Molecular oncology · 2013
Double-deleted vaccinia virus in virotherapy for refractory and metastatic pediatric solid tumors.
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Lun Xueqing, Ruan Yibing, Jayanthan Aarthi, Liu David J, Singh Anjali, Trippett Tanya, Bell John, Forsyth Peter, Johnston Randal N, Narendran Aru
Аннотация
BACKGROUND: Previous studies have shown successful antitumor effects of systemically delivered double-deleted vaccinia virus (vvDD) against a number of adult tumor models, including glioma, colon and ovarian cancers. The purpose of this study was to investigate the oncolytic potential of vvDD against a panel of cell lines representative of pediatric solid tumors that are currently difficult to cure.
METHODS: Cell lines derived from central nervous system atypical teratoid rhabdoid tumor (AT/RT) (BT12, BT16 and KCCF1), sarcoma (143B, HOS, RD and RH30), and neuroblastoma (SKNAS, SKNBE2, IMR-5 and IMR-32) were examined for vvDD mediated cytotoxicity defined by virus expansion followed by loss of tumor cell viability. The normal human fibroblast cell line HS68 was used as a control. Next, relevant orthotopic, subcutaneous and lung metastasis xenograft models were treated with intravenous doses of live vvDD or killed virus controls (DV). Tumor growth inhibition and viral replication were quantified and survival outcomes of these animals were assessed.
RESULTS: vvDD was able to infect and kill nine of eleven of the pediatric tumor cells (81.8%) in vitro. In xenograft models, intravenous administration of a single dose of vvDD significantly inhibited the growth of tumors and prolonged the survival of intracranial and metastatic tumors.
CONCLUSIONS: Oncolytic vvDD administered i.v. shows activity in preclinical models of pediatric malignancies that are resistant to many currently available treatments. Our data support further evaluation of vvDD virotherapy for refractory pediatric solid tumors.
METHODS: Cell lines derived from central nervous system atypical teratoid rhabdoid tumor (AT/RT) (BT12, BT16 and KCCF1), sarcoma (143B, HOS, RD and RH30), and neuroblastoma (SKNAS, SKNBE2, IMR-5 and IMR-32) were examined for vvDD mediated cytotoxicity defined by virus expansion followed by loss of tumor cell viability. The normal human fibroblast cell line HS68 was used as a control. Next, relevant orthotopic, subcutaneous and lung metastasis xenograft models were treated with intravenous doses of live vvDD or killed virus controls (DV). Tumor growth inhibition and viral replication were quantified and survival outcomes of these animals were assessed.
RESULTS: vvDD was able to infect and kill nine of eleven of the pediatric tumor cells (81.8%) in vitro. In xenograft models, intravenous administration of a single dose of vvDD significantly inhibited the growth of tumors and prolonged the survival of intracranial and metastatic tumors.
CONCLUSIONS: Oncolytic vvDD administered i.v. shows activity in preclinical models of pediatric malignancies that are resistant to many currently available treatments. Our data support further evaluation of vvDD virotherapy for refractory pediatric solid tumors.