Comparison of enzymatic and acid hydrolysis of bound flavor compounds in model system and grapes

Article abstract of DOI:10.1016/j.foodchem.2015.05.089

Four synthesized terpenyl-β-D-glycopyranosides (geranyl, neryl, citronellyl, myrtenyl) were subjected to enzymatic (AR 2000, pH 5.5) and acid (citric buffer, pH 2.5) hydrolysis. Decrease of glycosides was measured by HPLC and the volatiles released - by comprehensive gas chromatography-mass spectrometry (GC x GC-ToF-MS). Enzymatic hydrolysis performed for 21 h yielded 100% degree of hydrolysis for all glycosides but citronellyl (97%). Degree of acid hydrolysis was highly dependent on type of aglycone and the conditions. The highest degree was achieved for geraniol, followed by citronellol and nerol. Myrtenylo-β-D-glycopyranoside was the most resistant glycoside to hydrolysis. Acid hydrolysis degree was also related to temperature/time combination, the highest being for 100 °C and 2 h. In a result of enzymatic hydrolysis 85-91% of total peak areas was terpene aglycone, whereas for acid hydrolysis the area of released terpene aglycone did not exceed 1.3% of total peak area indicating almost complete decomposition/transformation of terpenyl aglycone.

Full text of DOI:10.1016/j.foodchem.2015.05.089

Lung Cancer 88 (2015) 349–351
Contents lists available at ScienceDirect
Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan
Case report
Successful treatment with alectinib after crizotinib-induced
esophageal ulceration
Yasuto Yoneshimaa, Isamu Okamotoa,b,∗, Tomotsugu Takanoa, Aimi Enokizua,
Eiji Iwamaa,c, Taishi Haradaa, Koichi Takayamaa, Yoichi Nakanishia,b
a Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
b Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
c Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Crizotinib was the first clinically available inhibitor of the tyrosine kinase ALK, and next-generation ALK
inhibitors, such as alectinib, are now under development. Although crizotinib is generally well tolerated,
severe esophageal injury has been reported as a rare but serious adverse event of crizotinib therapy.
We now describe the successful treatment with alectinib of a patient who developed crizotinib-induced
esophageal ulceration.
Received 18 January 2015
Received in revised form 10 March 2015
Accepted 11 March 2015
Keywords:
Alectinib
© 2015 Elsevier Ireland Ltd. All rights reserved.
Crizotinib
Esophageal ulceration
Anaplastic lymphoma kinase (ALK)
Non-small-cell lung cancer (NSCLC)
1. Introduction
2. Case report
Crizotinib is a tyrosine kinase inhibitor for MET and ALK and has
shown marked antitumor activity in patients with non-small cell
lung cancer (NSCLC) positive for ALK rearrangement [1]. Although it
is generally well tolerated, less than a third of patients treated with
crizotinib develop significant adverse events (AE) that require dose
interruption or reduction [2]. Severe esophageal injury has been
reported as a rare but serious AE associated with crizotinib therapy
[3,4].
Alectinib is a highly selective ALK inhibitor and was approved in
2014 for the treatment of ALK fusion gene-positive NSCLC in Japan.
It has shown promising activity in patients with crizotinib-resistant
disease and has been generally well tolerated in clinical trials [5].
The safety of alectinib for patients who develop crizotinib-induced
esophageal ulceration has not been determined. We now describe
the successful treatment with alectinib of a patient who developed
crizotinib-induced esophageal ulceration.
A 52-year-old Japanese female never-smoker was diagnosed
with stage IV (cT2aN2M1a) adenocarcinoma of the lung. The patient
received 4 cycles of carboplatin and gemcitabine as a first-line
chemotherapy followed by pemetrexed as a second-line. After 8
cycles of pemetrexed, the patient underwent palliative radiothe-
rapy for superior vena cava syndrome. The patient subsequently
showed evidence of progressive disease with bilateral pulmonary
metastases and multiple bone metastases. After multiple regi-
mens of chemotherapy, the primary tumor was found to harbor
an ALK rearrangement by fluorescence in situ hybridization. The
capsule form of crizotinib was administered orally at a dose of
250 mg twice daily. After 4 days of crizotinib treatment, the patient
developed odynophagia and dysphagia. The patient had no condi-
tion such as rheumatological disease that predisposed her to have
dysphagia. Although no esophageal abnormality was detected by
computed tomography (CT) before crizotinib treatment (Fig. 1A),
severe esophageal wall thickening was apparent after 4 days
of treatment (Fig. 1B). Upper endoscopy showed circumferential
ulcer with a white coating in the esophagus (Fig. 1C). Histopatho-
logic examination of the ulcer edge revealed acute inflammatory
changes. Crizotinib was discontinued, and the symptoms amelio-
rated within 1 week. Repeat endoscopy 10 days later showed no
ulcer (Fig. 1D). Two months after crizotinib treatment, the patient
showed evidence of progressive disease with growth of the lung
∗
Corresponding author at: Center for Clinical and Translational Research, Kyushu
University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Tel.: +81 92 642 5378; fax: +81 92 642 5390.
E-mail address: okamotoi@kokyu.med.kyushu-u.ac.jp (I. Okamoto).
http://dx.doi.org/10.1016/j.lungcan.2015.03.012
0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.

350
Y. Yoneshima et al. / Lung Cancer 88 (2015) 349–351
Fig. 1. CT and endoscopic imaging of esophageal ulceration. A CT scan showed no esophageal abnormality before crizotinib treatment (A) but severe circumferential
esophageal wall thickening after 4 days of such treatment (B). Arrows indicate the esophagus. Endoscopy revealed circumferential ulcer of the esophagus after 4 days of
crizotinib treatment (C) and disappearance of the ulcer at 10 days after cessation of the treatment (D).
tumors. After obtaining full informed consent regarding the risk of
recurrent esophageal ulceration, we restarted the patient on crizo-
tinib at an oral dose of 200 mg once daily ingested with a sufficient
quantity of liquid in the sitting position and with co-administration
of alginate sodium. After 7 days of crizotinib treatment, however,
the patient manifested the same symptoms and upper endoscopy
showed esophageal ulcer. Crizotinib was discontinued, and repeat
endoscopy 10 days later revealed no ulcer. The clinical, endoscopic,
and pathological findings were thus consistent with crizotinib-
induced esophageal ulceration. The patient next received three
regimens of chemotherapy, but she showed evidence of progressive
disease with liver metastases. One year after crizotinib treatment,
the patient was started on alectinib at an oral dose of 300 mg twice
daily. Upper endoscopy showed no esophageal ulcer after 10 days
of alectinib treatment. One month after the initiation of alectinib
treatment, a CT scan revealed shrinkage of the tumors. The patient
has remained on continuous alectinib treatment for 2 months with
no evidence of esophageal ulcer.
standing position was previously found to prevent the recurrence
of crizotinib-induced esophageal ulceration [4]. In the present case,
however, the esophageal ulcer was recurrent with a sufficient
quantity of liquid ingested in an adequate position and with co-
administration of a mucosal protectant.
The biological mechanism of crizotinib-induced esophageal
ulceration remains unclear.
A previous study indicated that
esophageal ulcer activates signaling by hepatocyte growth factor
(HGF) and its receptor (MET) as a repair mechanism [7]. Given
that crizotinib was originally developed as a MET inhibitor, block-
ade of HGF-MET signaling might contribute to the pathogenesis
of crizotinib-induced esophageal ulceration. In contrast, alectinib
is highly selective for ALK among various types of kinase enzyme
[8]. The present patient received alectinib with no evidence of
esophageal ulcer, suggesting that this AE is not the result of ALK
inhibition but rather an off-target effect of crizotinib.
In conclusion, we successfully managed
a patient who
developed crizotinib-induced esophageal ulceration by full-dose
treatment with alectinib. Alectinib is thus a potential effective and
well-tolerated treatment option for patients for whom crizotinib
has been discontinued because of severe esophageal injury.
3. Discussion
Crizotinib was the first clinically available ALK tyrosine kinase
inhibitor for the treatment of ALK rearrangement-positive non-
small cell lung cancer (NSCLC). Safety data from clinical trials
indicate that crizotinib is well tolerated, with most adverse events
(AEs) being of grade 1 or 2 [1,2,6]. Severe esophageal injury has
been reported as a rare but serious AE associated with crizotinib
therapy [3,4].
Disclosure
The authors report that they have no relevant relationships to
disclose.
Conflict of interest statement
We here describe a case of crizotinib-induced severe esophageal
ulceration that reappeared after discontinuation and resump-
tion of crizotinib treatment. Adequate liquid intake in the
None declared.

Y. Yoneshima et al. / Lung Cancer 88 (2015) 349–351
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