title: Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice.
abstract: Cancer is an increasingly recognized problem associated with immunosuppression. Recent reports, however, suggest that the immunosuppressive agent rapamycin has anti-cancer properties that could address this problem. Thus far, rapamycin's effects on immunity and cancer have been studied separately. Here we tested the effects of rapamycin, versus cyclosporine A (CsA), on established tumors in mice simultaneously bearing a heart allograft. In one tumor-transplant model, BALB/c mice received subcutaneous syngenic CT26 colon adenocarcinoma cells 7 days before C3H ear-heart transplantation. Rapamycin or CsA treatment was initiated with transplantation. In a second model system, a B16 melanoma was established in C57BL/6 mice that received a primary vascularized C3H heart allograft. In vitro angiogenic effects of rapamycin and CsA were tested in an aortic ring assay. Results show that CT26 tumors grew for 2 weeks before tumor complications occurred. However, rapamycin protected allografts, inhibited tumor growth, and permitted animal survival. In contrast, CsA-treated mice succumbed to advancing tumors, albeit with a functioning allograft. Rapamycin's antitumor effect also functioned in severe combined immunodeficient BALB/c mice. Similar effects of the drugs occurred with B16 melanomas and primary vascularized C3H allografts in C57BL/6 mice. Furthermore, in this model, rapamycin inhibited the tumor growth-enhancing effects of CsA. Moreover, in vitro experiments showed that CsA promotes angiogenesis by a transforming growth factor-beta-related mechanism, and that this effect is abrogated by rapamycin. This study demonstrates that rapamycin simultaneously protects allografts from rejection and attacks tumors in a complex transplant-tumor situation. Notably, CsA protects allografts from rejection, but cancer progression is promoted in transplant recipients.
authors.affiliation: Department of Surgery, The University of Regensburg, Regensburg, Germany.
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Koehl
authors.forename: Joachim
authors.initials: J
authors.lastname: Andrassy
authors.forename: Markus
authors.initials: M
authors.lastname: Guba
authors.forename: Sebastian
authors.initials: S
authors.lastname: Richter
authors.forename: Alexander
authors.initials: A
authors.lastname: Kroemer
authors.forename: Marcus N
authors.initials: MN
authors.lastname: Scherer
authors.forename: Markus
authors.initials: M
authors.lastname: Steinbauer
authors.forename: Christian
authors.initials: C
authors.lastname: Graeb
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000150:complications / Q000188:drug therapy*; D016572:Cyclosporine / Q000494:pharmacology; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000150:complications / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D020123:Sirolimus / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000150:complications / Q000188:drug therapy; D014184:Transplantation, Homologous
chemical_list: D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus