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Drug repositioning from bench to bedside
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Supplementary material available online
Supplementary Figures 1–2
Supplementary Tables I–II
Drug repositioning from bench to bedside: Tumour remission by the
antihelmintic drug mebendazole in refractory metastatic colon cancer
PETER NYGREN1 & ROLF LARSSON2
1Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, Uppsala,
Sweden and 2Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University, Uppsala, Sweden
To the Editor,
Despite recent progress in the knowledge in cancer
biology and considerable expenditure and efforts in
the development of new ‘targeted’ cancer drugs, progress has been limited in the major cancer types; the
newly introduced drugs mostly provide very modest
benefit at high costs, both in terms of healthcare
expenditure and patient adverse effects [1]. Drug repositioning, i.e. the finding of new indications for drugs
in development or use in other diseases is an attractive
approach to more efficient drug development by
making use of the preclinical and clinical knowledge
already available, allowing for considerable shortcuts
in many steps in the drug development process [2].
In an ongoing drug screening project in our laboratory aiming at repositioning drugs for use in advanced
colorectal cancer, we observed high activity in colon
cancer models in vitro for several members of the
bendazole group of compounds, including the approved
antihelmintic drug mebendazole (tradename Vermox).
Shortly following this observation, a 74-year-old
man with metastatic colon cancer was considered
for further treatment at Department of Oncology,
Uppsala University Hospital. He had been healthy
until emergency surgery after presentation with
ileus in 2011. An advanced sigmoid colon cancer was
radically resected. Histopathological examination
showed a moderately differentiated adenocarcinoma
with KRAS mutation. Synchronous multiple bilateral lung and paraaortic lymph node metastases
were observed and the patient started palliative chemotherapy with a combination of capecitabine,
oxaliplatin and bevacizumab. A partial remission
was observed at CT evaluations after two and
four months of treatment. Following a period of
maintenance treatment with capecitabine alone,
progressive disease was observed in August 2012.
Capecitabine, oxaliplatin and bevacizumab was
restarted and resulted in stable disease at the first
evaluation. However, this treatment was stopped due
to intolerable oxaliplatin-induced neuropathy. Second line treatment with capecitabine and irinotecan
was started in December 2012. At first evaluation
March 2013, significant progression was observed in
Correspondence: P. Nygren, Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, 751 85 Uppsala, Sweden.
E-mail: [email protected]
(Received 7 September 2013 ; accepted 9 September 2013)
ISSN 0284-186X print/ISSN 1651-226X online © 2014 Informa Healthcare
DOI: 10.3109/0284186X.2013.844359
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428
P. Nygren & R. Larsson
Figure 1. Axial computerized tomography at baseline showing multiple liver (A) and lung (C) metastases (arrows) and good regression
at first evaluation (B and D), following 6 weeks of treatment with mebendazole.
the lungs and abdominal lymph nodes and there
were new partly poorly defined liver metastases up
to 8 cm in diameter (Figure 1). Despite the progress
the patient was still in excellent performance status
and had essentially no disease-related symptoms,
except for the therapy-induced neuropathy.
In this situation with no standard therapy left, the
drug screen observation in mind, the recent preclinical finding of antitumour effects of mebendazole in
a mice model [3] and a case report indicating antitumour effect from mebendazole in a patient with
metastatic adrenocortical carcinoma [4], the patient,
after informed consent, started mebendazole at the
standard antihelmintic dose of 100 mg twice daily,
to be continued for six weeks. The patient experienced no adverse effects from the treatment and at
CT evaluation May 2013 there was near complete
remission of the metastases in the lungs and lymph
nodes and a good partial remission in the liver
(Figure 1). At this stage, the liver enzymes AST and
ALT were found elevated up to five and seven times
above upper limit of normal and mebendazole was
temporarily stopped and then reintroduced at half
dose. Liver enzymes slowly decreased and the patient
still reported no adverse effects from mebendazole.
The disease was stable at a new CT, confirming the
response observed earlier. The patient is now on drug
holiday, pending a new CT.
We conclude that mebendazole is seemingly a
promising ‘new’ drug for treatment of advanced
colorectal cancer. A number of pharmacodynamic,
clinical trial, drug formulation and dosing issues need
to be addressed before mebendazole might become
an established drug in this indication. However, the
case, together with its preclinical background, illustrates the potential of drug repositioning to improve
the development of new and better cancer therapy.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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