Sirolimus: Continuing the Evolution of Transplant Immunosuppression

Ingle, Gordon R.; Sievers, Theodore M.; Holt, Curtis

doi:10.1345/aph.19380

Cited by 52 publications

(39 citation statements)

References 65 publications

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“…Treatment of NSCLC has yielded limited success both in transplant recipients and in the general population (31,32). Currently, rapamycin is used as a component of a multidrug regimen in some of the transplant recipients (10). Our study supports the idea that rapamycin may be useful for constraining tumor growth and metastatic progression.…”

Section: Discussionsupporting

confidence: 77%

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Rapamycin Inhibits the Growth and Metastatic Progression of Non-Small Cell Lung Cancer

Boffa

Luan

Thomas

et al. 2004

Clinical Cancer Research

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Purpose: Lung cancer has a dismal prognosis and comprises 5.5% of post-transplant malignancies. We explored whether rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer (NSCLC).Experimental Design: Murine KLN-205 NSCLC was used as the model tumor in syngeneic DBA/2 mice to explore the effect of rapamycin on tumor growth and metastastic progression. We also examined the effect of rapamycin on cell cycle progression, apoptosis, and proliferation using murine KLN-205 NSCLC cells and human A-549 NSCLC cells as targets. The in vivo and in vitro effects of cyclosporine and those of rapamycin plus cyclosporine were also investigated.Results: Rapamycin but not cyclosporine inhibited tumor growth; s.c. tumor volume was 1290 ؎ 173 mm 3 in untreated DBA/2 mice, 246 ؎ 80 mm 3 in mice treated with rapamycin, and 1203 ؎ 227 mm 3 in mice treated with cyclosporine (P < 0.001). Rapamycin but not cyclosporine prevented the formation of distant metastases; eight of eight untreated mice and four of six mice treated with cyclosporine developed pulmonary metastases whereas only one of six mice treated with rapamycin developed pulmonary metastases (P ‫؍‬ 0.003). In vitro, rapamycin induced cell cycle arrest at the G 1 checkpoint and blocked proliferation of both KLN-205 and A-549 cells but did not induce apoptosis. Cyclosporine did not prevent cell cycle progression and had a minimal antiproliferative effect on KLN-205 and A-549 cells.Conclusions: The immunosuppressive macrolide rapamycin but not cyclosporine prevents the growth and metastatic progression of NSCLC. A rapamycin-based immunosuppressive regimen may be of value in recipients of allografts.

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Section: Discussionsupporting

confidence: 77%

“…In some but not all post-transplant immunosuppression protocols, rapamycin is currently used as a component of a multidrug regimen (10). Rapamycin binds the immunophilin FKBP12, targets, and inactivates mammalian target of rapamycin, a serine threonine kinase (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Inhibits the Growth and Metastatic Progression of Non-Small Cell Lung Cancer

Boffa

Luan

Thomas

et al. 2004

Clinical Cancer Research

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“…At birth, these animals appear normal, but, within a few days, they become markedly hypertriglyceridemic and develop fatty livers as hepatocytes become engorged with large lipid droplets (26). Hypertriglyceridemia is one of the most frequent side effects when rapamycin is used in immunosuppressant therapy in humans (38). Although the effect of mTOR-dependent phosphorylation of lipin is still unknown, inhibition of lipin phosphorylation by rapamycin represents a potential link to the increase in blood lipids.…”

Section: Discussionmentioning

confidence: 99%

Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin

Huffman

Mothe-Satney

Lawrence

2002

Proc. Natl. Acad. Sci. U.S.A.

210

200

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The phosphorylation of a previously uncharacterized protein of apparent Mr Ϸ 140,000 was found to be increased when rat adipocytes were incubated with insulin. The sequences of peptides generated by digesting the protein with trypsin matched perfectly with sequences in mouse lipin. Lipin is the product of the gene that is mutated in fatty liver dystrophy ( fld) mice [Peterfy, M., Phan, J., Xu, P. & Reue, K (2001) Nat. Genet. 27, 121-124], which exhibit several phenotypic abnormalities including hyperlipidemia, defects in adipocyte differentiation, impaired glucose tolerance, and slow growth. When immunoblots were prepared with lipin antibodies, both endogenous adipocyte lipin and recombinant lipin overexpressed in HEK293 cells appeared as bands ranging in apparent Mr from 120,000 to 140,000. Incubating adipocytes with insulin decreased the electrophoretic mobility and stimulated the phosphorylation of both Ser and Thr residues in lipin. The effects of insulin were abolished by inhibitors of phosphatidylinositol 3-OH kinase, and by rapamycin, a specific inhibitor of the mammalian target of rapamcyin (mTOR). The inhibition by rapamycin was blocked by FK506, which competitively inhibits those effects of rapamycin that are mediated by inhibition of mTOR. Moreover, amino acids, which activate mTOR, mimicked insulin by increasing lipin phosphorylation in a rapamycin-sensitive manner. Thus, lipin represents a target of the mTOR pathway, and potentially links this nutrient-sensing pathway to adipocyte development.

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“…Additional work is warranted to develop or to test existing rapamycin ana- logs (42) with a greater selective toxicity for lower eukaryotes. There is a clear advantage for the use of analogs of known immunosuppressive drugs, such as rapamycin, since there is a wealth of structural, molecular, and pharmacological information on the activity of these compounds (13,37,57). Rapamycin was approved by the Food and Drug Administration as an immunosuppressant for renal transplant recipients in August 1999.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin and Less Immunosuppressive Analogs Are Toxic to Candida albicans and Cryptococcus neoformans via FKBP12-Dependent Inhibition of TOR

Cruz

Goldstein²,

Blankenship

et al. 2001

Antimicrob Agents Chemother

147

137

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Candida albicans and Cryptococcus neoformans cause both superficial and disseminated infections in humans.Current antifungal therapies for deep-seated infections are limited to amphotericin B, flucytosine, and azoles. A limitation is that commonly used azoles are fungistatic in vitro and in vivo. Our studies address the mechanisms of antifungal activity of the immunosuppressive drug rapamycin (sirolimus) and its analogs with decreased immunosuppressive activity. C. albicans rbp1/rbp1 mutant strains lacking a homolog of the FK506-rapamycin target protein FKBP12 were found to be viable and resistant to rapamycin and its analogs. Rapamycin and analogs promoted FKBP12 binding to the wild-type Tor1 kinase but not to a rapamycin-resistant Tor1 mutant kinase (S1972R). FKBP12 and TOR mutations conferred resistance to rapamycin and its analogs in C. albicans, C. neoformans, and Saccharomyces cerevisiae. Our findings demonstrate the antifungal activity of rapamycin and rapamycin analogs is mediated via conserved complexes with FKBP12 and Tor kinase homologs in divergent yeasts. Taken together with our observations that rapamycin and its analogs are fungicidal and that spontaneous drug resistance occurs at a low rate, these mechanistic findings support continued investigation of rapamycin analogs as novel antifungal agents.Cryptococcus neoformans and Candida albicans are two common opportunistic fungal pathogens. Current antifungal agents in clinical use include amphotericin B, fluconazole, and flucytosine (29), which have side effects, lack fungicidal activity, or lack activity against emerging resistant mutants (66). Thus, additional antifungal agents are needed.Several new antifungal agents are in development. The candins are 1,3-␤-glucan synthase inhibitors and are potently active against Candida species and Aspergillus fumigatus (23,40,51,52). The pneumocandin caspofungin acetate-MK-0991 is in phase III clinical trials for candida infections and has been approved for refractory aspergillosis. Broad-spectrum triazoles, including voriconazole, posaconazole, and ravuconazole, are being studied in human trials (50). Combination therapy with different antifungal agents may also improve therapy (20,28,62).Rapamycin (sirolimus) is a natural product of the bacterium Streptomyces hygroscopicus originally discovered in a screen for antimicrobial activity against C. albicans and later found to have potent immunosuppressive activity (4, 63). Rapamycin diffuses into the cell and associates with the peptidylprolyl isomerase FKBP12. Rapamycin inhibits FKBP12 enzymatic activity; however, this inhibition is not related to immunosuppressive or antifungal activity. The targets of the FKBP12-rapamycin complex are the TOR kinases. Two TOR proteins, Tor1 and Tor2, have been characterized in the yeasts S. cerevisiae and Schizosaccharomyces pombe, and a single TOR homolog has been identified in C. albicans, C. neoformans, Drosophila melanogaster, and humans (10,18,33,39,49,56,64). The Tor kinase has been functionally conserved from yeast to ...

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Sirolimus: Continuing the Evolution of Transplant Immunosuppression

Abstract: The definitive role of sirolimus will continue to be determined; however, sirolimus offers an excellent addition to the transplant immunosuppression armamentarium.

Cited by 52 publications

References 65 publications

Rapamycin Inhibits the Growth and Metastatic Progression of Non-Small Cell Lung Cancer

Rapamycin Inhibits the Growth and Metastatic Progression of Non-Small Cell Lung Cancer

Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin

Rapamycin and Less Immunosuppressive Analogs Are Toxic to Candida albicans and Cryptococcus neoformans via FKBP12-Dependent Inhibition of TOR

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