Assessment of the Safety of Olmesartan in Combination with Sorafenib in Mice Bearing Ehrlich’s Ascites Carcinoma

doi:10.4236/jct.2013.48160

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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.

Email: *[email protected]

Received September 17th, 2013; revised October 14th, 2013; accepted October 22nd, 2013

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

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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

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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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