Strange Bedfellows in Transplant Drug Therapy

The Faculty of 1000 is a Web-based literature awareness tool published by BioMed Central. It provides a continuously updated insider's guide to the most important peer-reviewed papers within a range of research fields, based on the recommendations of a faculty of more than 1,400 leading researchers. Each issue, The Scientist publishes a list of top-rated papers from a specific subject area, as well as a short review of one or more of the listed papers. We also publish a selection of comments on interesting recent papers from the Faculty of 1000's output. For more information visit www.facultyof1000.com. Since the early 1980s, physicians have relied on the immunosuppressive drug cyclosporine (CsA) as a way to prevent allograft rejection in organ transplant patients. The problem with CsA, however, is that it also promotes tumor growth. Indeed, cancer kills many transplant patients. "It's a very bad situation to be in," says Edward Geissler of the University of Regensburg, Germany, and senior author in this issue's featured F1000 paper.1 "If you keep administering CsA, you promote cancer. But if you take the patients off the drug, the transplant will reject. In general, most physicians around the world don't know how to treat these patients." Faculty of 1000 Picks Molecular Medicine 1. J.J. Wyrick et al., "Genome-wide distribution of ORC and MCM proteins in S. cerevisiae: High-resolution mapping of replication origins," Science, 294:2357-60, Dec. 14, 2001. 2. G. Pereira et al., "Modes of spindle pole body inheritance and segregation of the Bfa1p-Bub2p checkpoint protein complex," EMBO Journal, 20:6359-70, Nov. 15, 2001. 3. H. Masumoto et al., "S-Cdk-dependent phosphorylation of Sld2 essential for chromosomal DNA replication in budding yeast," Nature, 415:651-5, Feb. 7, 2002. 4. L. Zou et al., "Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin," Genes & Development, 16:198-208, Jan. 15, 2002. 5. E. Sobel et al., "Detection and integration of genotyping errors in statistical genetics," American Journal of Human Genetics, 70:496-508, February 2002. 6. P. Meraldi et al., "Aurora-A overexpression reveals tetra-ploidization as a major route to centrosome amplification in p53(-/-) cells," EMBO Journal, 21:483-92, Feb. 15, 2002. 7. M. Guba et al., "Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor," Nature Medicine, 8:128-35, Feb. 1, 2002. 8. R. Pawliuk et al., "Correction of sickle cell disease in transgenic mouse models by gene therapy," Science, 294:2368-71, Dec. 14, 2001. 9. M.C. Morris et al., "A peptide carrier for the delivery of biologically active proteins into mammalian cells," Nature Biotechnology, 19:1173-6, Dec. 1, 2001. 10. J. Mellor et al., "Mediation of hippocampal mossy fiber long-term potentiation by presynaptic Ih channels," Science, 295:143-7, Jan. 4, 2002. A new drug on the market may change this situation. Rapamycin (RAPA), an immunosuppressant, was approved by the Food and Drug Administration three years ago for use in transplant patients. While reading through the literature, Geissler and his colleagues came across some indications that RAPA could alter intracellular signaling pathways in a way that might potentially inhibit angiogenesis, the growth of new blood vessels. If so, it could serve as an anti-cancer agent, as well as an immunosuppressant, by cutting off the blood supply to the growing tumor. But no evidence existed to suggest that RAPA was actually an antiangiogenic agent. And, more importantly, "all immunosuppressants eventually cause cancer in transplant patients," says Geissler, or at least that is what he and other researchers had been led to believe. "You wouldn't predict it to be so effective," Geissler says, "because it is an anti-rejection drug, and generally these are thought to promote cancer." Still, Geissler's team was curious enough to test the drug in mouse models to see what would happen. The results surprised them. Not only did RAPA inhibit angiogenesis, but it also had a very pronounced effect. The team compared the RAPA-treated mice to CsA-treated mice, which, as expected, showed increased angiogenesis and tumor growth. The researchers showed that RAPA's antitumor effect is likely due, at least in part, to reduced production and activity of vascular endothelial growth factor (VEGF), a central regulator of vessel development. Although RAPA inhibits tumor formation, it does not necessarily prevent it. "We also do not know whether RAPA can completely eliminate a tumor," says Geissler. "This is something we are currently testing." The results are exciting, says Geissler, because RAPA is a "clinically approved drug, it is relatively safe, and it certainly can be incorporated right now to help these patients." Geissler has fielded many phone calls from physicians as a result of the study. "We really believe that if people read this paper and they have patients like this, they will be able to try this. There are no alternatives right now." Because popular thinking is that immunosuppressive drugs do not make good anti-cancer agents, and vice versa, not many research groups are studying drugs like RAPA. In fact, Geissler suspects that his team may be the only one. They are continuing their search for other drugs with similarly combined immunosuppressive and anti-cancer capabilities, "so that if a transplant patient does develop cancer, we have other tactics to tackle the cancer while still preserving the organ." Leslie Pray (lpray@nasw.org) is a freelance writer in Leverett, Mass. 1. M. Guba et al., "Rapamycin inhibits primary and metastatic tumor growth by anti-angiogenesis: involvement of vascular endothelial growth factor," Nature Medicine 8:128-135, Feb. 2, 2002.

Strange Bedfellows in Transplant Drug Therapy

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