Human tissue-type plasminogen activator: from the laboratory to the bedside.

IN AUGUST 1983, it was anticipated from biochemical observations and physiologic results in experimental animals that human tissue-type plasminogen activa-tor (t-PA) held considerable promise as a clot-specific, coronary thrombolytic agent for patients with acute myocardial infarction.' This anticipation has been fulfilled remarkably promptly by clinical research.2-1 Recently reported results from several randomized clinical trials3-1 punctuate a long series of antecedent laboratory, preclinical, and clinical investigations. Accordingly , research focused on t-PA serves as a particularly good example of productive, sequential developments and collaborations involving investigators from disparate disciplines in academe and industry. This report summarizes some of the seminal studies in the development and characterization of native t-PA and the recombinant DNA-produced t-PA used in multicenter trials reported recently.3-5 Although t-PA was identified in the 1 940s, its isolation and characterization were hampered by inadequate sources and purification procedures. In 1980, an attractive procedure for the isolation of human t-PA was developed by Rijken et al. ,6 yielding approximately 1 mg of t-PA from 5 kg of human uterine tissue. Subsequent development of t-PA and its application to coronary thrombolysis has progressed along four main lines: (1) isolation and characterization of t-PA from the Bowes melanoma cell line, (2) cloning and expression of the human t-PA gene, (3) delineation of the efficacy of purified t-PA in experimental animals with induced coronary thrombosis, and (4) evaluation of the coronary thrombolytic efficacy of t-PA in patients with acute myocardial infarction. Isolation and characterization of t-PA from the Bowes melanoma cell line. The Bowes melanoma cell line was provided to us by Dr. sity Medical School, toward the end of 1978. It had been obtained originally from pulmonary, metastatic melanoma cells from a patient named Bowes by Dr. G. Moore in 1974 and was maintained and exchanged among investigators because it secreted large amounts of plasminogen activator activity. However, the nature of the activity had not been elucidated. In collaboration with Dr. A. Billiau in the Laboratory of Virology at the University of Leuven, we introduced the Bowes cell line in our laboratory to study the spectrum of inhibition of plasminogen activators of malignant cells by synthetic inhibitors. In retrospect, selection of this cell line was fortuitous. Most malignant cell lines in culture produce urokinase-like plasminogen activators. Some produce mixtures of urokinase and an activator that does not react with urokinase antibodies.7 Cell lines that secrete t-PA primarily or exclusively are quite rare. …