RELATIONSHIP OF LRP-HUMAN MAJOR VAULT PROTEIN TO IN-VITRO AND CLINICAL RESISTANCE TO ANTICANCER DRUGS

Multidrug resistance (MDR) has been related to two members of the ABC- superfamily of transporters, P-glycoprotein (Pgp) and Multidrug Resist ance-associated Protein (MRP). We have described a 110 kD protein term ed the Lung Resistance-related Protein (LRP) that is overexpressed in several non-Pgp MDR cell lines of different histogenetic origin. Rever sal of MDR parallels a decrease in LRP expression. In a panel of 61 ca ncer cell Lines which have not been subjected to laboratory drug selec tion, LRP was a superior predictor for in vitro resistance to MDR-rela ted drugs when compared to Pgp and MRP, and LRP's predictive value ext ended to MDR unrelated drugs, such as platinum compounds. LRP is widel y distributed in clinical cancer specimens, but the frequency of LRP e xpression inversely correlates with the known chemosensitivity of diff erent tumour types. Furthermore, LRP expression at diagnosis has been shown to be a strong and independent prognostic factor for response to chemotherapy and outcome in acute myeloid leukemia and ovarian carcin oma (platinum-based treatment) patients. Recently, LRP has been identi fied as the human major protein. Vaults are novel cellular organelles broadly distributed and highly conserved among diverse eukaryotic cell s, suggesting that they play a role in fundamental cell processes. Vau lts localise to nuclear pore complexes and may be the central plug of the nuclear pore complexes. Vaults structure and localisation support a transport function for this particle which could involve a variety o f substrates. Vaults may therefore play a role in drug resistance by r egulating the nucleocytoplasmic transport of drugs.