[Adenovirus-delivered tissue inhibitor of metalloproteinases-3 transfection increases the sensitivity of cervical cancer cells to cisplatin].
OBJECTIVE
To investigate the effects of adenovirus-delivered tissue inhibitor of metalloproteinases-3 ( Ad-TIMP-3) on sensitivity of cervical cancer cells to cisplatin and evaluate the potential application of this combined scheme in cervical cancer treatment.


METHODS
Cells of cervical cancer CaSKi cell line were infected with Ad-TIMP-3 in vitro. Apoptotic effect, cell cycle changes and p53 protein expression were detected. After combined treatment of those cells with cisplatin, colony formation test was performed and cytotoxicity was detected by MTT. The growth curve and tumor growth inhibition in vivo were evaluated.


RESULTS
The expressions of TIMP-3 mRNA and protein were significantly upregulated after transfection. As a result, massive apoptosis was induced and the cells were arrested at G2/M phase. Exogenous overexpression of TIMP-3 increased p53 protein level markedly in spite of the backgrounds of p53 gene in cells. Combined with cisplatin treatment, the cloning efficiency was decreased. A synergism was observed by isobolic method ( D < 1 ) in vitro and tumor growth was significantly inhibited in vivo.


CONCLUSIONS
Ad-TIMP-3 is a powerful proapoptotic agent. It increases sensitivity of the cells to cisplatin and the Ad-TIMP-3 gene therapy in combination with cisplatin could be a promising alternative in cervical cancer treatment.
Zhang
Ying
Y
Beijing Obstetrics and Gynecologic Hospital, Capital Medical University, Beijing 100006, China.
Lin
Chen
C
Qian
Hai-li
HL
Lang
Jing-he
JH
Fu
Ming
M
Zhang
Xue-yan
XY
Liang
Xiao
X
Duan
Hua
H
Xiang
Yang
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D019717:Tissue Inhibitor of Metalloproteinase-3; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin