Multidrug-resistant human neuroblastoma, Chinese hamster lung, and mouse tumor cells are cross-resistant to a wide variety of agents, such as vincristine and actinomycin D, and have decreased drug permeability. Resistance development is accompanied by change toward a more normal phenotype, i.e., more normal morphology and growth characteristics in vitro and decreased tumor-forming potential in animals compared to the parental control cells. All of the resistant cell sublines are characterized by the presence of cytogenetic markers of gene amplification. New studies show that resistant cells have increased amounts of epidermal growth factor (EGF) receptor compared to their respective parental lines. Evidence was obtained from studies of EGF binding, affinity labeling, phosphorylation, and anti-EGF receptor immunoprecipitation. EGF receptor increase as a concomitant of multidrug resistance was investigated because a) in several different systems malignant transformation has been associated with decreased EGF receptor and reverse transformation with increased receptor, and b) characteristics of the receptor are quite similar to those of the multidrug-resistant cell marker plasma membrane phosphoglycoprotein found in resistant sublines. These characteristics included Mr (approximately 170 kDa), pI (7.0), and EGF-enhanced autophosphorylation. The strong correlation between increased EGF receptor and drug resistance suggests that the receptor is involved in multidrug-resistance development. This interrelationship will be explored by 1) examining how functions of EGF and EGF receptor affect characteristics of the multidrug-resistant phenotype; 2) determining whether a relationship between EGF receptor and ggp150-180 function exists; 3) investigating a possible association between EGF receptor increase in resistant cells and reverse transformation or "normalization"; and 4) investigating whether increased EGF receptor occurs during the development of resistance or is an attribute of nonresponsiveness in tumor cells of drug-treated patients. Potentially, data from these studies will extend and increase knowledge of the complex multidrug-resistant phenotype and will lead to improved cancer drug therapy.