MULTIPLE-DRUG RESISTANCE AND INTERMEDIATE FILAMENTS

One major obstacle to the successful treatment of epithelial derived t umors, such as breast and prostate carcinoma, is the presence of a mul tiple drug resistance phenotype. The drug resistance which is observed in growing epithelial derived cancer cells could either be an intrins ic, selected and/or an acquired characteristic. A survey of the surviv al data from several laboratories suggests that epithelial derived tum or cells, which have never been challenged with damaging agents, are i n some cases 10 to 2,000 times more resistant to various chemotherapeu tic agents as compared to hematopoietic cell lines. An intrinsic chara cteristic of epithelial cells is their resistance to the lethal effect s of multiple types of damaging agents. A major feature of epithelial derived tumors is the expression of the intermediate filament type pro teins known as cytokeratin. The simplest cytokeratin combination, cyto keratin 8 and 18, is a major cytoplasmic element within the cells of e pithelial derived tumors. Earlier work showed that cytokeratin could b e modified by mitoxantrone, a chemotherapeutic agent used in the treat ment of breast cancer. Increasing data indicates that the intrinsic dr ug resistance phenotype is due in part to the presence of continued ex pression of the cytokeratin 8 and 18. The cytokeratin dependent drug r esistance (C-MDR) has been observed in two different cell types that w ere engineered to contain cytokeratin 8 and 18 expression. The cytoker atin monomers are known to self assemble into intermediate filament ne tworks as shown by numerous basic studies. Experiments using transfect ed cell lines which are unable to assemble networks indicated that C-M DR does not depend upon the formation of an intermediate filament netw ork. Selection of cytokeratin network defective tumor cells did not in crease their sensitivity to chemotherapeutic agents. These data are in teresting since it suggests that the C-MDR phenotype is not dependent upon the structural nature (i.e. network forming ability) of the cytok eratin. Our current working hypothesis is that the interaction of the damaging agent with cytokeratin may initiate signaling response(s) for cell survival.