Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells.
BACKGROUND
Reovirus type 3 Dearing strain (ReoT3D) has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers. Its human safety and potential efficacy are currently being investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC).


RESULTS
ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with the 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 +/- 0.12 approximately 2.68 +/- 0.25 (mean +/- SD) log10 pfu/cell. Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent. Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose) polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptotic cells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells.


CONCLUSIONS
These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.
Sei
Shizuko
S
Laboratory of Human Toxicology and Pharmacology, SAIC-Frederick, Inc, NCI-Frederick, Frederick, Maryland, USA. seis@mail.nih.gov
Mussio
Jodie K
JK
Yang
Quan-en
QE
Nagashima
Kunio
K
Parchment
Ralph E
RE
Coffey
Matthew C
MC
Shoemaker
Robert H
RH
Tomaszewski
Joseph E
JE
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D012089:Mammalian orthoreovirus 3 / Q000502:physiology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D017239:Paclitaxel / Q000008:administration & dosage; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014747:Vinblastine / Q000008:administration & dosage; D014771:Virion / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism; D000093542:Gemcitabine
D003841:Deoxycytidine; D014747:Vinblastine; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D018631:ras Proteins; D017239:Paclitaxel; D000093542:Gemcitabine