Synergistic anticancer effect of exogenous wild-type p53 gene combined with 5-FU in human colon cancer resistant to 5-FU in vivo.
OBJECTIVE
To investigate the anticancer effect of a recombinant adenovirus-mediated p53 (rAd-p53) combined with 5-fluorouracil (5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of rAd-p53 in reversal of 5-FU resistance.


METHODS
Nude mice bearing human colon cancer SW480/5-FU (5-FU resistant) were randomly assigned to four groups (n = 25 each): control group, 5-FU group, rAd-p53 group, and rAd-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C (PKC), permeability-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) (Western blot) and apoptosis (TUNEL) were determined.


RESULTS
The area ratios of tumor cell apoptosis were larger in the rAd/p53 + 5-FU group than that in the control, 5-FU and rAd/p53 groups (P < 0.05), and were larger in the rAd/p53 group than that of the control group (P < 0.05) and the 5-FU group at more than 48 h (P < 0.05). The p53 expression was higher in the rAd/p53 and the rAd/p53 + 5-FU groups than that of the control and 5-FU groups (P < 0.05), and were higher in the rAd/p53 + 5-FU group than that of the rAd/p53 group (P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the rAd/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups (P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and rAd/p53 groups at more than 48 h (P < 0.05). In the rAd/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h (P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h (P < 0.05).


CONCLUSIONS
5-FU combined with rAd-p53 has a synergistic anticancer effect in SW480/5-FU (5-FU resistance), which contributes to reversal of 5-FU resistance.
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Qi
Q
Xie
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Min-Yi
MY
Wu
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Ding-Xuan
DX
Zhang
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Yi-Ming
YM
Yang
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Bao-Shuai
BS
Wang
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Jing
J
Zhang
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Jin
J
Xu
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Wei-De
WD
Zhong
Qi Xie, Min-Yi Wu,Ding-Xuan Zhang, Yi-Ming Yang, Bao-Shuai Wang, Medical Imaging Department, Nansha Central Hospital, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 511457, Guangdong Province, China.
Jia-Ni
JN
Hu
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D016158:Genes, p53; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil
5-Fluorouracil; Human colon cancer; Multidrug resistance; Recombinant adenovirus-mediated p53; Xenografts in nude mice