Path. Res. Pract. 188, 804-807 (1992) What's New in ... The Genetic Basis of Multidrug Resistance M. Pauly, F. Ries 1 and M. Dicato 1 Laboratoire de Recherche sur fe Cancer et fes Mafadies du Sang, Z.f. Grasbusch, Leudefange, Grand Duchy of Luxembourg; 1 Centre Hospitalier de Luxembourg, Departement d'Hemato-Oncofogie, Luxembourg SUMMARY Celhtlar multidrug resistance, a common side-effect of anticancer chemotherapy frequent- ly leading to failure of the treatment, has been characterized as an acquired resistance to several antimitotic drugs simultaneously. Multidrug resistance could mainly be attributed to the overexpression of the P-170 glycoprotein, considered as a drug-efflux pump encoded by the mdr 1 gene. Overexpression of this protein can be induced either by an accidental amplification or activation or both of the mdr 1 gene. Recent investigations focused on these mechanisms, aiming at a better understanding of the appearance of multidrug resistance during a chemotherapy. P-glycoprotein mediated drug resistance, however, is only one, albeit quite an important detoxification pathway, and some observations revealed genetic interactions with other systems. On the basis of this new knowledge, the development of novel therapeutic strategies to circumvent this clinical side-effect of cancer treatment has already begun. Introduction The Problem of Multidrug Resistance in Cancer Chemotherapy Cellular multidrug resistallCe is known to be a frequent side-effect in the treatment of advanced cancer diseases using antimitotic drugs. Statistically, it is quite often the main cause leading to failure in chemotherapy. Multidrug resistance is characterized as an acquired resistance to several drugs simultaneously. A number of anticancer drugs have now been classified in a multidrug resistance group (Table 1). Ir has been found that a prolonged exposure to one of these drugs not only induces a specific cellular resistance to this product, but frequently also an unspecific cross-resistance to all other, even structurally unrelated members in that same group. Given the enor- mous impact of multidrug resistance on cancer therapy, it is of major importance to elucidate the underlying mole- cular mechanisms, and many efforts have been undertaken in this field over the last years. 0344-0338/92/0188-0804$3.50/0 Role of MDR Genes in Multidrug Resistance Cellular multidrug resistance could mainly be attributed to the overexpression of a specific gene called mdr 1 (for multidrug resistance) in resistant Chinese hamster cells l9 , in resistant mouse cells 9 , in resistant human normal cells 1 and in resistant human cancer cells 20 . In all cases, the mdr 1 gene was found amplified to a high copy number, over-producing a membrane glycoprotein of a molecular weight of about 170 Kd.Furthermore, it could be dem on- strated that the acquired multidrug resistance (mdr) Table 1. Some common anti cancer drugs in the multidrug resis- tance group Actinomycin D Anthracyclines Daunomycin Doxorubicin Epirubicin Mitoxantrone Taxol Vinblastine Vincristine © 1992 by Gustav Fischer Verlag, Stuttgart