Human KB cells which are resistant to adriamycin (A), vinblastine (V), colchicine (C) and actinomycin D (AcD) have been shown to contain an amplified gene (mdrl) responsible for the drug resistance. A fragment of this gene has been cloned and used to screen a cDNA library and identify cDNAs encoding a 170 kd cell membrane protein also found to be increased in multidrug resistant cells. The 170 kd protein binds vinblastine and related drugs, and this binding is overcome by drugs such as verapamil, quinidine, and diltiazem which overcome multidrug resistance. The cDNA sequence indicates the 170 kd protein should bind ATP; this was directly confirmed by ATP binding studies. Expression of the mdrl gene was found to be elevated in normal colon, kidney, liver and adrenals and cancers of the colon, kidney and adrenal. Expression was also increased in a few tumors showing acquired drug resistance. The mdrl cDNA has been cloned into an animal cell expression vector and when inserted into drug sensitive cells makes them drug resistant.
