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`Rapamycin: Something Old, Something New,
`Sometimes Borrowed and Now Renewed
`CM Hartford1,2 and MJ Ratain1,3,4
`
`The molecular target of rapamycin (mTOR) is central to a complex intracellular signaling pathway and is involved in
`diverse processes including cell growth and proliferation, angiogenesis, autophagy, and metabolism. Although sirolimus
`(rapamycin), the oldest inhibitor of mTOR, was discovered more than 30 years ago, renewed interest in this pathway is
`evident by the numerous rapalogs recently developed. These newer agents borrow from the structure of sirolimus and,
`although there are some pharmacokinetic differences, they appear to differ little in terms of pharmacodynamic effects
`and overall tolerability. Given the multitude of potential applications for this class of agents and the decrease in cost
`that can be expected upon the expiration of sirolimus patents, renewed focus on this agent is warranted.
`
`Rapamycin (or sirolimus, the official generic name) is the
`prototypical inhibitor of the molecular target of rapamycin
`(mTOR). It was discovered more than 30 years ago as an
`antifungal agent and was approved in 1999 as an immuno-
`suppressant for the prevention of renal allograft rejection.
`Over
`the years, with the elucidation of
`the complex
`intracellular signaling network in which mTOR participates
`and the realization of the multitude of potential therapeutic
`applications of
`interfering with this network,
`interest in
`agents that can inhibit mTOR has increased. There are
`currently three mTOR inhibitors in clinical trials, all either
`prodrugs or analogs of sirolimus, including temsirolimus,
`which was
`recently approved by the Food and Drug
`Administration (FDA) for the treatment of renal cancer.
`Although these newer agents (rapalogs) exhibit slightly
`different pharmacokinetic properties, they appear to differ
`little pharmacodynamically from sirolimus. This review will
`provide an overview of the mTOR pathway, discuss the
`pharmacokinetics and tolerability of the different mTOR
`inhibitors, and highlight the many potential clinical applica-
`tions of these agents.
`
`THE mTOR PATHWAY
`The mTOR protein is a serine-threonine kinase that is central
`to a complex intracellular signaling pathway (Figure 1) and is
`involved in a number of important processes such as cell
`growth and proliferation, cellular metabolism, autophagy,
`
`and angiogenesis. It responds to signals from the extracellular
`environment such as nutrient and growth factor supply,
`energy, and stress. Signaling through the pathway is
`promoted when there is an abundance of nutrients or energy
`and is downregulated in states of depletion and stress.1
`mTOR exists within the cell complexed to the proteins
`GbL and either raptor or rictor.2 The mTOR/rictor protein
`complex is not responsive to inhibition by rapalogs and will
`not be discussed in detail except to mention its interaction
`with mTOR/raptor. The mTOR/GbL/raptor complex can be
`activated by various stimuli
`through different upstream
`molecules. Insulin (via the insulin receptor substrate-1) or
`other growth factors affect mTOR via the phosphoinositide-3
`kinase (PI3K)/Akt pathway1 (Figure 1). After stimulation,
`PI3K initiates a cascade that ultimately results
`in the
`phosphorylation and activation of Akt. Akt then acts via
`the tuberous sclerosis complex (TSC), consisting of the
`proteins TSC1 and TSC2, to exert its effect on mTOR.
`Phosphorylation of TSC2 by Akt inhibits TSC2, thereby
`releasing the inhibition that TSC2 otherwise exerts on mTOR
`via inhibition of Rheb, an activator of mTOR.1
`The energy status of the cell also affects mTOR signaling
`and acts via serine/threonine protein kinase 1 (LKB1) and
`AMP-activated kinase (AMPK). In states of energy depletion
`(increased AMP relative to ATP), LKB1 activates AMPK,
`which then activates TSC2, resulting in inhibition of the
`pathway.1 Stress signals,
`for example, DNA damage and
`
`1Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, USA; 2Department of Pediatrics, The University of
`Chicago, Chicago, Illinois, USA; 3Department of Medicine, The University of Chicago, Chicago, Illinois, USA; 4Cancer Research Center, The University of Chicago,
`Chicago, Illinois, USA. Correspondence: MJ Ratain (mratain@medicine.bsd.uchicago.edu)
`
`Published online 29 August 2007. doi:10.1038/sj.clpt.6100317
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`including those that are needed for cell cycle progression and
`are involved in cell cycle regulation.6 Phosphorylation and
`activation of S6K1 are also involved in cell growth and
`proliferation, possibly via translation of mRNAs that have a
`terminal 50-oligopyrimidine tract such as those that encode
`ribosomal proteins and elongation factors. However, because
`translation of these latter genes was shown to be intact in
`/
`/
`/S6K2
`mice, other mechanisms are probably
`S6K1
`involved.7 Importantly, S6K1 also has an inhibitory feedback
`function on the pathway by phosphorylating and inhibiting
`insulin receptor substrate-1, thus reducing growth factor–-
`stimulated signaling through PI3K/Akt/mTOR.8
`It also
`phosphorylates and inactivates BCL2 antagonist of cell death
`(BAD), a proapoptotic molecule.6 The numerous proteins
`whose translation is regulated through mTOR and its
`downstream targets include cyclin D1, MYC avian myelocy-
`tomatosis viral oncogene homolog (c-MYC), and hypoxia-
`inducible factor-la (HIF-1a).6
`
`INHIBITORS OF THE mTOR PATHWAY
`Mechanisms of action and mechanisms of resistance
`Inhibitors of the mTOR pathway that are actively being
`studied include sirolimus,
`temsirolimus, everolimus, and
`AP23573 (now called deferolimus) (Figure 2). Sirolimus and
`the rapalogs exert their effects by the same mechanism. Each
`drug binds to the intracellular binding protein FK506-
`binding protein (FKBP12) to form a complex, which then
`binds to mTOR at the FKBP12–rapamycin binding domain,
`interfering with its ability to signal adequately to its
`downstream effectors. Exactly how the sirolimus–FKBP12
`complex interrupts mTOR signaling is not known, but it may
`involve a destabilization of the interaction between mTOR
`and raptor.1
`Given the complexity of the mTOR pathway, there are
`many potential sites of resistance. Defects in the binding of
`sirolimus to FKBP12 because of mutations in FKBP12 and
`mutations in the FKBP12–rapamycin binding domain both
`confer resistance by interfering with the binding of the
`sirolimus–FKBP12 complex to mTOR.9 Other potential
`mechanisms of resistance include decreased levels of 4E-
`BP1 and mutations in S6K1.10 The complexity of the pathway
`and feedback loops within it may also contribute to
`resistance. For example,
`it is possible that inhibiting the
`negative feedback of S6K1 on insulin receptor substrate-1
`may contribute to resistance to the antiproliferative effects of
`mTOR inhibition.9
`
`In the early 1970s, sirolimus, the first inhibitor of
`Sirolimus.
`mTOR, was discovered as part of a screening program for
`new antifungal agents and was first named rapamycin
`because it was isolated from a soil sample from Rapa
`Nui.11 Not long after, the inhibitory effect on the immune
`system was recognized in rats,12 but it was not until the late
`1980s13 and early 1990s14 that
`it was developed as an
`immunosuppressant. Both the antifungal and immunosup-
`pressive activities are the result of the drug’s ability to
`
`Figure 1 Schematic of the mTOR pathway. mTOR receives input from a
`number of upstream pathways, including PI3K/Akt, TSC1/TSC2, and AMPK,
`and acts through downstream effectors S6K and E4BP1 to exert its effects.
`
`hypoxia, also act via the TSC to cause an inhibition of mTOR
`signaling. The nutrient status of the cell, for example, amino-
`acid supply, influences the activity of mTOR. Although the
`mechanisms by which this occurs are less well characterized,
`it is known that the pathway is active when nutrients are
`readily available and downregulated in states of starvation.3
`A number of other pathways can interact with the
`signaling described thus far. For example, phosphatase and
`tensin homolog (PTEN) is a tumor suppressor that counter-
`acts the effects of PI3K by dephosphorylating phosphati-
`dylinositol
`(3,4,5)-trisphosphate and therefore prevents
`activation of Akt.4 Neurofibromin 1 (NF1) inhibits Ras,
`which can activate the mTOR pathway via PI3K/Akt.5
`Moreover,
`the mTOR/rictor complex can phosphorylate
`Akt, which therefore results in feedback and further signaling
`through the pathway.2
`Downstream of mTOR are two main effectors, S6K1 and
`4E-BP1, both of which control the translation of specific
`mRNAs and the synthesis of particular proteins. Phosphor-
`ylation of 4E-BP1 by mTOR ultimately results
`in the
`initiation of
`translation of certain mRNAs
`that have
`regulatory subunits in the 50-untranslated terminal regions,
`
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`Figure 2 Inhibitors of the mammalian target of rapamycin (mTOR) pathway that are actively being investigated. The chemical structure of sirolimus and the
`newer analogues are similar. The bars indicate sites of structural differences among the agents.
`
`interrupt the complex intracellular signaling cascade of the
`mTOR pathway, which is relatively conserved from yeasts to
`humans.15 As described, this ultimately causes a decrease in
`protein synthesis. In yeast and molds, the interruption of
`synthesis of proteins involved in cell cycle progression
`the microorganisms.16
`In
`interferes with growth of
`T lymphocytes, this interferes with the ability of the cell to
`respond to cytokines and therefore blocks their proliferation
`and differentiation,17 leading to immunosuppression. As
`sirolimus had been used for the prevention of allograft
`rejection, most of the pharmacology data come from solid
`organ transplant patients.
`Sirolimus is a macrocyclic lactone produced by Strepto-
`myces hygroscopicus.18 It
`is poorly soluble in water and
`therefore can only be given orally. It is available in both liquid
`and tablet formulations. A study of stable renal allograft
`recipients in which patients were converted from liquid
`sirolimus to the tablet form demonstrated relative bioequi-
`valent pharmacokinetics for the two formulations. Although
`the tablet
`formulation resulted in a lower maximum
`concentration (Cmax), the area under the concentration–time
`the two formulations were similar.19
`curves (AUCs) of
`
`Absorption of sirolimus is rapid with peak concentrations
`attained in about 2 h, but bioavailability is low (B15%)20
`and exhibits wide interpatient variability. This variability has
`been largely attributed to the effects of intestinal cytochrome
`P450 3A enzymes (CYP3A) and P-glycoprotein activity on
`sirolimus absorption.21 Studies on renal transplant patients
`have shown that the coadministration of cyclosporine affects
`the bioavailability of sirolimus and that when the drugs are
`administered concomitantly, both the Cmax and the AUC of
`sirolimus are increased, possibly because of inhibition of
`CYP3A4 and P-glycoprotein by cyclosporine.22 The adminis-
`tration of a high-fat meal will also affect absorption. In a
`study of healthy volunteers, coadministration of sirolimus
`with a high-fat meal resulted in a slower absorption but a
`35% increase in AUC.23
`The volume of distribution of sirolimus is large (B12 l/
`kg), indicating wide distribution into tissues and necessitat-
`ing, in many instances, a loading dose. Most of the drug
`partitions into red blood cells (B95%), with small amounts
`in lymphocytes and granulocytes (B1% each).24 Of the 3%
`in plasma, only 2.5% is free and the remainder is protein-
`bound.24
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`The metabolism of sirolimus is mainly via hepatic CYP3A
`enzymes. In a study of 18 adults with mild to moderate
`hepatic impairment, AUC and half-life of sirolimus were
`significantly increased and weight-normalized apparent oral
`clearance was significantly decreased, as compared with
`healthy controls,25 suggesting that dose adjustments may be
`needed for patients with hepatic impairment. Sirolimus has
`multiple metabolites, all with low immunosuppressive
`activity (o10% relative to sirolimus).26 The excretion is
`primarily
`fecal.
`The
`clearance
`is widely
`variable
`(1.45–6.93 ml/min/kg) and the half-life is long (B62 h),20
`allowing for once-daily dosing.
`and
`The
`interaction of
`sirolimus with CYPA34
`P-glycoprotein not only leads to wide interpatient variability
`in absorption and metabolism but also to the potential for a
`number of drug interactions. Commonly encountered
`inhibitors of CYP3A4 and P-glycoprotein include ketocona-
`zole, cyclosporine, erythromycin, and ritonavir, along with
`grapefruit juice; inducers of CYP3A4 include dexamethasone,
`phenytoin, carbamazepine, rifampin, and phenobarbital, to
`name a few. These medications should be used cautiously and
`avoided if possible in patients treated with sirolimus.
`When used as an immunosuppressant for the prevention
`of solid organ graft rejection, therapeutic drug monitoring
`has been an important issue. A study of 150 renal transplant
`patients showed a correlation between trough drug levels
`(which correlate well with sirolimus AUC) and both
`incidence of adverse side effects (for levels 415 ng/ml) and
`acute graft rejection (for levels o5 ng/ml).27 One approach
`that has been recommended is to monitor all patients during
`the initial phase of treatment (for B2 months) and thereafter
`based on individual patient characteristics.28
`
`deferolimus
`and
`everolimus,
`Rapalogs. Temsirolimus,
`(Figure 2) are all structurally similar to sirolimus, differing
`mainly at a single position of
`the lactone ring (C-40)
`unrelated to both the mTOR- and FKBP12-binding sites.
`Temsirolimus is a water-soluble dihydroxymethyl propionic
`acid ester prodrug of sirolimus. Both intravenous and oral
`formulations are available, although recent development has
`focused on the intravenous formulation. To date, temsiro-
`limus has been mainly developed as an anticancer agent, and
`it was approved by the FDA on 30 May 2007 for the
`treatment of advanced renal cell carcinoma. Everolimus is an
`oral 40-O-(2-hydroxyethyl) derivative (not prodrug) of
`sirolimus approved in Europe as an immunosuppressant
`for the prevention of cardiac and renal allograft rejection in
`adults.29 More recently, it has been studied as an anticancer
`agent. Deferolimus is the newest addition to the rapalogs.
`It contains a phosphine oxide substitute on the lactone ring
`and is available in both oral and intravenous formulations. It
`is currently being investigated for the treatment of a number
`of different malignancies.
`As mentioned, sirolimus and the rapalogs inhibit mTOR
`by forming a complex with FKBP12, which then binds to
`mTOR. Few data are available regarding differences in the
`
`ability of the drugs to inhibit mTOR. One study showed that
`the binding of everolimus to FKBP12 was approximately
`threefold weaker than that of sirolimus in vitro.30 However,
`further in vivo studies on rats showed similar efficacy of the
`two agents in terms of immunosuppressive activity. The
`mTOR inhibitors are very specific in their action, and there is
`no evidence to date of any effects other than those on mTOR.
`All are known to result in a decrease in the phosphorylation
`of the downstream effectors 4E-BP1 and S6K131–34 and the
`degree of this effect is being studied as a potential biomarker
`of mTOR inhibition.
`An often stated reason for the development of new mTOR
`inhibitors is to improve the pharmacokinetic properties of
`sirolimus, mainly the poor bioavailability and insolubility in
`water. The chemical modifications of
`temsirolimus and
`deferolimus have resulted in water-soluble formulations that
`are currently being studied as intravenous agents. Few data
`are available regarding the oral formulations of these rapalogs
`and,
`to date,
`the main oral alternative to sirolimus is
`everolimus. Although everolimus exhibits greater polarity
`than sirolimus, the bioavailability is only slightly improved
`and is still relatively low (B16%).35 Similar to sirolimus,
`CYP3A4 and P-glycoprotein affect
`its absorption and
`contribute to wide interpatient variability.36
`The rapalogs share many characteristics with sirolimus,
`including extensive partitioning into red blood cells,36,37
`metabolism by hepatic CYP3A enzymes,38,39 and primarily
`fecal excretion.35 In a study of patients with liver cirrhosis,
`the clearance of everolimus was reduced by 53% and the half-
`life prolonged 84%, showing the need for dose reductions in
`patients with liver impairment.40 Although similar studies of
`temsirolimus have not been published, given the extensive
`hepatic metabolism, it is possible that this agent may also
`require dose adjustment in patients with liver dysfunction. As
`the rapalogs are substrates of CYP3A4 and P-glycoprotein,
`potential drug interactions are also a concern, as with
`sirolimus. There are differences in the half-lives, potentially
`affecting the optimal dosing schedules. The half-life of
`everolimus in stable renal transplant patients was 24–35 h41
`and 13–2542,43 and 45–74 h,37 respectively, for the intravenous
`formulations of temsirolimus and deferolimus.
`Temsirolimus is the only rapalog that is a prodrug. It
`quickly undergoes hydrolysis to sirolimus after intravenous
`administration. Sirolimus can be seen as early as 15 min after
`the start of temsirolimus infusion, reaches peak concentra-
`tion at 0.5–2.0 h, and then decreases monoexponentially.43
`After a dose of temsirolimus, the exposure to sirolimus
`exceeds that of parent drug because of the differences in half-
`lives, with the mean sirolimus/temsirolimus ratio being
`2.5–3.5.43 Although temsirolimus exhibits inhibitory activity
`against mTOR, most of its clinical effects are probably due to
`the sirolimus metabolite.44,45
`
`Tolerability of the mTOR inhibitors
`The four mTOR inhibitors exhibit remarkably similar side
`effect profiles and are in general well tolerated by patients,
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`Table 1 Multiple applications of mTOR inhibitors that have been studied, both clinically and preclinically, along with the rationale
`for possible efficacy of mTOR inhibition
`
`Clinical
`data
`
`Preclinical data
`
`Refs. 51–61
`
`Refs. 17, 62–71
`
`Refs. 72–75
`
`Refs. 5, 67, 76–89
`
`Application
`
`Rationale
`
`Comments
`
`Immune
`
`Graft rejection
`GVHD
`Autoimmune diseases
`ALPS
`Asthma
`
`Inhibition of proliferation of T cells in response to
`growth-promoting cytokines (IL-2)
`Inhibition of proliferation of B cells and mast
`cells
`Suppression of B-cell immunoglobulin
`production in response to certain stimuli
`
`Cancer
`
`Malignant tumors
`Benign hamartomas
`Radiation and
`chemosensitization
`
`Antiproliferative effect by inhibiting cell cycle
`progression and causing G1 arrest
`Proapoptotic effect by interfering with
`phosphorylation of BAD
`Antiangiogenic effect by interfering with HIF-1a
`Many proteins involved in hamartoma
`syndromes are linked to the mTOR pathway
`Radiation can induce signaling of Akt/mTOR,
`which can be attenuated by mTOR inhibition
`
`Benign diseases characterized by abnormal proliferation
`
`Effects of mTOR inhibitors on T-cell subsets and
`function:
`Increase in the suppressor function of CD4+ T cells
`Thymic atrophy and a reduction in CD4+CD8+
`thymocytes secondary to increased apoptosis
`without affecting total numbers of T and B cells in
`the periphery
`An increase in the percent of CD4+CD25+
`regulatory T cells
`An increase in the numbers of alloreactive
`CD103+CD8+ regulatory T cells
`
`Many different tumor types have shown
`responsiveness to mTOR inhibition, including both
`solid tumors and hematologic malignancies
`At doses used for anticancer treatment, mTOR
`inhibitors do not appear to be immunosuppressive
`TSC1/TSC2 (tuberous sclerosis), PTEN (cowden
`disease), LKB1 (Peutz–Jeghers syndrome), NF1
`(neurofibromatosis) are hamartomas syndromes
`linked to the mTOR pathway
`Other potential applications of the antiangiogenic
`effect of mTOR inhibitors include diseases
`characterized by neovascularization, such as
`endometriosis and keratitis
`
`Cardiac stents
`Hypertrophic
`myocarditis
`Pulmonary fibrosis
`Hepatic fibrosis
`ADPKD
`
`Neurodegenerative disorders
`
`Huntington disease
`
`Infectious diseases
`
`Fungal infections
`HIV
`
`Metabolic disorders
`
`Type II diabetes
`Obesity
`
`By blocking progression through the cell cycle
`and causing G1 arrest, mTOR inhibitors have an
`antiproliferative effect that may be beneficial for
`a number of different benign diseases
`
`Sirolimus-eluting stents were approved in 2003 for
`angioplasty to open clogged coronary arteries
`
`Refs. 90–92
`
`Refs. 93–98
`
`Huntington disease is characterized by
`accumulation of intraneuronal proteins that
`interfere with cellular processes. Increased
`autophagy, through inhibition of mTOR, may
`increase the degradation of the intracellular
`proteins that characterize Huntington disease
`
`The mTOR pathway is relatively conserved from
`yeasts to humans. Blocking the pathway in
`yeasts and fungi interferes with their growth and
`proliferation
`Infection with HIV-1 requires expression of the
`viral coreceptor CCR5 on the cell surface. In T
`cells, this expression depends on signaling
`through IL-2, which is blocked by mTOR
`inhibition
`
`Via intracellular connection with the insulin
`receptor/IRS-1/PI3K/Akt pathway and its role in
`cellular response to nutrients, mTOR may be
`important in the development of insulin
`resistance and obesity
`
`Early studies demonstrated potent activity against
`Candida albicans and Aspergillus, among other
`species. However, because of the
`immunosuppressive effects, these are not typically
`used for treatment of fungal infections
`
`Refs. 99, 100
`
`Refs. 16, 18, 101,
`102
`
`Refs. 103, 104
`
`ADPKD, autosomal dominant polycystic kidney disease; ALPS, autoimmune lymphoproliferative syndrome; CCR5, CC chemokine receptor 5; GVHD, graft-versus-host disease;
`HIV, human immunodeficiency virus; IL-2, interleukin-2; IRS-1, insulin receptor substrate-1; mTOR, molecular target of rapamycin; PI3K, phosphoinositide-3 kinase; TSC,
`tuberous sclerosis complex.
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`adding to the attractiveness of this class of drugs. Classically
`described adverse effects include fatigue, rash, mucositis,
`anorexia, and gastrointestinal effects such as diarrhea and
`nausea; hematologic
`effects
`include
`thrombocytopenia,
`leukopenia, and anemia; and metabolic effects
`include
`hyperlipidemia,
`hyperglycemia,
`and
`hypercholesterole-
`mia.20,33,43,46 In most cases,
`the adverse effects can be
`managed with dose reductions or, in the case of metabolic
`disturbances, with the addition of insulin or a cholesterol-
`lowering medication.
`A rarer and potentially serious side effect that has been
`noted with these agents is interstitial pneumonitis.47 In a
`series of 24 renal
`transplant patients who developed
`pneumonitis associated with sirolimus, symptoms included
`cough, fatigue, and fever in the majority of patients, and eight
`patients also developed dyspnea.48 One patient was asympto-
`matic. Imaging by computed tomography revealed patchy
`bilateral
`infiltrates to be the most common finding (19
`patients). Sirolimus was discontinued in all patients and all
`recovered completely within 6 months. Similar reports after
`treatment with temsirolimus exist49 and pneumonitis is listed
`as an uncommon side effect of everolimus (Certican,
`prescribing information).
`The first approved application of mTOR inhibitors was as
`an immunosuppressant. The effects on the immune system
`may be of some concern when these agents are used for other
`purposes and especially when administered to patients with
`cancer. However, despite the ability to block proliferation of
`certain cells of the immune system, there has not been a
`significant number of infectious complications with the doses
`and schedules used in clinical oncology trials. Most published
`trials have not reported specific analyses of T-cell subsets or
`function, but a phase I study of temsirolimus mentioned that
`lymphocyte cell-surface phenotype analysis and mitogen
`proliferation assays did not
`show any trend toward
`immunosuppression.42
`
`Applications of mTOR inhibitors
`Because of mTOR’s complex effects on protein synthesis and
`cell cycle progression, interfering with its signaling can lead
`to a number of potentially therapeutic outcomes. For
`example, by interfering with the translation of proteins
`involved in cell cycle progression, inhibition of mTOR results
`in arrest in G1 of the cell cycle and an antiproliferative effect
`that may be beneficial for the treatment of cancer and a
`number of benign diseases associated with abnormal
`proliferation. Immunosuppression can occur by interfering
`with protein synthesis within certain cells of the immune
`system, such as T cells. Interfering with the translation of
`HIF-1a has an antiangiogenic effect, and inhibiting the
`phosphorylation of BAD by S6K1 may promote apoptosis.
`Another effect of mTOR inhibition is to promote autophagy,
`although the exact mechanism of this remains unknown.50
`These multiple and diverse effects may potentially result in a
`number of
`important
`therapeutic applications
`for
`the
`treatment of a wide range of diseases. The various diseases
`
`for which inhibition of the mTOR pathway has been studied,
`both clinically and preclinically, along with the rationale for
`why inhibiting the pathway may be efficacious, are listed in
`Table 1.
`
`CONCLUSION
`The mTOR pathway plays a central role in a number of
`important intracellular processes. Blocking the pathway with
`sirolimus or a rapalog has implications for the treatment of
`many diverse diseases. Although many studies are currently
`underway and more data will be collected, the newer mTOR
`inhibitors appear to be potentially interchangeable with
`sirolimus
`(if administered at a comparable dose and
`schedule). Wide interpatient variability in pharmacokinetics,
`metabolism by CYP3A4, and therefore the potential
`for
`numerous drug interactions, poor bioavailability of the oral
`agents, and generally good tolerability are characteristics of
`this class of drugs. There is no convincing evidence thus far
`to suggest that the newer agents offer a large advantage to
`sirolimus. Given the limited patent exclusivity and the
`decrease in cost that can be expected upon expiration of
`the sirolimus patents, perhaps more focus should be given to
`the oldest agent so that it can be effectively applied for the
`multitude of new potential uses being discovered, rather than
`continuing to borrow from it for the production of more new
`inhibitors of mTOR.
`
`ACKNOWLEDGMENTS
`Dr Hartford was supported by T32 GM007019 from the NIH.
`
`CONFLICT OF INTEREST
`The authors declared no conflict of interest.
`
`& 2007 American Society for Clinical Pharmacology and Therapeutics
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