PLEIOTROPIC RESISTANCE RELATED TO TOPOISO MERASES

There are at least two well-characterized mechanism of resistance to T opo I and II inhibitors : modifications of intracellular accumulation and reduced formation of cleavable complexes. Limited drug accumulatio n is usually due to P-glycoprotein(MDR) or to Multidrug Resistance ass ociated Protein (MRP). Reduction of Topo I (or II) cleavable complexes not related to drug transport can either be due to decreased enzyme l evels or enzyme mutations. For Topo II inhibitors, differential expres sion of the Topo II isoforms alpha and beta and changes in Topo II pho sphorylation may also contribute to resistance. For dual Topo I and II inhibitors, resistance mechanisms are more complex to analyze but may also involve dual Topo land II alterations, Finally, in a given cell line, several mechanisms are commonly associated in pleiotropic resist ance to Topo inhibitors.