PubMed · 3216313
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H Mahler. 1988. Collaboration across borders.. https://pubmed.ncbi.nlm.nih.gov/3216313/
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This Perspective includes an essay on modifying phase I clinical trials, written by George Zimmer, who was a professor of English and a commentary on that essay. Professor Zimmer was a cancer patient who participated in the phase I clinical trial program at the University of Chicago. His ideas are eloquently expressed and have had a profound effect on our investigational research for anticancer agents. Although at times his suggestions may seem radical, Professor Zimmer urges us to reconsider the 50-year-old Nuremberg paradigm that participants in human research are ignorant and vulnerable and must be protected. Although we must protect patients who have life-threatening diseases from coercive inducements and misplaced hopes, we must also listen carefully and thoughtfully to our patients. This is particularly true when, as research participants in the face of sacrifice and the threat of a life-ending diagnosis, they have made the effort to express their concerns. With the effect of the acquired immunodeficiency syndrome movement on clinical studies and on drug research and development, a precedent has been set that allows patients to reshape their role as participants in research trials. On a personal level, the essay by Professor Zimmer has had a significant effect on our research methods and, indeed, the focus of our research efforts. Thus, it is with a sense of respect and honor that we share George Zimmer's thoughts and our comments about the influence he has had on our research practices.
The soluble IL-6R (slL-6R alpha)/IL-6 complex and oncostatin M (OM), which exert biologic activities through the signal-transducing protein gp130, are potent growth factors for AIDS-associated Kaposi's sarcoma (KS) cells. Clinical observations indicate that glucocorticoid therapy is a possible risk factor in KS; however, little is known of specific interactions in KS cells between glucocorticoid and gp130-related growth factors. We obtained evidence that dexamethasone (Dex), in a synergistic manner, enhances gp130-mediated growth of KS cells. Anti-gp130 Abs or the glucocorticoid antagonist RU-486 abolished this synergistic effect. In addition, Dex had additive but not synergistic effects on stimulation of KS cell growth with IL-1beta or TNF-alpha, the signals of which are not mediated through gp130. Immunoblot analysis revealed sIL-6R alpha/IL-6- or OM-induced tyrosine phosphorylation of a similar set of proteins in KS cells, and which was augmented significantly in Dex-treated KS cells. Stimulation of KS cells with sIL-6R alpha/IL-6 or OM induced rapid tyrosine phosphorylation of the transcription factor STAT3, and Dex significantly enhanced the accumulation of tyrosine-phosphorylated STAT3. Electrophoretic mobility shift assays showed sIL-6R alpha/IL-6- or OM-induced DNA-binding activity of STAT3 in KS cells, and Dex further increased this activity. Thus, Dex appears to participate in the gp130-STAT3 signaling and transcriptional events by enhancing STAT3 activation, thereby leading to selective synergistic stimulation of KS cell growth with Dex and the gp130-related growth factors.
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