Repurposing the Thalidomide to the Treatment of Irinotecan-Induced Intestinal Mucositis: An Old Drug to a New Use
Rafaela Miranda Pessoa#, William Gustavo Lima#, Kátia Duarte Vital, Valbert Nascimento Cardoso and Simone Odília Antunes Fernandes*
Department of Clinical and Toxicological Analyses, University of Minas Gerais, Brazil
#These authors contributed equally.
Submission: August 31, 2018;Published: October 09, 2018
*Corresponding author: Simone Odília Antunes, Radioisotope Laboratory, Department of Clinical and Toxicological Analyses, School of Pharmacy, Federal University of Minas Gerais, Av. Antônio Carlos, Brazil
How to cite this article: Rafaela M P, William G L, Kátia D V, Valbert N C, Simone O A F. Repurposing the Thalidomide to the Treatment of Irinotecan- Induced Intestinal Mucositis: An Old Drug to a New Use. Glob J Pharmaceu Sci. 2018; 6(2): 555682. DOI: 10.19080/GJPPS.2018.06.555682.
Intestinal mucositis (IM) is an inflammation caused by antitumor therapy, it seems as side effect especially in irinotecan-based protocols. This condition has a negative impact on patient’s quality of life and treatment effectiveness, once restricts food intake and may predispose the patient to secondary infections. Currently in the clinical practice, only palliative measures are used to treat the IM, which represent the main clinical limitation in management this condition. In this scenario, the repurposing of compounds that are already in clinical use highlight as a rapid and effective strategy against IM caused by chemotherapy. The use of thalidomide has already been demonstrated as a good therapeutic option in preclinical models of irinotecan-induced IM, due its ability to modulate proinflammatory response and to reduce the levels of enterotoxic metabolite of this antitumor agent (i.e., SN-38). In this sense, thalidomide appears as a promising compound for repositioning the therapy of IM, since it exhibits high clinical efficacy and does not affect the activity of ongoing antitumor treatment.
Keywords: Intestinal mucositis; Irinotecan; Thalidomide; Cancer therapy
Intestinal mucositis (IM) is an adverse reaction characterized by acute inflammation of mucosa in small intestine and/or colon induced by a variety of chemotherapeutic agents, particularly irinotecan and 5-fluorouracil . This condition has a great impact on patient’s quality of life, since it limits their tolerability to antineoplastic therapy, restricts food intake (i.e., has been associated to fatigue and sub nutrition), and may predispose the patient to secondary infections, thus generating an increase in time of hospital stay and higher cost to public health [1,2]. As the first-line treatment for colorectal cancer, the clinical benefit of irinotecan is many times limited by IM, which occurs in 15-40% of patients that receiving conventional doses and virtually all on the regimens of high-doses this antitumor [2,3].
Among the main limitations in the clinical management of IM is the absence of curative or prophylactic treatments that are effective and safe in these cases, being available only palliative measures currently . In this direction, the search for new pharmacotherapeutic strategies become imperative to reduce the morbidity and mortality associated with IM and ensure a better quality of life for patients susceptible to this manifestation. Recently, the concept of repurposing is gaining space in the pharmaceutical market by allowing the reduction of costs, optimization of release time for the regulatory agencies and reducing the final price of new drugs . In this development model, compounds that are already in clinical use are diverted from your original employment and assigned to a new application, being required only clinical trials demonstrating the effectiveness of the new use [4,5].
While the activity of many non-enteroprotective drugs has been recognized, only now the interest in exploring these compounds in the treatment of IM is increasing . The thalidomide, a derivative of glutamic acid that is widely employed in the treatment of inflammatory and autoimmune diseases, has showed as a good therapeutic option also in IM . Govindarajan and collaborators  observed that the combination of thalidomide and irinotecan in patients with metastatic colorectal cancer eliminated the diarrhea and nausea associated to the treatment, thereby ensuring that the patients completed the chemotherapy course without suspensions or reduction in dose
of drug. This clinical evidence indicates that thalidomide might
increase the tolerability to antineoplasic therapy preventing the
IM, and basic studies have confirmed these findings.
In mice with irinotecan-induced IM (75 mg/kg/day for four
days), the treatment with thalidomide (60 mg/kg/day for 7 days,
starting 1 day before the first antitumor injection) was able to
reduce the inflammatory process in the ileum, but did not reduce
late-onset diarrhea associated with chemotherapy . On the
other hand, co-administration of thalidomide (100 mg/kg/day
for 8 days, starting 1 day before the first antitumor injection)
and irinotecan (60 mg/kg/day for four days) in Sprague-
Dawley rats produced a considerable reduction in diarrhea and
weight loss associated with chemotherapy, as well as protecting
animals from other adverse reactions of the antitumor, such
as myelosuppression, inflammation of the intestinal mucosa,
and apoptosis of enteric epithelial cells. In these animals, the
mechanisms involved were the TNF-α, IL-1β, IL-6 and IFN-γ
inhibition, and activation of IL-2 .
Importantly, thalidomide treatment did not reduce the antitumor
effect of irinotecan, and in C57BL/6 mice the use this
drug was able to protect the weight loss and intestinal damage,
as well as speed up the intestinal epithelia renovation without
affecting efficacious of tumor growth inhibition by irinotecan
. The biochemical mechanisms that support the therapeutic
effect of thalidomide have been associated with the ability of this
drug to modulate the proinflammatory response in IM, as well
as to modify the pharmacokinetics of the irinotecan, reducing
its enterotoxic fraction [9-14]. Thalidomide is known by inhibits
TNF-α production, a key cytokine in irinotecan-induced IM, by
enhancing the degradation of its messenger RNA . In addition,
thalidomide has been associated to inhibition of inflammasome,
an important proinflammatory system that leads to maturation
and secretion of cytokines associated with IM such as IL-1β and
IL-18 . Recent studies have also showed that the hydrolytic
products of thalidomide interfere with the pharmacokinetics of
irinotecan, which was associated to the enteroprotective effect
of this drug . Irinotecan is a prodrug which is activated to
the metabolite SN-38 thought of hepatic carboxylesterases. In
addition to a higher cytotoxic effect that irinotecan, SN-38 is
characterized also by high enterotoxicity, been it related to IM
. The metabolites of thalidomide decreasing the systemic
exposure of SN-38, reducing half-life and inducing intracellular
accumulation of this active metabolite in liver, besides diminishing
the biliary excretion and cecal exposure of both, irinotecan and
SN-38 [12-14] (Figure 1).
Despite recent advances in the development of prophylactic
and curative treatments for irinotecan-induced IM, no universally
effective and safe drug is currently licensed in these cases. The
fact that the IM is the acute disease limits the time required for
the use of therapeutic compounds, which reduces the interest
of large pharmaceutical companies in investing to research and
development of news drugs directed to these chemotherapyassociated
adverse reactions. Thus the repositioning stands
out as a strategy that aims to dribble the incipient investments
of pharmaceutical companies, as well as the strict legislation
applied to the release of new compounds in market. The antiinflammatory
effect and the ability of thalidomide to reduce the
plasma concentration of the enterotoxic metabolite of irinotecan
are shown to have a profound impact on the development of IM.
In this context, we can conclude that thalidomide appears as a
promising compound for repositioning the therapy of IM, since
it exhibits high clinical efficacy and does not affect the activity of
ongoing antitumor treatment.
We would like to thank Conselho Nacional de Desenvolvimento
Cientifico and Tecnologico (CNPq), Coordenacao de Aperfeicoamento
de Pessoal de Nivel Superior (CAPES), and Fundacao
de Amparo a Pesquisa do estado de Minas Gerais (FAPEMIG) by
financial support. RMP and WGL are grateful to CAPES for a graduate