الفهرس 
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Abstract
Fluorouracil (5-FU) is a common chemotherapeutic drug for treatment of oral cancer.
However, its toxicity to normal tissues has limited its role as an effective cancer therapy. This
research aimed to investigate the effect of combining 5-FU with honokiol (HNK) on enhancing
the anticancer activity of 5-FU without increasing its toxicity. Honokiol (HNK) was formulated
in nano-capsules (HNK-NP) for better bioavailability, efficient penetration and sustained
release. They were used for treatment of tongue carcinoma induced chemically by 4-
nitroquinoline 1 oxide (4-NQO) in albino rats. Rats were divided into seven groups:
group (1): Negative control group, were given regular tap water only for 24 weeks. Group
(2): Positive control group, were given 4NQO (0.002%) in drinking water for 20 weeks, then
regular tap water for 4 weeks. group (3): The animals were given 4NQO (0.002%) as in G2,
then, injected with 5-FU, (40mg/kg/day), three times/week for 4 weeks, i.p. group (4): The
animals were given 4NQO (0.002%) as in G2, then, injected with HNK dissolved in corn oil,
(20mg/kg/day), three times/week for 4 weeks, i.p. group (5): The animals were given 4NQO
(0.002%) as in G2, then, injected with HNK-NP, (20mg/kg/day), three times/week for 4 weeks,
i.p. group (6): The animals were given 4NQO (0.002%) as in G2, then injected with both 5-
FU (40mg/kg/day) and HNK (20mg/kg/day), three times/week for 4 weeks, i.p. group (7):
The animals were given 4NQO (0.002%) as in G2, then, injected with both 5-FU
(40mg/kg/day) and HNK-NP (20mg/kg/day), three times/week for 4 weeks, i.p.
At end of the experiment and before animals’ decapitation, a blood sample (2 ml.) was
withdrawn (from each animal into a sterile tube), and stored in the refrigerator at -20°C for
toxicity tests. The final weight of all animals was recorded directly before decapitation. After
decapitation, the tongues were removed and treated in two different ways:
(1) A snap was frozen in liquid nitrogen and kept in the -80°C until RT-qPCR analysis for
detection of the expression level of P53 gene.
(2) The remaining tongue tissues were fixed overnight in buffered 10% neutral formalin
for routine hematoxylin and eosin (H&E), and IHC stains for detection of mutant p53
expression.
Summary
Discussion
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Results: The used technique for HNK-NP preparation had resulted in mean particle size of
93.93 ± 1.22 nm, with zeta potential of ±30.1 mV, and encapsulation efficiency of 99.2 ± 0.3%.
The histopathologic results showed treatment with both 5-FU in combination with HNK and
HNK-NP had significantly regressed tumor growth as compared to treatment with either drug
alone. The group treated with 5-FU and HNK-NP showed dysplastic criteria and superficially
invasive well differentiated SCC. While well, moderate, and poorly differentiated SCC were
recorded in the 4-NQO only group. No significant increase in the toxicity of 5-FU was noted in
the combination groups. IHC results revealed strong immunostain for p53 in the 4NQO only
group that extended throughout epithelium. Weak immunostain confined to the basal layer was
recorded in the group treated with both FU and HNK-NP. RT-qPCR results revealed statistically
significant differences (P ≤0.05/ P=0.0083) in the expression levels of P53 gene between the
combined treatment and the positive control groups.
Summary.