer, R; Weber, T K; Morse, B et al. (1993) Constitutive expression of multidrug resistance in human colorectal tumours and cell lines. Br J Cancer 67:959-68 |
| Kramer, R; Weber, T K; Arceci, R et al. (1993) Modulation of mdr-1 expression by a H-ras oncogene in a human colon carcinoma cell line. Int J Cancer 54:275-81 |
