Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse.
Nuclear factor-kappaB (NF kappaB) plays a pivotal role in cancer progression. In this study, we developed a decoy cis-element oligo-deoxyribonucleic acid against NF kappaB-binding site (NF kappaB-decoy), which effectively inhibits NF kappaB activity, and tested the effect of combined therapy comprising local transfection of NF kappaB-decoy into the liver and transportal injection of paclitaxel on cancer growth and metastasis using an orthotopic murine model of colon cancer liver metastasis. For NF kappaB-decoy transfection, we employed a novel approach using ultrasound exposure with an echocardiographic contrast agent, Optison. We examined the influence of NF kappaB-decoy transfer on susceptibility to paclitaxel in cancer cells and the mechanism involved using several in vitro analysis systems. We then studied the in vivo effect of combined NF kappaB-decoy transfer and paclitaxel in preventing cancer progression using a murine model of liver metastasis created by splenic injection of a human colon cancer cell line, HT29. In vitro experiments, including MTT-assay, fluorescence-activated cell sorter and cDNA array analysis, revealed that NF kappaB-decoy transfer significantly increased the susceptibility of cancer cells to paclitaxel, and that decreased expression of anti-apoptotic genes along with increased expression of genes relevant to the apoptosis-promotor may be involved. In vivo experiments showed that local transfection of NF kappaB-decoy into the liver followed by portal injection of paclitaxel effectively induced cancer cell apoptosis in the liver metastasis, and significantly prolonged animal survival compared to controls, without notable side effects. In conclusion, a combination of local NF kappaB-decoy transfer into the liver and transportal injection of paclitaxel may be a safe and effective new therapy for liver metastasis.
Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan. uro004@poh.osaka-med.ac.jp
Haruhito
H
Azuma
Naruya
N
Tomita
Takeshi
T
Sakamoto
Satoshi
S
Kiyama
Teruo
T
Inamoto
Kiyoshi
K
Takahara
Yatsugu
Y
Kotake
Naoki
N
Segawa
Ryuichi
R
Morishita
Shiro
S
Takahara
Hana
H
Hayasaki
Yoshinori
Y
Otsuki
Shigeo
S
Horie
Nobuhiko
N
Tanigawa
Yoji
Y
Katsuoka
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000473:pathology*; D003124:Colorimetry; D015536:Down-Regulation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D015151:Immunoblotting; D007275:Injections, Intravenous; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D011169:Portal Vein; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection / Q000379:methods; D014465:Ultrasonics; D014463:Ultrasonography
D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D017239:Paclitaxel