Download The mTOR inhibitors and the skin wound healing

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EWMA 2012
Farida Benhadou, MD
Veronique del Marmol,
MD, PhD
Dermatology department, ULB Erasme Hospital, Brussels, Belgium
Correspondence:
Farida.Benhadou@
ulb.ac.be
Conflict of interest: none
The mTOR inhibitors and
the skin wound healing
ABSTRACT
Background: The wound healing process is divided into four phases: haemostasis/coagulation,
inflammation, proliferation, and wound remodelling. The wound closure needs a perfect control
of these phases thus wound management is always
a challenge. Numerous factors, like medications,
can markedly affect most aspects of the wound
healing process.
Aim: We want to focus our attention on the mammalian target of rapamycin (mTOR). Deregulation of the mTOR signalling pathway occurs
frequently in human malignancies. The pharmacological inhibition of mTOR with rapamycin
and its analogs is used in organ transplantation to
prevent rejection and to slow skin carcinogenesis
in organ recipients.
Methods: This article reviews the recent literature
on the mTOR inhibitors and the potential cellular and/or molecular mechanisms involved in
the wound healing process.
Results and conclusions: The mTOR inhibitors can affect all steps of the healing process by
decreasing the inflammatory cell number, angiogenesis, and myofibroblast proliferation. The
frequent association, among organ recipients
treated by mTOR inhibitors, with other immunosuppressive therapies and comorbidities exacerbate the risk of wound healing complications.
The complexity of the mTOR pathway is not
completely understood but its role in the wound
healing process is crucial. The indication for the
mTOR therapy has to be discussed carefully for
each patient.
INTRODUCTION
The mTOR inhibitors are new immunosuppressive agents mainly used in transplant medicine
and in oncology.
The first agent developed was the rapamycin
or rapamune and was initially isolated in the soil
of Easter Island and was used as a fungicide(1).
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The discovery of the immunosuppressant
properties of rapamycin led to the understanding
of the mammalian target of rapamycin (mTOR)
pathway.
The mTOR pathway is a complex network
playing a key role in the synthesis of cellular proteins important for angiogenesis, metabolism and
cell proliferation(2).
Many clinical trials have shown the effectiveness of rapamycin in decreasing the incidence of
malignancy and skin cancers in solid organ transplant recipients(3,4).
The development of rapamycin and its analogs
is a promising therapeutic option but important
adverse events have been described such as hyperlipidemia, anaemia, leukopenia, and thrombocytopenia(5). Their cutaneous side effects and
especially their effect on the wound healing process will be discussed in this article.
MECHANISMS OF ACTION
The mTOR is an important kinase necessary for
physiological cellular activities acting by forming
two complexes; the mTOR complex 1 and the
mTOR complex 2. The result of the activation of
complex 1 is the promotion of cell proliferation,
the angiogenesis process and protein synthesis.
The mTOR complex 2 activity is essential for the
transformation and vitality of a number of cancer cell types, but in many normal cells, mTOR
complex 2 activity is less essential.
The rapamycin can inhibit the activation of
the mTOR complex 1 by binding to an intracellular receptor FKBP12, but how this interaction
antagonises the mTOR complex 1 is not well
understood.
In that way, rapamycin is able to cause an immunosuppression by inhibiting the signal transduction pathway required for the progression of
cytokine-stimulated T-cells from G1 into S phase.
In addition, many enzymes along the signalling
pathway that are inhibited by the rapamycin play
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Science, Practice and Education
a role in the development and progression of different
cancers and metabolic disorders such as diabetes or atherosclerosis.
The mTOR pathway is upregulated in many other
conditions such as in polycystic kidney disease and neurofibromatosis.
The mTOR pathway is a complex network with a
variety of positive and negative regulators but all these
mechanisms are not completely explained(6,7,8).
SIDE EFFECTS
Despite their attractive pharmacological properties, side
effects are associated with mTOR use in 20-40%(9) of
patients. Some side effects are easily manageable, whereas
others lead to discontinuation of the drug. The anaemia,
thrombocytopenia, neutropenia, proteinuria, lymphedema
and hyperlipidemia are the most reported dose dependent
side effects(10,11).
Cutaneous side effects have also been reported such as
wound healing impairment. Such skin side effects have
also been reported with the use of anti-vascular endothelial
growth factor (VEGF) therapy and could therefore be a
limiting factor for their use(12).
CUTANEOUS SIDE EFFECTS
Pruritic follicular papulo-pustular eruption represents a
typical side effect occurring early after the initiation of the
mTOR inhibitors therapy. This effect is mostly temporary
and usually improves within a few weeks(13).
Pruritus and xerosis are frequently reported by the patients receiving mTOR inhibitors therapy(13).
Cases of angioedema have been reported but all the
patients were simultaneously treated with angiotensinconverting enzyme inhibitors. The resolution of the angioedema was observed after the withdrawal of the angiotensin-converting enzyme inhibitors(14).
The development of buccal ulcerations and stomatitis are a common and potentially dose limiting toxicity
associated with the use of mTOR inhibitors in cancer
treatment(13).
The interactions of the mTOR inhibitors on the healing process are important cutaneous side effects. Wound
infections, incisional hernias and wound dehiscence have
also been reported(15).
WOUND HEALING IMPAIRMENT
A normal healing process can be divided in four steps:
haemostasis and coagulation, inflammation, proliferation
and remodelling. A perfect control on each step is necessary for a correct healing(16).
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The mTOR inhibitors can directly interfere with each
step of the healing process but more specifically on the
inflammation and proliferation stages. They are able to
inhibit the angiogenesis process by decreasing the level
of the VEGF, they can also decrease the activity of the
intraepithelial gd T cells and cause an inhibition of the
smooth muscle cells, fibroblast proliferation and matrix
deposition. This would decrease the formation of scar tissue and compromise blood flow to the defect.
The crucial role played by the mTOR in the healing
process has yet to be examined in detail(17).
The mTOR inhibitors can also indirectly interfere with
the repair process. Their immunosuppressant properties
increase the risk of infection. The anaemia, hypoproteinemia and lymphedema secondary to the mTOR inhibitors
therapy are also risk factors for healing complication and
delayed healing(18,19).
MANAGEMENT
The management of wound healing complications in
patients treated by mTOR therapy is difficult. The clinicians have to be aware of the potential healing impairment
caused by mTOR therapy.
We have reviewed the recent literature concerning
mTOR therapy and its impact on the wound healing
process. There is no standardised guideline concerning
the management of healing complications. We have found
some recommendations; with a level three of evidence
based medicine, proposed for the use of the mTOR inhibitors in the transplantation medicine(20).
We have summarised the important points:
䡲 Before starting the mTOR inhibitors therapy, it is
recommended that the risk factors for wound healing complications are checked. Factors like the use
of concomitant immunosuppressive therapy, obesity,
and smoking are modifiable risk factors. The patient’s age, sex and ethnic origin are non–modifiable
risk factors. Any modifiable risk factor should be addressed. If a non-modifiable risk factor is identified,
a risk–benefit analysis should be performed and, if
appropriate, an alternative treatment to mTOR inhibitors should be considered.
䡲 Some clinicians are narrowing or even discontinuing the use of steroids in the early post-transplant
period. It is also recommended to avoid the use of
the mTOR inhibitors during the first week posttransplantation.
䡲 The impaired healing is a dose-dependent side effect.
A cumulative rapamycin dose of more than 35 mg
during the first four days post-transplantation is a
risk factor for impaired healing. It is highly recom-
䊳
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Science, Practice and Education
mended to avoid the loading doses and to initiate
and maintain rapamycin at a dose of 2–4 mg/day,
with an increase in dose above this level only if target
levels are not reached by day seven. Recommended
target levels are between 5 and 10 ng/ml, depending
on concomitant immunosuppressant therapy.
It is also important to know that some medications
can increase the blood level of the rapamycin like
the inhibitors of CYP3A4 (verapamil, ketoconazole,
erythromycin…) and their concomitant use with the
mTOR inhibitors therapy can be a risk factor for
impaired healing.
Concerning the risk for surgery, it is important to
identify the type of surgery. For major surgery, the
mTOR inhibitors have to be stopped five to 10 days
before the surgery and restarted one to three months
after the surgery.
Regarding non-surgical wounds such as traumatic
wounds and vascular ulcers, the recommended attitude is classical wound care management. The risk
factors for a wound healing complication have to
be checked and corrected if possible. The diagnosis and treatment of infections are important steps
for helping the correct healing. The withdrawal or
the decreasing of the dose of the mTOR inhibitors
therapy has to be considered only for complicated
wounds where there is an inability to correct the risk
factors(20).
䡲
䡲
䡲
References:
1 Sharp ZD, Strong Rather role of mTOR signaling in controlling mammalian life
span: what a fungicide teaches us about longevity. J Gerontol A Biol Sci Med Sci
2010: 65:580–589.
CONCLUSIONS:
The development of the mTOR inhibitors is an interesting
therapeutic option thanks to their different immunosuppressive properties. They are mainly used in transplant
medicine and oncology. The involvement of the mTOR
pathway in many disorders such as neurofibromatosis and
polycystic kidney disease has enlarged their indications.
One of the major benefits of rapamycin is that it is an
immunosuppressant that inhibits carcinogenesis, whereas
other immunosuppressants are thought to increase carcinogenesis like the calcineurin inhibitors. The effect of
the mTOR inhibitors on carcinoma is likely inhibition
of angiogenesis and an associated decrease in vascular endothelial growth factor.
Unfortunately the use of the mTOR inhibitors is associated with many side-effects. Some of these are manageable, whereas others could be limiting factors for mTOR
use.
This article gives you a general overview of the effects
of mTOR inhibitor therapy. Our article sought to point
out their important impact on the skin healing process.
The management of this side effect is based on a
number of recommendations with a level three of evidence
based medicine. Control of the risk factors for wound
complication is a crucial step before starting such therapy.
The complexity of the mTOR pathway is not completely
understood but its role in the wound healing process is
crucial. The indication for the mTOR therapy has to be
fully discussed and the risk-benefits balance must be considered carefully for each patient.
It would also be interesting in the future to develop
guidelines regarding their use in the oncology field. 䡵
10 Kim M et al. Marked erythrocyte microcytosis under primary immunosuppression
with sirolimus. Transpl Int.2006:19 :12-18.
11 Kasiske B et al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney
transplant recipients. Am J Transplant.2008:8 : 1384-1392.
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