Combination of Targeting Gene-ViroTherapy with 5-FU enhances antitumor efficacy in malignant colorectal carcinoma.
To improve the therapeutic effect of ONYX015, an E1B55kD-deleted replication-competent adenovirus, ZD55 was constructed and armed with the therapeutic gene hTRAIL to form ZD55-hTRAIL, which was used for cancer therapy and which we call Targeting Gene-ViroTherapy. In vitro experiments with SW620, HCT116, and HT29 colorectal carcinoma cell lines demonstrated that they were all sensitive to ZD55-hTRAIL, and especially sensitive to ZD55-hTRAIL plus 5-fluorouracil (5-FU) treatment. In the SW620 xenograft tumor model, various treatment groups showed marked differences at week 11, with the tumor volume for the phosphate-buffered saline (PBS) treatment group >1700 mm3, for 5-FU > 1300 mm3, for ONYX015 1051.3 mm3, for ZD55-hTRAIL 600.05 mm3, and for ZD55-hTRAIL plus 5-FU 230.2 mm3. At the end of week 14, tumor-bearing mice in the other groups almost all died, whereas all the mice in the combined treatment group were alive, with one mouse tumor free. By transmission electron microscopy (TEM) assay, most tumor cells treated with ONYX015 or with ZD55-hTRAIL singly or in combination with 5-FU were lysed due to viral propagation. RT-PCR analysis and immunohistochemistry examination revealed that hTRAIL was expressed in ZD55-hTRAIL-treated SW620 tumor tissue. Furthermore, no detectable hepatoxicity was found by serum enzyme level analysis. These results suggest that ZD55-hTRAIL alone or in combination with 5-FU may have potential clinical implications.
Qiu
Songbo
S
Institute of Molecular Virology, College of Life Science, Wuhan University, Wuhan 430072, China.
Ruan
Hongmei
H
Pei
Zifei
Z
Hu
Baoli
B
Lan
Ping
P
Wang
Jinhui
J
Zhang
Zilai
Z
Gu
Jinfa
J
Sun
Lanying
L
Qian
Cheng
C
Liu
Xinyuan
X
Qi
Yipeng
Y
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D005472:Fluorouracil