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Cloning of carrier cells infected with oncolytic adenovirus driven by midkine promoter and biosafety studies
Author(s) -
Hamada Katsuyuki,
Takagi Soichi,
Kuboshima Hajime,
Shimada Hideaki,
Takagi Kazuko,
Yasuoka Toshiaki,
Matsubara Keiichi,
Sassa Yukiko,
Furuya Tetsuya,
Suzuki Kazuhiko,
Uchide Tsuyoshi,
Mizutani Tetsuya,
Tani Kenzaburo,
Itoh Hiroshi,
Sugiyama Takashi
Publication year - 2019
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.3064
Subject(s) - midkine , oncolytic adenovirus , oncolytic virus , ovarian cancer , cancer research , intraperitoneal injection , cell culture , oxaliplatin , medicine , microbiology and biotechnology , biology , immunology , cancer , pharmacology , immune system , colorectal cancer , growth factor , genetics , receptor
Background A549 carrier cells infected with oncolytic adenovirus can induce complete tumor reduction of subcutaneous ovarian tumors but not intraperitoneal disseminated ovarian tumors. This appears to be a result of the insufficient antitumor effect of A549 carrier cells. Therefore, in the present study, we cloned a novel carrier cell with the aim of improving the antitumor effects. Methods Carrier cells infected with oncolytic adenovirus AdE3‐ midkine with a midkine promoter were cloned by limiting dilution. We examined the antitumor effects of these cells on subcutaneous and intraperitoneal OVHM ovarian tumors in a syngeneic mouse model. Biosafety tests were conducted in beagle dogs and rabbits. Results We cloned EHMK‐51‐35 carrier cells with 10‐fold higher antitumor effects compared to A549 carrier cells in vitro . EHMK‐51‐35 carrier cells co‐infected with AdE3‐ midkine and Ad‐ mGM‐CSF induced a 100% complete tumor reduction in subcutaneous tumors and a 60% reduction of intraperitoneal disseminated tumors. Single‐dose acute toxicity test on beagle dogs with EHMK‐51‐35 carrier cells co‐infected with AdE3‐ midkine and Ad‐ cGM‐CSF showed no serious side effects. Biologically active adenoviruses were not detected in the blood, saliva, feces, urine or whole organs. In a chronic toxicity test, VX2 tumors in rabbits were injected five times with EHMK‐51‐35 carrier cells infected with AdE3‐ midkine and these rabbits showed no serious side effects. Conclusions Significant antitumor effects and safety of cloned EHMK‐51‐35 carrier cells were confirmed in intraperitoneal ovarian tumors and toxicity tests, respectively. These findings will be extended to preclinical efficacy studies using dogs and cats, with the aim of conducting human clinical trials on refractory solid tumors.