Rapamycin in transplantation: A review of the evidence

Saunders, R. N.; Metcalfe, M.; Nicholson, Michael L.

doi:10.1046/j.1523-1755.2001.00460.x

Cited by 413 publications

(314 citation statements)

References 102 publications

Supporting

Mentioning

299

Contrasting

Unclassified

Order By: Relevance

“…Rapamycin is regarded as a global inhibitor of cell cycle progression, although patients do not experience a higher incidence of infections that would suggest a global state of immunosuppression (clinical trials reviewed in Ref. 4). We anti-bcl-x L antibody, and proteins were visualized by ECL (lower panel).…”

Section: Discussionmentioning

confidence: 99%

“…The potent immunosuppressive activity of rapamycin has led to its wide clinical use in solid organ transplantation (reviewed in Ref. 4). More recent studies demonstrated successful islet cell transplantation in patients with type I diabetes treated with low dose rapamycin in combination with humanized anti-IL-2 1 receptor monoclonal antibody (mAb) and FK506, which prevented autoimmune destruction of islet cells (5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Rapamycin-resistant Proliferation of CD8+ T Cells Correlates with p27 Down-regulation and bcl-xL Induction, and Is Prevented by an Inhibitor of Phosphoinositide 3-Kinase Activity

Slavik

Lim

Burakoff

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Rapamycin inhibits the proliferation of many mammalian cell types, including lymphocytes, making the compound useful as an immunosuppressant. Rapamycin has also been a useful tool for studying signaling mechanisms regulating cellular proliferation. However, the effects of rapamycin remain poorly understood, and the precise mechanisms of clinical action remain elusive. Previously, we found that, depending on the strength of the signal delivered to the T cell via both the T cell receptor and the costimulatory molecule CD28, CD8؉ T cells are capable of rapamycin-resistant proliferation. Here, we have further elucidated the mechanism of rapamycin-resistant proliferation of human CD8؉ T cells. Under conditions where rapamycin inhibited proliferation, p27 kip1 down-regulation was prevented, whereas under conditions resulting in rapamycin-resistant proliferation, p27 kip1 was down-regulated. Further, T cell receptor/CD28-dependent induction of bcl-x L expression was not inhibited by rapamycin, which correlated with both rapamycin-resistant proliferation and increased cell survival. Moreover, an inhibitor of phosphoinositide 3-kinase activity was able to eliminate rapamycin-resistant proliferation of freshly isolated CD8؉ human cells, strongly suggesting that phosphoinositide 3-kinase activity was required for the rapamycin-resistant proliferation of CD8؉ T cells. The selective immunosuppressive effect of rapamycin in human CD8؉ T cell populations could be predictive of a selective effect allowing cytotoxic responses during microbial infections where there are strong strengths of signals associated with high affinity T cell receptors and strong costimulatory second signals. In contrast, the weaker autoimmune and perhaps allogeneic responses can be selectively inhibited by the actions of rapamycin.Rapamycin is an immunosuppressant that functions by inhibiting entry into the cell cycle. This inhibition of proliferation by rapamycin occurs at a later stage of cellular activation than the inhibition by cyclosporin A and FK506, which inhibit calcineurin or calcineurin-dependent transcriptional activation of lymphokine genes (Ref. 1; reviewed in Ref. 2). It is thought that rapamycin primarily inhibits growth factor signaling rather than growth factor synthesis (3). The potent immunosuppressive activity of rapamycin has led to its wide clinical use in solid organ transplantation (reviewed in Ref. 4). More recent studies demonstrated successful islet cell transplantation in patients with type I diabetes treated with low dose rapamycin in combination with humanized anti-IL-2 1 receptor monoclonal antibody (mAb) and FK506, which prevented autoimmune destruction of islet cells (5). However, the clinical mechanism of action of rapamycin in suppressing immune responses is not well defined.Although it is clear that entry into the cell cycle is generally inhibited by rapamycin, we recently made the surprising observation that increasing the strength of signal delivered to the T cell via both the T cell receptor (TcR) and the costimula...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Rapamycin-resistant Proliferation of CD8+ T Cells Correlates with p27 Down-regulation and bcl-xL Induction, and Is Prevented by an Inhibitor of Phosphoinositide 3-Kinase Activity

Slavik

Lim

Burakoff

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…[126][127][128][129] Several rapamycin analogs have already been approved for use in transplant patients as immunosuppressants. 130 RAD001 and CCI-779 are currently in phase I and II trials, respectively, as anticancer agents. 125 The PI3-K-Akt pathway appears to be a promising therapeutic target for cancer treatment.…”

Section: Molecular Biomarkers Based On Akt Activitiesmentioning

confidence: 99%

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Ittmann

Ayala

et al. 2005

Prostate Cancer Prostatic Dis

112

View full text Add to dashboard Cite

The PI3-K-Akt pathway plays a central role in the development and progression of prostate cancer and other malignancies. We review original studies and summarize relevant sections of previous reviews concerning the relationships between abnormalities in the PI3-K-Akt pathway and prostate cancer progression. We discuss laboratory and clinical data that indicate gene perturbation and dysregulation of PI3-K-Akt pathway is common in prostate cancer and other malignancies. We further discuss the critical role of the PI3-K-Akt pathway in the oncogenic signaling network and provide examples that establish the PI3-K-Akt pathway as a focal point for the future development of informative biomarkers and effective therapies for prostate cancer.

show abstract

“…MTIs are a class of signal transduction inhibitors with anticancer activity that were initially developed as immunosuppressive agents. [2][3][4][5] Rapamycin, a macrocyclic lactone produced by Streptomyces hydroscopicus, 6 was the first MTI to be used in a clinical setting. Rapamycin is well tolerated in humans.…”

mentioning

confidence: 99%

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

Teachey

Obzut

Cooperman

et al. 2006

Blood

158

128

View full text Add to dashboard Cite

Acute lymphoblastic leukemia (ALL) in adult patients is often resistant to current therapy, making the development of novel therapeutic agents paramount. We investigated whether mTOR inhibitors (MTIs), a class of signal transduction inhibitors, would be effective in primary human ALL. Lymphoblasts from adult patients with precursor B ALL were cultured on bone marrow stroma and were treated with CCI-779, a second generation MTI. Treated cells showed a dramatic decrease in cell proliferation and an increase in apoptotic cells, compared to untreated cells. We also assessed the effect of CCI-779 in a NOD/SCID xenograft model. We treated a total of 68 mice generated from the same patient samples with CCI-779 after establishment of disease. Animals treated with CCI-779 showed a decrease in peripheralblood blasts and in splenomegaly. In dramatic contrast, untreated animals continued to show expansion of human ALL. We performed immunoblots to validate the inhibition of the mTOR signaling intermediate phospho-S6 in human ALL, finding down-regulation of this target in xenografted human ALL exposed to CCI-779. We conclude that MTIs can inhibit the growth of adult human ALL and deserve close examination as therapeutic agents against a disease that is often not curable with current therapy. IntroductionWhile children with precursor B-cell acute lymphoblastic leukemia (ALL) are often cured, children with relapsed ALL and adults with ALL usually succumb to their disease with current therapy. Even with aggressive therapy, these patient groups have 5-year diseasefree survival rates of only 28% to 39%. 1 Thus, the development of novel therapeutic agents is crucial.One potential class of novel therapeutics is mTOR inhibitors (MTIs). MTIs are a class of signal transduction inhibitors with anticancer activity that were initially developed as immunosuppressive agents. [2][3][4][5] Rapamycin, a macrocyclic lactone produced by Streptomyces hydroscopicus, 6 was the first MTI to be used in a clinical setting. Rapamycin is well tolerated in humans. 7 MTIs also have been shown to be active against a wide variety of tumor types. [8][9][10] We have previously shown that rapamycin induces apoptosis in precursor B ALL lines in vitro and has in vivo activity in transgenic mice with pre-B leukemia/lymphoma. 11 Second generation MTIs, CCI-779 and RAD-001, are currently in phase 1 to phase 3 clinical trials in patients with various cancers, 12-15 but preclinical studies have not previously been performed in primary human ALL.Preclinical testing of chemotherapeutic agents often involves using transformed tumor lines and transgenic mouse models. While these are valuable tools, they may not be representative of human disease. More clinically relevant data may be obtained from systems using primary human ALL cells. Two of these systems, bone marrow stroma-supported culture 16 and xenografting human ALL in nonobese diabetic/severe combined immunodeficient (NOD/ SCID) mice, have recently been developed. 17 Both of these systems allow for direct testing...

show abstract

Rapamycin in transplantation: A review of the evidence

Cited by 413 publications

References 102 publications

Rapamycin-resistant Proliferation of CD8+ T Cells Correlates with p27 Down-regulation and bcl-xL Induction, and Is Prevented by an Inhibitor of Phosphoinositide 3-Kinase Activity

Rapamycin-resistant Proliferation of CD8+ T Cells Correlates with p27 Down-regulation and bcl-xL Induction, and Is Prevented by an Inhibitor of Phosphoinositide 3-Kinase Activity

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

Contact Info

Product

Resources

About