Journal of Cancer Therapy, 2013, 4, 1355-1361
http://dx.doi.org/10.4236/jct.2013.48160 Published Online October 2013 (http://www.scirp.org/journal/jct)
1355
Assessment of the Safety of Olmesartan in Combination
with Sorafenib in Mice Bearing Ehrlich’s Ascites
Carcinoma
Mohammad M. Abd-Alhaseeb1*, Sawsan A. Zaitone2, Soad H. Abou-El-Ela3, Yasser M. Moustafa2
1Department of Pharmacology and Toxicology, Faculty of Pharmacy & Pharmaceutical Industries, Sinai University, Arish, Egypt;
2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt; 3Department of Bio-
chemistry, Faculty of Pharmacy & Pharmaceutical Industries, Sinai University, Arish, Egypt.
Received September 17th, 2013; revised October 14th, 2013; accepted October 22nd, 2013
Copyright © 2013 Mohammad M. Abd-Alhaseeb et al. This is an open access article distributed under the Creative Commons Attri-
bution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
ABSTRACT
Sorafenib was the first multikinase inhibitor to be approved for use in metastatic renal cell carcinoma. Olmesartan me-
doxomil used in treatment of hypertension and was reported to inhibit angiogenesis in several models. The present
study was designed to assess the safety of a combination of sorafenib plus olmesartan compared to monotherapies in
mice bearing Ehrlich’s ascites carcinoma cell line. Mice were divided to seven groups, 1) normal mice, 2) Ehrlich’s
ascites carcinoma control, 3 - 5) olmesartan (3, 10, 30 mg/kg/day), respectively, 6) sorafenib (30 mg/kg/day) and 7) the
combination group: mice received olmesartan (30 mg/kg/day) plus sorafenib. All drug treatments continued for 21 days.
At the end of the experiment, a complete blood count was performed and kidney and liver functions were estimated.
The combination therapy produced a non-significant change in most of the measurements of complete blood count and
liver enzymes when compared to normal animals. On the other hand, the combined therapy significantly increased
blood urea nitrogen when compared to normal group but did not change the serum creatinine level. Concomitant ad-
ministration of olmesartan with sorafenib did not significantly augment the toxicity of the later. Therefore; olmesartan
might be a safe candidate with sorafenib in treatment of cancer if clinical data proved the benefit of this combination.
Keywords: Mice; Ehrlich’s Ascites Carcinoma; Olmesartan; Sorafenib
1. Introduction
Sorafenib was the first multikinase inhibitor to be ap-
proved for use in metastatic renal cell carcinoma in the
US (2005) and in Europe (2006) [1]. Sorafenib (Nexavar)
significantly prolonged the progression-free survival in
903 patients versus placebo [2]. Sorafenib is an oral,
biaryl urea RAF kinase inhibitor that acts against both
vascular endothelial growth factor (VEGF) and platelet-
derived growth factor receptors, simultaneously targeting
both tumor cell proliferation and angiogenesis [3,4]. In
contrast to the traditional adverse effects from cytotoxic
chemotherapeutic agents, sorafenib seems to have a dis-
tinct adverse effect profile. It has been shown to increase
the risk of hypertension, bleeding, hand-foot discolora-
tion, arterial thromboembolism, and elevated liver transa-
minases [5]. Thrombocytopenia and other hematologic
toxicities have been reported in some clinical trials using
sorafenib [6]. The exact etiology of these toxic responses
is still unclear [7].
Angiotensin receptor blockers (ARBs) are widely used
as antihypertensive drugs [8]. Olmesartan medoxomil
was introduced as selective angiotensin II receptor block-
er used in treatment of hypertension [9]. In addition,
ARBs inhibit VEGF, so it can be used to inhibit angio-
genesis. In our laboratory (unpublished data), we found
that olmesartan potentiated the anti-angiogenic effect of
sorafenib in mice bearing Ehrlich’s ascites carcinoma
(EAC) cell line.
The objective of the current study was to assess some
of the toxic effects of a three-week therapeutic period
using a combination of sorafenib plus olmesartan com-
pared to monotherapies in mice bearing EAC cell line.
*Corresponding author.

Assessment of the Safety of Olmesartan in Combination with Sorafenib in Mice Bearing Ehrlich’s Ascites Carcinoma 1356
2. Materials and Methods
2.1. Chemicals
Olmesartan medoxomil was purchased from Daiichi
Sankyo Pharmaceutical Co. (Tokyo, Japan) and dissolv-
ed in dimethylsulfoxide (DMSO) supplied by Sigma-
Aldrich (MO, USA). Sorafenib tosylate was purchased
from Bayer AG (Leverkusen, Germany) and dissolved in
DMSO. Urea colorimetric kit was purchased from Bio-
diagnostic® (Cairo, Egypt). Creatinine colorimetric kit
was purchased from Diamond Diagnostic® (Cairo, Egypt).
SGPT (ALT) and SGOT (AST) colorimetric kits were
purchased from BioSTC® (Cairo, Egypt). All other che-
micals were of analytical grade and were purchased from
ADWIC Co. (Cairo, Egypt).
2.2. Tumor Cell Line and Induction of
Solid Tumor
Ehrlich’s ascites carcinoma cell line was purchased from
Tumor Biology Department at the National Cancer Insti-
tute, Cairo University (Cairo, Egypt). The EAC cells
were suspended in normal saline to obtain a diluted sus-
pension; each 0.1 ml of this suspension contained 2.5
million of EAC cells. Each mouse was inoculated intra-
dermally at both sites on the lower ventral side with 100
µl of EAC suspension.
2.3. Animals and Experimental Design
All the experimental protocols were approved by the
Animal Care and Use Committee at Faculty of Pharmacy,
Suez Canal University, Ismailia, Egypt. Forty nine fe-
male Swiss albino mice, each weighing 20 - 25 g were
obtained from the Modern Veterinary Office for Labora-
tory Animals, Cairo, Egypt. All animals were allowed to
acclimatize under standard animal house conditions
fourteen days prior to assignment to the experimental
protocol. Animals were fed on a standard pellet diet, and
allowed free access to tap water. They were kept at a
temperature of 22˚C ± 3˚C and constant relative humidity
throughout the experimental protocol.
Mice were randomly divided into seven groups, seven
mice each. Mice received the following treatments.
Group I: mice received DMSO (5 ml/kg, p.o.) and served
as a normal control group. Group II: EAC-bearing mice
received DMSO (5 ml/kg, p.o.) and served as a positive
control group. Group III: mice were treated with soraf-
enib (30 mg/kg/day, p.o.) [10]. Group IV: mice were
treated with olmesartan (3 mg/kg/day, p.o.) [11]. Group
V: mice were treated with olmesartan (10 mg/kg/day,
p.o.). Group VI: mice were treated with olmesartan (30
mg/kg/day, p.o.). Group VII: mice received a combina-
tion of sorafenib (30 mg/kg/day, p.o.) and olmesartan (30
mg/kg/day, p.o.). All treatments started at day 8 and con-
tinued for 21 days (the therapeutic period was three
weeks).
2.4. Percentage Survival of Animals and
Body Weight
Percentage survival of animals was followed daily and
calculated in each group as: [Number of living animals/
initial total number of animals] × 100. Body weight of
each mouse was registered before treatments (base line
body weights) and at the end of experiment (final body
weights). In addition, the percent change in animal
weights was calculated.
2.5. Blood Collection and Assessment of
Hematological Parameters
Fresh blood samples (1 ml) were collected in a tube con-
taining either ethylenediaminetetraacetic acid solution
(29 µg/ml blood) for complete blood count (CBC). Sam-
ples were analyzed within 2 h in an automated cell coun-
ter (Cell-DYN 1700, Model: CD-1700, ABOTT Diag-
nostics, USA). Thirty min after collection, blood samples
were centrifuged at 2000 × g for 15 min. Another blood
sample was withdrawn and collected in a dry centrifuge
tube and allowed to stand for 30 min. After that, blood
samples were processed by centrifugation at 2000 × g for
15 min. Then, serum samples were separated, collected
in clean tubes and stored at −80˚C until used for colori-
metric assays.
2.6. Assessment of Serum ALT & AST Enzymes
Alanine aminotransferase (ALT) and aspartate amino-
transferase (AST) catalyzed the transfer of an amino
group between the amino acids L-alanine and L-aspartate,
respectively [12]. The ketoacids formed-pyruvate and
oxaloacetic acid, respectively-reacted with diazonium
salt to form a colored complex. The optical density foe
this colored product was measured at 505 - 530 nm using
a spectrophotometer (UV-1601PC, Schimadzu, Japan).
2.7. Assessment of Serum Creatinine and Blood
Urea Nitrogen
Creatinine assessment based on its reaction with sodium
picrate [13]. Creatinine reacted with alkaline picrate
forming a red complex. The intensity of the color formed
is proportional to the creatinine concentration in the
sample. Blood urea nitrogen (BUN) assessment was
measured where urea in the sample by urease enzyme
give a colored complex [14]. The developed colored
complex measured at 530 - 560 nm using a spectropho-
tometer (UV-1601PC, Schimadzu, Japan).
2.8. Statistical Analysis
Results are expressed as mean ± S.E.M. Data were ana-

Assessment of the Safety of Olmesartan in Combination with Sorafenib in Mice Bearing Ehrlich’s Ascites Carcinoma 1357
lyzed using one-way analysis of variance, ANOVA, fol-
lowed by Bonferroni’s post-hoc test. All statistical tests
were performed employing the Statistical Package for
Social Sciences, version 19 (SPSS Software, SPSS Inc.,
Chicago, USA) and the differences were considered sig-
nificant at P < 0.05.
3. Results
3.1. Percentage Survival of Animals and Animal
Body Weights
The percentage survival of animals showed a significant
decrease in all groups when compared to normal group.
However, the combined therapy showed a significant (P
< 0.05) increase in percentage survival of animals in
comparison with EAC-control and olmesartan (10 mg/kg)
groups (Table 1).
There were no significant differences among the study
groups at the beginning of the study. However, EAC-
control group showed a significant increase in percentage
body weight gain compared to normal group (P < 0.05,
Table 1). After three-week therapeutic period, sorafenib
decreased animal weight and the percentage body weight
gain compared to normal and EAC-control group. Fur-
thermore, treatment with olmesartan (3 and 10 mg/kg)
produced a non-significant difference compared to the
normal group but showed significant differences from
both EAC-control and sorafenib group. Additionally,
olmesartan (30 mg/kg) produced a significant (P < 0.05)
decrease in percentage body weight compared to EAC-
control and sorafenib groups (Table 1). In addition, the
combination therapy did not producea significant change
in percentage body weight compared to normal group but
produced a significant change in comparison to EAC-
control group and sorafenib group (P < 0.05).
3.2. Hematological Parameters
Tables 2 and 3 demonstrate hematological changes ob-
served after treating mice with sorafenib, different doses
of olmesartan, as well as their combination. The results
showed that sorafenib significantly (P < 0.05) reduced
RBCs, Hgb, Hct, RDW, platelet count, MPV, Pct, PDW,
lymphocytes and monocytes when compared to normal
control group (Tables 2 and 3). On the other hand, dif-
ferent doses of olmesartan (3, 10 and 30 mg/kg) did not
produced a significant change in almost all hematological
parameters when compared to normal control group. This
with the exception of the effect of olmesartan on % PDW;
where olmesartan (3 and 30 mg/kg) produced a signifi-
cant reduction in % of PDW while olmesartan (10 mg/kg)
produced a significant increase in the (Ta ble s 2 and 3).
Further, olmesartan (30 mg/kg) produced a significant
increase in % of Pct when compared to normal control
group.
Furthermore, the combination therapy of olmesartan
with sorafenib produced non-significant changes in the
complete blood count when compared to normal control
except in case of RDW%; the combination therapy pro-
duced a significant reduction in RDW% while the com-
bination produced a significant increase in Pct% and
PDW% which indicate the safety of the two drugs when
used with each other. In addition, the combined therapy
produced a significant increase in lymphocytes when
compared to normal, EAC-control, sorafenib and olme-
sartan (3 and 30 mg/kg) groups (Table 3).
3.3. Serum ALT and AST Enzymes
Liver transaminases (AST/ALT) are biomarkers which
indicated the degree of liver injury caused by any
chemical substances or pathogens. Liver enzymes are
significantly (P < 0.05) increased in EAC-Control group
when compared to normal control group (Table 4). On
the other hand, sorafenib significantly (P < 0.05) in-
creased ALT enzyme only when compared to normal
group while AST enzyme non-significantly increased.
Olmesartan (3 and 30 mg/kg) did not produced any sig-
Table 1. Effect of sorafenib (30 mg/kg/day, p.o.) and/or olmesartan (3, 10 and 30 mg/kg/day, p.o.) on animal weights and per-
centage survival in EAC-bearing mice.
Normal EAC-Control
Sorafenib
(30 mg/kg)
Olmesartan
(3 mg/kg)
Olmesartan
(10 mg/kg)
Olmesartan
(30 mg/kg)
Sorafenib +
Olmesartan
(30 mg/kg)
Body weight (baseline) 24 ± 0.43 23 ± 0.75 24 ± 1.35 24 ± 0.48 22 ± 0.69 23 ± 0.51 24 ± 1.21
Body weight (final) 29 ± 0.43 34 ± 0.51a 19 ± 0.26ab 26 ± 0.92bc 26 ± 0.53bc 25 ± 1.30abc 27 ± 0.77bc
% ∆wt (g) 21 ± 1.86 47 ± 4.65a -20 ± 3.9ab 12 ± 6.31bc 16 ± 2.61bc 9 ± 7.34bc 12 ± 6.57bc
% survival of animals 98 ± 2 50 ± 5.5a 62 ± 0.8a 63 ± 0.3a 52 ± 0.2a 63 ± 4.3a 74 ± 4.7abf
EAC-control: Ehrlish ascites carcinoma control. Mice were treated with the selected drugs for three weeks. Results are expressed as mean ± S.E.M. and ana-
lyzed using one-way ANOVA followed by Bonferroni’s post-hoc test. aP < 0.05 compared to normal group, bP < 0.05 compared to EAC-Control group, cP <
0.05 compared to Sorafenib (30 mg/kg) group. dP < 0.05 compared to olmesartan (30 mg/kg). eP < 0.05 compared to olmesartan (3 mg/kg) group. fP < 0.05
compared to olmesartan (10 mg/kg) group.

Assessment of the Safety of Olmesartan in Combination with Sorafenib in Mice Bearing Ehrlich’s Ascites Carcinoma 1358
Table 2. Effect of sorafenib (30 mg/kg/day, p.o.) and/ or olmesartan (3, 10 and 30 mg/kg/day, p.o.) on complete blood count
in EAC-bearing mice
Normal
control EAC-Control Sorafenib (30 mg/kg)
Olmesartan
(3 mg/kg)
Olmesartan
(10 mg/kg)
Olmesartan
(30 mg/kg)
Sorafenib +
Olmesartan
(30 mg/kg)
RBC (M/µL) 9 ± 0.53 7 ± 0.54 6 ± 0.11a 8 ± 0.26 8 ± 0.42 7 ± 0.41 8 ± 0.07
Hgb (g/dl) 12 ± 0.38 10 ± 0.97 8 ± 0.06a 11 ± 0.66 12 ± 0.85c 10 ± 0.64 12 ± 0.15c
Hct (%) 36 ± 1.02 31 ± 1.59 24 ± 0.34a 34 ± 1.75c 42 ± 2.36bce 29 ± 1.87f 35 ± 0.94cf
MCV (fL) 38 ± 1.15 44 ± 2.35 38 ± 0.63 31 ± 2.31b 48 ± 1.17ace 39 ± 2.56ef 44 ± 1.31e
MCH (Pg) 14± 0.68 15 ± 0.38 13 ± 0.28b 14 ± 0.35 15 ± 0.45 14 ± 0.45 15 ± 0.05c
MCHC (g/dl) 34 ± 1.85 34 ± 1.63 34 ± 0.47 34 ± 2.92 31 ± 1.86 36 ± 3.01 34 ± 1.22
RDW (%) 16 ± 0.21 14 ± 0.77 12 ± 0.17a 14 ± 0.52 15 ± 0.39c 15 ± 0.81c 13 ± 0.38a
Platelet (K/µL) 624 ± 6.17 660 ± 20.76 490 ± 2.57ab 624 ± 24.57c 630 ± 20.84c 619 ± 2.43c 641 ± 14.14c
MPV (fL) 9.3 ± 0.4 10 ± 0.64 6 ± 0.19ab 8 ± 0.5b 9 ± 0.3 9 ± 0.72c 9.4 ± 0.57c
Pct (%) 0.412 ± 0.01 0.665 ± 0.02a 0.304 ± 0.01ab0.403 ± 0.02bc 0.474 ± 0.02bc 0.534 ± 0.02abce 0.581 ± 0.02abcef
PDW (%) 9 ± 0.55 10 ± 0.32 2 ± 0.13ab 5 ± 0.41abc 12 ± 0.2abce 7 ± 0.57abcef 12 ± 0.73abced
EAC-Control: Ehrlish ascites carcinoma control, RBCs: red blood cells, Hgb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean
corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, RDW: red cell distribution width, MPV: mean platelet volume, Pct: plateletcrit,
PDW: platelet distribution width. Mice were treated with the selected drugs for three weeks. Results are expressed as mean ± S.E.M. and analyzed using one-
way ANOVA followed by Bonferroni’s post-hoc test. aP < 0.05 compared to normal group, bP < 0.05 compared to EAC-control group, cP < 0.05 compared to
sorafenib (30 mg/kg) group. dP < 0.05 compared to olmesartan (30 mg/kg) group. eP< 0.05 compared to olmesartan (3 mg/kg) group. fP < 0.05 compared to
olmesartan (10 mg/kg) group, n = 7.
Table 3. Effect of sorafenib (30 mg/kg/day, p.o.) and/or olmesartan (3, 10 and 30 mg/kg/day, p.o.) on leukocyte formula in
EAC-bearing mice.
Normal EAC-Control
Sorafenib
(30 mg/kg)
Olmesartan
(3 mg/kg)
Olmesartan
(10 mg/kg)
Olmesartan
(30 mg/kg)
Sorafenib + Olmesartan
(30 mg/kg)
WBC (K/µL) 10 ± 0.56 12 ± 0.32 6 ± 0.06b 9 ± 2.13 8 ± 0.79 7 ± 0.47b 8 ± 0.15
Lymphocytes (%) 81 ± 1.81 86 ± 0.89 73 ± 0.2ab 85 ± 3.25c 87 ± 0.32c 84 ± 0.82c 92 ± 0.77abced
Neutrophils (%) 5 ± 1.38 6 ± 1.16 1 ±.0.09b 7 ± 0.94c 5 ±.0.99 4 ± 0.75 4 ± 0.15
Monocytes (%) 11 ± 2.2 6 ± 1.05 3 ± 0.31a 9 ± 3.13 6 ± 0.99 8 ± 1.36 4 ± 0.2
EAC-control: Ehrlish ascites carcinoma control, WBC: white blood cells. Mice were treated with the selected drugs for three weeks. Results are expressed as
mean ± S.E.M. and analyzed using one-way ANOVA followed by Bonferroni’s post-hoc test. aP < 0.05 compared to normal group, bP < 0.05 compared to
EAC-Control group, cP < 0.05 compared to Sorafenib (30 mg/kg) group. dP < 0.05 compared to olmesartan (30 mg/kg) group. eP< 0.05 compared to olmesartan
(3 mg/kg) group. fP < 0.05 compared to olmesartan (10 mg/kg) group. n = 7.
Table 4. Effect of sorafenib (30 mg/kg) and/or olmesartan (3, 10 and 30 mg/kg) on liver and kidney functions in EAC-bearing
mice.
Normal
control EAC-Control Sorafenib (30 mg/kg)
Olmesartan
(3 mg/kg)
Olmesartan
(10 mg/kg)
Olmesartan
(30 mg/kg)
Sorafenib +
Olmesartan (30 mg/kg)
ALT (U/L) 66 ± 1.29 85 ± 3.24a 102 ± 0.29a63 ± 6.49bc 71 ± 5.05c 66 ± 4.03bc 54 ± 0.87bcf
AST (U/L) 90 ± 0.14 106 ± 3.39a 109 ± 0.14102 ± 12.98116 ± 3.24a 108 ± 2.43 103 ± 0.71
BUN (g/dl) 29 ± 0.29 40 ± 1.10a 45 ± 2.16a 50 ± 2.84ab 65 ± 2.13abce 64 ± 1.42abce 43 ± 0.44adf
Creatinine (mg/dl) 0.74 ± 0.021.46 ± 0.09a 1.29 ± 0.01a1.2 ± 0.1a 1.59 ± 0.16ae1.46 ± 0.06a 0.94 ± 0.03bef
EAC-Control: Ehrlisch ascities carcinoma control, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BUN: blood urea nitrogen. Mice were
treated with the selected drugs for three weeks. Results are expressed as mean ± S.E.M. and analyzed using ANOVA followed by Bonferroni’s multiple com-
parisons test. aP < 0.05 compared to normal group, bP < 0.05 compared to EAC-Control group, cP < 0.05 compared to Sorafenib (30 mg/kg). dP < 0.05 com-
pared to olmesartan (30 mg/kg) group. eP < 0.05 compared to olmesartan (3 mg/kg) group. fP < 0.05 compared to olmesartan (10 mg/kg) group, n = 7.

Assessment of the Safety of Olmesartan in Combination with Sorafenib in Mice Bearing Ehrlich’s Ascites Carcinoma 1359
nificant (P < 0.05) changes in liver enzymes when com-
pared to normal group while olmesartan (10 mg/kg) sig-
nificantly (P < 0.05) increased AST enzyme when com-
pared to normal group (Table 4). The combined therapy
produced insignificant effect on liver enzymes when
compared to normal group and this indicated the safety
of this combined therapy on liver functions.
3.4. Serum Creatinine & Blood Urea Nitrogen
The results showed that sorafenib treatment caused sig-
nificant increase (P < 0.05) in serum blood urea nitrogen
and creatinine when compared to normal group (Table 4).
In the same time olmesartan doses produced similar ef-
fects. The combined therapy significantly (P < 0.05) in-
creased blood urea nitrogen when compared to normal
group but doesn’t change creatinine levels (Tabl e 4).
4. Discussion
Carcinogenesis leads to several pathologies including
hematological complications [15]. Moreover, almost all
therapeutic regimens available for cancer generally pro-
duce a lot of side effects, including hematological toxic-
ity [15,16]. Hematological parameters are routinely mo-
nitored during the course of treatment of malignancy for
assessing the overall well being as well as the effects of
the treatment employed [15]. In the present study we evalu-
ate the toxicity produced after three weeks of treatment
with sorafenib or/and olmesartan in mice with Ehrlich’s
ascites carcinoma (EAC). The result of the current study
showed that over a period of three weeks, sorafenib led
to decreased RBCs, Hgb, platelets and lymphocytes. In
addition, sorafenib increased ALT, blood urea nitrogen
and creatinine levels. Consistent with our results, soraf-
enib has been shown to produce bleeding, anemia and
lymphopenia in phase 2 and 3 clinical trials [2,5,17,18].
In addition, hematological toxicities associated with
sorafenib have been reported in some clinical trials, but
they have not been well documented [5,6]. Another study
demonstrated that sorafenib with higher doses aggravated
liver injury [19] and this result came in parallel with the
previous results in our study. The exact mechanism for
the hematological toxicities associated with sorafenib
still unclear however, can be explained through the tyro-
sine kinase inhibition of FLT-3 and c-KIT [5]. FLT-3 is
primary expressed on committed myeloid and lymphoid
precursors and its activation by FLT ligand plays a criti-
cal role in normal hematopioesis and cellular growth [20].
On the other hand, in the current study the treatment with
olmesartan reduced mostly all hematological parameters
but these changes not significantly from normal animals.
In agreement, the stimulation of the angiotensin type 1
receptor by angiotensin II stimulate activities of the
erythropoietin, thrombopoietin and other hematopoietic
cytokines during normal hematopoiesis and in myelopro-
liferative neoplasms [21] so blocking of angiotensin type
1 receptor by olmesartan reduced hematological parame-
ters. In the same time olmesartan (30 mg/kg) produced
no significant changed in AST and ALT enzymes when
compared to normal animals. In agreement, olmesartan
treatment has not been shown to significantly affect liver
function testing including AST and ALT enzymes and
kidney damage [8,22] and this may be attributed to the
antioxidant activity of olmesartan as reported in two
studies using olmesartan [23-25].
In the current study, sorafenib produced a significant
reduction in animal weight when compared to normal
group and this came in parallel with the anorexia pro-
duced after sorafenib treatments as reported in some
clinical trials [2]. On the other hand, mice treated with
olmesartan (3 and 10 mg/kg) showed that no significant
change in body weight compared to normal ones, how-
ever the animals treated with olmesartan (30 mg/kg)
showed a significant reduction in body weight compared
to normal ones. Consistent with our results, olmesartan
produced reduction in animal weights alone or in combi-
nation with pioglitazone [26].
According to the best of our knowledge, the present
study was the first to assess the toxic responses produced
by the combination of sorafenib plus olmesartan (30
mg/kg). The results showed that this combination did not
influence each others in most of the hematological para-
meters and liver enzymes. However, lymphocytes and
creatinine levels significantly increased when compared
to normal group. Additionally, the combined therapy did
not reduce the animal body weights compared to normal
group. Finally, the percentage survival of animals in all
groups showed a significant decreased compared to nor-
mal group however, the combined therapy showed to
some extent minor increased but not significant from the
other treated animals.
5. Conclusion
Concomitant administration of Olmesartan with sora-
fenib did not significantly augment the toxicity of the
later. The present study suggested that this combination
offers no obvious toxicity, thus it might be evolved as a
promising regimen for treatment of tumor antihyperten-
sive patients. Further, long-term toxicity studies are
needed in order to rule out any long-term adverse effect
of the combination.
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