Maintenance Immunosuppression with Target-of-Rapamycin Inhibitors is Associated with a Reduced Incidence of De Novo Malignancies

Kauffman, H. Myron; Cherikh, Wida S.; Cheng, Yulin; Hanto, Douglas W.; Kahan, Barry D.

doi:10.1097/01.tp.0000184006.43152.8d

Cited by 570 publications

(332 citation statements)

References 16 publications

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“…9 Nonetheless, this proliferation-inhibiting effect of mTOR inhibition has been useful in preventing coronary restenosis after stenting and will likely be effective in the treatment of cancer. 29,30 On the other hand, in the context of cell therapy, interference with transplanted cell proliferation during organ replacement, as shown here, will have profound implications. In many situations, large portions of organs must be replaced for optimal therapeutic effects; for example, individuals with liver failure and various metabolic deficiency states will require extensive liver repopulation.…”

Section: Discussionmentioning

confidence: 89%

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Joseph

Gupta

2006

Hepatology

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Successful grafting of tissues or cells from mismatched donors requires systemic immunosuppression.It is yet to be determined whether immunosuppressive manipulations perturb transplanted cell engraftment or proliferation. We used syngeneic and allogeneic cell transplantation assays based on F344 recipient rats lacking dipeptidyl peptidase IV enzyme activity to identify transplanted hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate dehydrogenase inhibitor). First, suitable drug doses capable of inducing longterm survival of allografted hepatocytes were identified. In pharmacologically effective doses, rapamycin enhanced cell engraftment by downregulating hepatic expression of selected inflammatory cytokines but profoundly impaired proliferation of transplanted cells, which was necessary for liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil perturbed neither transplanted cell engraftment nor their proliferation. Therefore, mTOR-dependent extracellular and intracellular mechanisms affected liver replacement with transplanted cells. In conclusion, insights into the biological effects of specific drugs on transplanted cells are critical in identifying suitable immunosuppressive strategies for cell therapy. (HEPATOLOGY 2006;44:410-419.)

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Section: Discussionmentioning

confidence: 89%

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Joseph

Gupta

2006

Hepatology

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“…As described in several studies [33][34][35], mTOR inhibitors reduce the development and recurrence of DN and may be used in the complicated treatment of DN [36]. Moreover, a reduction in immunosuppression has also been reported to contribute to the management of DN.…”

Section: Discussionmentioning

confidence: 97%

Evolution and management of de novo neoplasm post-liver transplantation: a 20-year experience from a single European centre

et al. 2010

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Purpose Survival post-liver transplantation (LT) has improved; however, patients are considered at the, risk of malignancy due to prolonged immunosuppression. The long-term outcome of patients developing de novo neoplasm (DN) at our centre was evaluated. Methods Between October 1988 and December 2007, 800 LT were performed in 742 patients. Patients were divided into two study periods according to the time of LT; first: October 1988-December 1995; second: January 1996-December 2007.Results After a mean follow-up of 5 ± 4.6 years, 71 DN (9.5%) were detected in 742 patients. The cumulative risk of DN development increased with the time from LT although no differences at 3, 5, and 10 years were found when first and second periods were compared (3, 7, 16% vs. 2, 4, 11%, respectively; p = 0.4). DN incidence was higher in the first compared with the second period (10.7 vs. 7.8%; p \ 0.04); no significant differences were observed in mortality rate (50 vs. 27%; p = 0.052). Actuarial patient survival post-DN at 1, 3, and 5 years: 67, 48, 45% versus 82, 71, 65%, in the first versus second period, respectively, p \ 0.04.Conclusions DN incidence has decreased in recent years; however, as survival post-LT increases, so does the incidence of DN. Surveillance programmes are necessary to diagnose DN at early stages.

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“…En effet, le FGF2 (et non le VEGF), en synergie avec le PDGF-BB (platelet-derived growth factor-BB), intervient dans la maturité et la stabilité des vaisseaux. Il module la synthèse du récepteur au PDGF sur les cellules endothéliales ou sur les cellules de muscle lisse (péricytes) dont il potentialise la migration [11]. Il augmente également l'interaction entre les cellules par un mécanisme impliquant la VE(vascular endothelial)-cadhérine, renforçant ainsi l'intégrité des nouveaux vaisseaux formés.…”

Section: Les Inhibiteurs Multispécifiques De Kinase Et Du Complexe Maunclassified

“…D'autres facteurs angiogéniques dont le stromal derived factor-1 (SDF-1), le stem cell factor (SCF), le placental growth inactivation de la voie mTOR chez les patientes ayant une hormonorésistance acquise liée à un switch de signalisation. La rapamycine a également un effet bénéfique, comparée aux traitements classiques, dans le rejet des greffes de rein et dans la prévention de l'apparition des tumeurs post-transplantation [11]. Cet immunosupresseur agirait en bloquant la synthèse de HIF-1a et en inhibant mTOR.…”

Section: Les Inhibiteurs Multispécifiques De Kinase Et Du Complexe Maunclassified

La résistance aux traitements antiangiogéniques

Lű

Boisson-Vidal

et al. 2016

Med Sci (Paris)

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Maintenance Immunosuppression with Target-of-Rapamycin Inhibitors is Associated with a Reduced Incidence of De Novo Malignancies

Abstract: Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and non-skin solid malignancy.

Cited by 570 publications

References 16 publications

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Evolution and management of de novo neoplasm post-liver transplantation: a 20-year experience from a single European centre

La résistance aux traitements antiangiogéniques

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