Egypt. J. Exp. Biol. (Zool.

), 11(1): 15 21 (2015)

The E gypt ian S oc iet y of E xper im ent al B iology

RESEARCH ARTICLE
H e ba A. E l- G ha we t
Ab de la lim A. G ad alla h

AME L IOR AT IN G
R OL E
OF
J AMB OL AN
T EST IC U L AR D AMAG E OF R AT S

ABSTRACT:
Capecitabine (X el oda, Roche) is a proanticancer
drug,
that
is
enzym atically
converted to 5-fluorouracil in t he body. The
present
work
aim ed
to
evaluate
the
ameliorated role of the jambolan fruit-extract
against
testicular
damage
i nduced
by
capecitabine. Twenty male Wistar albino rats
(Rattus norvegicus) weighing approximatel y
120 g were used during experimentation.
Animals w ere divided into four groups; control
(saline-treated),
Jambolan-treatment
(400
mg/kg of fruit extract), capicit abine-treatm ent
(40 mg /Kg BW for 30 days), and capicitabine
and jambolan-treatm ent. Daily oral treatments
were carried out for 30 days. At the end of
experiment ation period, the animals were
sacrificed and their testis w ere incised and
processed for histopathologi cal investigation,
com et and flow cytom etri c analysis for
apoptosi s. The present findings revealed that
the
drug-treatm ent
possessed
dramati c
testicular damage in the f orm of focal
disorganization of t he seminiferous tubules
with almost missing of sperm, comparativel y
decreased sperm atogenic cells, sloughing and
deg en eration of spermatogenic cells and
interstitial
oedem atous
l esions.
Flow
cytom etric analysis showed apparent increase
of apoptic M1 spermatogenic and ovarian
cells.
Comet
assay
reveal ed
apparent
increase of detached spermatogenic cell s.
Jambolan-treatment
am eliorated
the
pathological picture and decreased the
incidence of apoptosis. Finally, the authors
concl uded that the jambolan-treatm ent wit h its
higher content of antioxidants resolut e the
toxi cological aspects of the anticancer drugs.
KEY WO RDS :
Capeci tabine, Jambol an, testi cular dam age,
ameliorat i on effect.

OF

IN D U CED

Ab de la l im A. G a da lla h

Zoology Departm ent, Faculty

Mansoura Uni versi ty, Egypt

of

Science,

ARTIC LE CO DE: 02.01.15

INTRO DU CTIO N:
Capecitabine (Xeloda, Roche) is a new
agent, orally-administered chemotherapeutic
agent used in the treatment of num erous
cancers
(Rossi,
2013).
It
is
orally
administ ered as a precursor of 5-fluorouracil
(5-FU),
which
is
converted
to
5-FU
preferentially in human liver and cancer tissue
(Miwa et al., 1998). Hepatic st eatosis, a mild
manifestation of nonalcoholic fatty liver
disease (NAFLD), may occur aft er treatm ent
with 5-FU. This has become a more
recognized complication in the era of hepatic
surgery for colorectal liver m etastases, w here
hepatic steatosis is associated with increased
post-operative morbidity (Zorzi et al., 2007).
Peppercorn et al. (1998) found that 47% of
patients with colorectal liver m et astases
treated with systemic 5-FU and folinic aci d
had computed tomography (CT) findings
consistent with fatty change.
O n the other hand, several authors
outlined the reproductive toxicities postanticancer-treatment s.
A
single
dose
administration of 5-fluorouracil (5-FU) t o
Wistar rats for 1, 3, 15, and 30 daystreatm ents were found to decrease t he testes
wei ght, seminiferous tubular diam et er, and
germ cell height ( D'Souza and
Narayana,

CO RRES PO NDENCE:
H e ba A. E l- G ha we t
Zool ogy Department , Facult y
Mansoura University, Egypt
E-m a il:

of

ISSN: 2090 - 0511

On Line ISSN: 2090 - 0503

Science,

C AP EC IT AB IN E

http://www.egyseb.org

16

Egypt. J. Exp. Biol. (Zool.), 11(1): 15 21 (2015)

2001). Sperm abnormalities including

amorphous, coiled, double headed, double
tailed and double headed/double tailed
spermatozoa whi ch are confirm ed by a
decrease of testosterone level were detected
in rats
received
administration
of
5Fl uorouracil
(5-FU)-treatm ent
(D'Souza,
2003). Also, 5-FU treatm ent was f ound to
cause germinal cell sloughi ng, tubular atrophy
and a decline in sperm concentration
(Narayana et al., 2000; D'Souza and
Narayana, 2002). A decrease of serum
prolactin and testosterone levels associ ated
with a reduced f unction of S ertoli cell were
also
reported
post
5-FU-treatm ent
by
Takizawa and H orii (2002). Decreased
test osterone level was found to be associ ated
with degeneration of Leydig cell s postbleomycin, etoposi de and cisplatin treatm ent
(Al-Bader and Kilarkaje, 2015).
Jambol an Jambolan, Syzgium cumin i
Linn. (Family Myrtaceae) is a tree cultivated
in t he gardens of Mansoura U niversity. The
tree flourished t heir good tast e fruits during
Septem ber to November. The fruits is rich in
compounds
containing
anthocyanins,
glucoside, elagic acid, isoquercetin, kamferol,
or antimellin (Ayyanar and Subash-B abu,
2012) raffinose, glucose, fruct ose, citric aci d,
mallic acid (Lewis et al., 1956), gallic aci d,
anthrocyanin (Par Jain and S eshadri, 1975)
and
crude
fibre,
magnesi um,
calcium,
phosphorus, iron, potassium, cupper, vitamin
A, thiamine, riboflavin, niacin, folic aci d,
ascorbic acid, choline (Ayyanar and S ubashBabu, 2012).
There is no available work concerning
the reproductive toxicity of the anticancer
drug capecitabine and the beneficial effects of
the crude fruit of jambolan. The present work
illustrates the cytotoxicity of anticancer drug
through descriptive histol ogical investigation
and quantitative flow cytom etry, as well as the
impact of phytotherapy of jambolan in resolut e
the t oxicologi cal aspects of drugs.
M ATER IAL AND METHO DS:
Capecitabine and applied dose-treatment:
Capecitabine (Xeloda, Roche) is an
orally-administered chem otherapeutic agent
used i n the treatment of num erous cancers. It
is a pro-drug, that is enzym atically converted
to 5-fluorouracil in the body. The used
therapeutic daily dose is 40 mg/kg BW in 0.4
ml saline solution, orally administ ered for one
month for rat. The dose was calcul ated
according to Paget and B arnes (1964). The
chosen dose was nearly comparable to the
hum an effective therapeutic dose (ETD).
Phytotherapy-treatment with Jambolan-fruit:
The j ambolan fruits are oval-shaped
dark-brown col our and edible in taste. In the
present study, the fruits were hom ogenate in
ISSN: 2090 - 0511

sali ne sol ution and dosed orally at doses of

400 mg/kg BW.
Experimental work:
Twenty mal e Wistar albino rats ( Rattus
norvegicus) w eighing approximately 120 g
were used in the present study. All rats were
kept under good ventilation and aerated room.
Excess standard diet was supplied ad libitum
during the experim ental period. They were
allowed free acc ess to water. Animals were
divi ded i nto four groups (n = 5). The first
group served as control, the second recei ved
Jambolan-treatment (400 mg/kg BW) of fruit
hom ogenized w ith saline solution), the third
group received capicitabine-treatm ent (40
mg/kg BW ), and the fourth group received
daily oral doses of jambolan equal to 400 mg
/Kg BW f or 30 days. At the end of treatm ent,
the animals were sacrificed and thei r liver and
kidney were i ncised. Parts of the tissues were
kept i n refrigerator and the other ones were
fixed in 10% phosphate buffered f ormalin (pH
7.4) for routine histological investigati on.
Histological i nvestigations:
Testis of control and experim ental
groups were dissected and fixed in 10%
phosphate
buffered
formalin
(pH
7.4),
dehydrated in ascending grades of ethyl
alcohol, cleared in xyl ene, and mounted i n
molt en pararplast 5862C. Serial 5 m thick
sections
were
cut
and
stained
wit h
haem atoxylin and eosin (H&E), exami ned
under bright fi el d light microscopy, and t hen
photographed.
Com et assay:
The com et assay was perform ed as
described by Sasaki et al. (1997), Tw o
hundred
microliters
of
106
cells/ml
suspension were mixed wit h 600 l of 1% low
m elting poi nt agarose at 37C (0.75% final
concentration). The slides were placed on a
chilled plate to solidify the agarose followed
by immersing i n freshl y prepared lysing
solution (2.5 M NaCl, 10 mM Tris-base, 0.1%
sodium sarcosinat e, pH = 12.3) in t he dark f or
one hour at room temperature. After this, the
slides were pl aced in alkaline el ectrophoresis
buffer (0.3 N NaOH, 1 mM EDTA, pH 12.3) f or
30
minutes,
allowing
D NA
unwinding.
Electrophoresis was perform ed at 20 V and
400 mA for 10 minutes. Then were stai ned
with propi dium iodide (2.5 mg/ml) for 20
minutes and covered with a glass cover sli p
before
analysis.
The
image
of
the
el ectrophoresed DNA appears like a com et,
with undamaged DNA in the head, and
fragm ented DNA migrating to form a tail.
Com et images were captured on an Axioscope
fluorescent microscope equipped with a
st andard Photonics C amera.
Flow cytometric analysis of cell cycle apoptosis:
DNA
pl oidy
and
apoptosis
were
anal yzed using fl uorescence activated cell
sorting (FACS) flow cytometer (Becton

On Line ISSN: 2090 - 0503

http://www.egyseb.org

E l-Ghawet & G adall ah, Am eliorat ing Rol e of J am bolan of Cap ecit abine I nduc ed Test ic ular Dam age of Rat s

Dickinson, S unnyvale, CA) equipped with a 15

mW air-cooled 488 nm argon-i on l aser. FL1
(FITC) signals were detected through a
530/30 nm band-pass filter; FL2 (PI) signal s
were detected through a 585/42 nm bandpass filter. A total of 20 000 events were
recorded in list mode and analyzed using the
Cell Q uest Pro software (Becton Dickinson) at
Mansoura Uni versity Hospital. The testicular
cell populations were gated assuming the
linear forward scatter (FSC) and side scatter
(SSC) properties. Biopsies from liver and
kidney of studied animals were t aken, and cell
suspension was prepared w ith Tris-EDTA
buffer at pH 7.4 (Sigma-Aldrich Co.). Cell
suspension w as fixed in ice-cold 96100%
ethanol (Sigma) at 4C overnight, centrifuged
at 1500 rpm for 10 min, and then resuspended i n PBS containing 50 g/mL

17

propi dium iodide (PI) (Sigma-Aldrich Co.).

The c ell s were incubated at 37C for 30 min
before anal ysis by flow cytometry. PI
fluorescence excit ation at 512 nm, with a
rel atively l arge Stokes shift, emits at a
maximum wavel ength of 617 nm. Apoptosis
was indicated by the percentage of cells i n
G 0/G1, S, and G2/M phases of the cell cycle.
RESULTS:
Morphom etric assessments:
From table 1, capecitabi ne-treatm ent
reduced the number of active seminiferous
tubules and increased the average of nonactive seminiferous tubules with apparent
increase of missing sperm, spermatids, germ
cell height and m ean tubul ar diameter.

Table 1. Morphometric assessments of testis of capecitabine-treatment with or without jambolan-treatment

Control

JB-Treatment

CAP-Treatment

JB & CAP-Treatment

120 (100%)

118 (100%)

216 (100%)

145 (100%)

Normal (active) seminiferous tubules (ST)

97%

93%

15%

73%

Non-active ST

1%

4%

85%

24%

ST lacking sperm

0%

3%

87%

15%

ST lacking spermatocytes

1%

0%

87%

4%

Total number and % of ST

ST without spermatids

2%

0%

27%

2%

Germ cells height (m)

64 2.6

63 3.1

38 2.8

52 4.5

230 12.3

228 11.7*

167 9.8**

194 10.8*

Mean tubular diameter (m)

Each replicate represent the M SE, n = 5, Significance at *P <0.05.

Histological investigations:
T he
c ontr ol
and
jamb ola n-tr eat ed
t esti s r eveal ed t he ty pic al f eat ures of
n orm al structur e. T he s em inif erous tub ul es
s how ed
t ypical
arra ng em ent
of
the
s permatog enic
cells,
inclu din g
s permatogoni a,
s perm ato cyt es
an d
s permatids,
as
w ell
as
gr ou pin g
s permatozoa. S ert oli cell s ar e r elativ ely f ew
a nd distrib ut ed at f airly r eg ul ar int erv al s.
Thi n c onnective tis su e w a s s een i n betw een
t h e t ubul es (Fi g. 1 A&B ).

Fig. 1 (A&B). Photomicrographs of histological sections of

control testis showing normal seminiferous tubules
(NST)
with
normal
arrangement
pattern
of
spermatogenic cells (Sertoli cell, St; Spermatogonia,
SG, Spermatocytes, SO and sperm, S). The intertubular
tissue appears rich of interstitial cells (ISC).

In capecitabine-treatm ent, the testis

show ed focal disorganization of seminiferous
tubules with marked depletion of the
spermatogenic cell populations. Many of the
seminiferous
tubules
lacked
sperm,
spermatids and secondary spermatocytes.
Exfoliation of the dam aged sperm atocytes and
spermatids were detected within the tubul ar
lumina of many seminiferous t ubules. The
intertubular
connective
tissue
becom e
ISSN: 2090 - 0511

On Line ISSN: 2090 - 0503

http://www.egyseb.org

18

Egypt. J. Exp. Biol. (Zool.), 11(1): 15 21 (2015)

hyalinised and showed comparative reduction

of interstitial cell s (Fig. 2 A-D).
O n the other hand, jambolan-treatm ent
of capecitabine-intoxicated rats revealed
marked amelioration and improvem ents of the
histologic picture of testis associated with
regeneration of spermatogenic cells and
flourishing of sperm within tubular lumina
(Fig. 2 E-F).

Fig. 2. Photomicrographs of histological sections of

tramadol-treated testis.
A&B:
Capecitabine-treatment
showing
inactive
seminiferous tubules with comparative reduction of
spermatogenic cells, decreased germ cell height and
oedematous lesions within interstitial cells (OISC).
C-F: Jambolan and capecitabine-treatment showing
amelioration, however restricted zone of interstitial
oedematous lesions are still appeared and flourishing
of sperm are observed (S).
E. Exfoliation of germ cells within tubular lumina and
oedematous interstitial cells).

ISSN: 2090 - 0511

On Line ISSN: 2090 - 0503

http://www.egyseb.org

E l-Ghawet & G adall ah, Am eliorat ing Rol e of J am bolan of Cap ecit abine I nduc ed Test ic ular Dam age of Rat s

Comet assay:
Following applying com et assay, the
single strand nucleotide /each testicular cells

19

were detached with i ncreased tail l ength and

DNA concentration, comparing with normal
pattern structure of testis (Fig. 3).

Fig. 3. Comet assay of capecitabine-treated testis with or without jambolan-treatment

Fl ow cytometry of cell cycle:

From tabl e 2 and figure 4, capecitabineintoxication revealed a considerable increase
o f M1 (s ubG 1 a poptosis) an d a decreas e i n

the other cell cycle phases (M2, M3, and M4).

Jambolan-treatment revealed a decrease in apoptic
cell death and amelioration of the drug toxicity.

Table 2. Flow cytometry of c ell c ycle of c apec itabine-treated t estis with or without jambol an-treatment
Control

JB-Treatment

CAP-Treatm ent

JB & CAP-Treatment

M1 (Sub-G0/G1 apoptosis)

10.6 0.8

8.6 1.5

42.1 3.7

23 3.2

M2 (G0/1phase)

34.1 5.6

36 4.1

24.6 2.8

30.5 4.1

M3 (S phase)

36.7 2.8

35 3.7

27.4 3.1

32 3.7

M4 (G2/M phase)

7.1 0.9

8.4 1.2

10.6 1.8

9.4 1.5

Eac h replic ate represent the M SE, n = 5, Significanc e at *P <0.05.

Fig. 4. Flow cytom etry of testicular c ells. C & J B. Control and J ambolan -treatm ent s howing normal range of
c ell c ycle. CAP. Capec it abine-treatment showing inc reas ed average of apoptosis. CAP & J B.
Combined Capec itabine and jambolan-treatment s howing reduc ed c ell damage.
ISSN: 2090 - 0511

On Line ISSN: 2090 - 0503

http://www.egyseb.org

20

Egypt. J. Exp. Biol. (Zool.), 11(1): 15 21 (2015)

DISC USSIO N:
From the present fi ndings treatm ent with
the
pro-anticancer
drug
capecitabinetreatm ent
possessed
dramatic
testicular
dam age in t he form of atrophied seminiferous
tubules
with
focal
disorganizati on
of
seminiferous tubules with marked depl eti on of
the
spermatogenic
cell
popul ations.
Exfoliation of the damaged sperm at ocyt es and
spermati ds were detected within the tubular
lumina of many of the seminiferous tubules.
The i ntertubular connective ti ssue becom e
hyalinized and showed comparative reduction
of interstiti al cells. The germ cell height was
markedly reduced.
The present findings agree with the work
of D 'Souza and Narayana (2001), Narayana
et al. (2000), D'Souza and Narayana (2002)
whom
repost
t esticul ar
damage
post
fluouracil-treatm ent.
The
observed
histological
picture
reveal ed oed ematous lesion within the
interstitial
cells
manifesting
alt ering
test osterone secretion. A decrease of serum
prolactin and testosterone levels associ ated
with a reduced f unction of S ertoli cell were
also
reported
post
5-FU-treatm ent
by
Takizawa and Horii (2002). Decreased
test osterone level was found to be associ ated
with degeneration of Leydig cell s postbleomycin, etoposi de and cisplatin treatm ent
(Al-Bader and Kilarkaje, 2015).
The blood-testis barrier (BTB) whi ch is
created by adj acent Sertoli cells near the
basem ent
membrane,
serves
as
a
'gat ekeeper' to prohibit harmful substances
from reaching developing germ cells, most
notably postmeiotic spermatids. It is divi des
the semi nif erous epithelium i nto the basal and
adluminal (apical) compartment allowing
spermiogenesis, to take place in a speci ali zed
microenvironm ent in the apical compartm ent
behind the B TB. Recent studies have shown
that
num erous
drug
transporters
are
expressed by Sertoli cells. How ever, many of
these same drug transporters are also
expressed by sperm atogoni a, spermatocytes,
round spermatids, elongating spermatids, and
elongated spermatids, suggesting that the
devel oping germ cells are also abl e to
selectivel y pump drugs 'in' and/or 'out' via
influx or efflux pumps (Su et al., 2011).
The observed f inding support ed by a
marked i ncrease of M1 (subG 1 apoptsi s) postdrug-treatm ent. Many anticancer drugs such

as cisplatin, doxorubicin and camptotheci n

exerted DNA damage such as cispl atin which
induced DNA damage through caspase
activation in enucleated cells (cytoplasts
lacking a cell nucleus) as well as associated
with rapid i nduction of cellular reactive
oxygen (Havelka et al., 2007). Other
m echani sm involved DNA damage cell cycl e
arrest (Swift and Golsteyn, 2014).
Phytotherapy belongs to the area of
compl em entary and alternative m edicine
(CAM) and use of plant in m edicinal uses.
Jambolan-treatment
of
capecitabineintoxicated rats revealed m arked amelioration
of the hi stologic picture of t esticul ar tissues
associated with a marked reduction of DNA
dam age. The am eli oration of t he hi stologic
picture m ay be attri buted to the antioxidant
capacity including al pha-glucosidase and
al pha-amylase inhibitory activities as well as
Cyanidin,
quercetin,
ellagic acid (E A),
proanthocyanidins, phenolic cont ent catechi n
and al so high-ascorbic acid (C orreia et al.,
2012).
Similar
am eli oration
of
testicul ar
dam age was detected i n several studies.
Lycium barbarum polysacchari des was found
to att enuate testicular oxidative stress and
protecti ng
testis-specific
toxicity
in
doxorubicin-exposed rats (Xin et al., 2012). I n
vitro studies reveal ed the cytoprotective
ef fects of fruit pulp of Eugenia jambo lana (50
250 g ml 1 )
against
hydrogen
peroxide
induced Leydig cell toxicity (Anand et al.,
2013).
O xidative
stress
occurri ng
during
chemotherapy through li beration of reactive
oxygen species such as cisplatin-induced
nephrotoxicity
may
be
ameliorat ed
by
lycopene the major carot enoid present i n
tomatoes, which is a potent antioxidant (Sahi n
et al., 2010).
The amelioration of the jambol an fruits
extracttreatm ent
attributed
to
the
antioxi dant
capacity
including
al phagl ucosidase and alpha-amyl ase i nhibitory
activities, as well as Cyanidin, quercetin,
ellagic acid (EA), proanthocyanidins, phenolic
content catechin and also hi gh-ascorbic aci d
(Correia et al., 2012).
Fi nally the authors concl uded that
during
chemotherapeutic
treatm ent,
the
patient must administered f ruit s and vegetabl e
containing antioxidants to am eliorate their
hepatic and renal toxicities.

REFERENCE S:
Al-Bad er M, Kilarkaje N . 2015. Effects of bleomyc in,
etopos ide and c is platin treatment on Leydig
c ell
structure
and
transcription
of
steroid ogenic enzym es in r at testis. Eur. J.
Pharmac ol., 747: 150-159.
ISSN: 2090 - 0511

Anand H, Misro MM, Sharma SB, Prakas h S. 2013.

Cytoprotective eff ects of fruit pulp of Eugenia
jambolana on H 2 O 2 -induced oxidative stress
and apoptos is in rat Leydig cells in vitro.
Andrologia, 45(3): 145-157.

On Line ISSN: 2090 - 0503

http://www.egyseb.org

E l-Ghawet & G adall ah, Am eliorat ing Rol e of J am bolan of Cap ecit abine I nduc ed Test ic ular Dam age of Rat s

Ayyan ar M, Subas h-Babu P. 2012. Syzygium cumin i

(L.) Skeels: A review of its phytochemical
c onst ituents and tradit ional us es. As ian Pac.
J. Trop. Biomed., 2(3): 240-246.
Correi a RT, Borges KC, Medeiros MF, G enoves e MI.
2012. Bioact ive c ompounds and phen oliclinked functionality of powd er ed tropic al fruit
residues. Food Sci. Technol. Int., 18(6): 539547.
D'Souza UJA, Narayana K. 2001. Induct ion of
s eminif er ous tubular atrophy by single dos e of
5-fluorouracil in W istar rats. Indian J. Phys iol.
Pharmac ol., 45(1): 87-94.
D'Souza UJ A, Narayan a K. 2002. Formation,
morphology and fate of mult inuc leated c ells
(symplasts) in the rat testis exp os ed to 5f luor ourac il. Indian J. Physiol. Pharmac ol.,
46(4): 504- 506.
D'Souza UJA. 2003. Toxic eff ects of 5-fluorourac il on
sperm count in W ist ar rats. Malays. J. Med.
Sci., 10(1): 43-45.
Havelk a AM, Ber ndtss on M, Olofss on MH, Shoshan
MC , Linder S. 2007. Mec hanis ms of act ion of
DNA-damaging ant ic anc er drugs in treat ment
of carc inomas: is ac ute apoptos is an " off t arget" effect? Mini Rev. Med. Chem., 7( 10):
1035-1039.
Lewis YS, Dwarakan ath CT, Johar DS. 1956. Ac ids
and s ugars in Eugenia jambolana. J. Sc i. Ind.
Res., 15C(12): 280-281.
Miwa

M, Ur a M, Nishida M, Sawada N, Is hikawa

T, Mori K, Shimma N , Umed a I, Ishits uka H.
1998. D es ign of a novel oral f luorop yrimidine
c arbamate, c apec it abine, which generates 5f luor ourac il s electively in tumors by enzymes
c oncentrated in hum an liver and c ancer tissue.
Eur. J. Canc er, 34(8): 1274-1281.

Narayana K, D'Souza UJA, San yal AK, R ao KPS.

2000. 5-Fluorour ac il (5-FU) induc es the
f orm at ion of giant c ells and sloughing of
s eminif er ous epithelium in the rat testis. Indian
J. Physiol. Phar mac ol., 44(3): 317-322.
Paget G E, Barnes JM. 1964. Evalu at ion of drug
activities and pharmacometrics. Laurenc e D.R.
and A. L. Bacharach, Eds., Ac ademic Press,
London, .1: 135.

21

Par J ain MC, Ses hadri TR. 1975. Anthocyanins of

Eugenia jambolana f ruits. Indian J. Chem.,
13(1): 20-23.
Pepperc orn PD, Rezneck RH, W ils on P, Slevin ML,
Gupta RK. 1998. Demonstration of hep atic
steatosis by c omput er ized tomography in
patients
rec eiving
5-Fluorouracil
bas ed
chemotherapy f or advanc ed c olorectal c anc er.
Br. J. Canc er, 77(11): 2008-2011.
Ross i S. 2013. Australian Medic ines Handbook, 2013
ed. Adelaid e: The Australian Medicines
Handbook Unit Trust.
Sahin K, Sahin N , Kucuk O. 2010. Lyc open e and
chemotherapy t oxicity. Nutr. Canc er, 62(7):
988-995.
Sas aki YF, Saga A, Akas aka M, Yoshida K, Nishidate
E, Su YQ, Matsus aka N, Tsuda S. 1997. In
vivo
gen ot oxicity
of
ortho-phenylphenol,
biphen yl, and t hiabendaz ol e detected in
mult iple mous e organs by t he alkalin e s ingle
c ell gel electrophores is ass ay. Mutat. Res.,
395(2-3): 189198.
Su L, Mruk DD , Cheng C Y. 2011. Drug transporters,
the blood-testis barrier, and s permatogen esis.
J. Endocrinol., 208(3): 207-23.
Swift LH, Golsteyn RM. 2014. G enotoxic anti-c ancer
agents and their r el ations hip to DNA damage,
mitosis,
and
checkpoint
adapt at ion
in
prolif er ating canc er c ells. Int. J. Mol. Sci.,
15(3): 3403-3431.
Takizawa LD, Horii I. 2002. Endocrinologic al
assessment of t oxic eff ects on the male
reproductive s ystem in rats tr eated with 5fluorouracil f or 2 or 4 weeks. J. T oxic ol. Sci.,
27(1): 49-56.
Xin YF, You ZG, G ao HY, Zhou GL, Chen YX, Yu J,
Xuan YX. 2012. Protective eff ect of Lyc ium
barbarum
polys accharides
against
doxorubic in-induced test ic ular toxic ity in rats.
Phytother. R es., 26(5): 716721.
Zorzi D, Laur ent A, Pawlik TM, Vauthey JN, Abdalla
EK.
2007.
Chemotherapy
ass ociat ed
hepatotoxic ity and s urger y f or c olorectal
metastases. Br. J. Surg., 94(3): 274-286.

.
.

. .
.
. :

(/
400)
. (/ 40)
.
: . 30

..

..
.

ISSN: 2090 - 0511

On Line ISSN: 2090 - 0503

http://www.egyseb.org