Survival efficacy of the combination of the methioninase gene and methioninase in a lung cancer orthotopic model.
We have previously demonstrated the antitumor efficacy of recombinant methioninase (rMETase) derived from Pseudomonas putida. To enhance the efficacy of rMETase, we have constructed the pLGFP-METSN retrovirus encoding the P. putida methioninase (MET) gene fused with the green fluorescent protein (GFP) gene. pLGFP-METSN or control vector pLGFPSN was introduced into the human lung cancer cell line H460. The methionine level of H460-GFP-MET cells was reduced to 33% of that of H460-GFP cells. rMETase (0.08 U/mL) in the medium resulted in 10% survival of H460-GFP-MET cells compared with untreated cells in vitro. In contrast, rMETase-treated H460-GFP cells survived at 90% of control. Tissue fragments harvested from subcutaneous tumors of H460-GFP-MET or H460-MET were implanted by surgical orthotopic implantation into the lungs of nude mice. A suboptimal dose of rMETase was administered intraperitoneally daily to mice in each group. Overall survival of rMETase-treated animals with H460-GFP-MET tumors was significantly longer than either rMETase-treated or -untreated animals with H460-GFP tumors (P < .05 in log-rank test). In two repeat experiments, rMETase-treated animals with H460-GFP-MET tumors had a 30-day survival of 80% and 83%, respectively. Untreated animals with H460-GFP-MET tumors had a 30-day survival of 40% and 58%, respectively. rMETase-treated animals with H460-GFP tumors had a 30-day survival of 0% and 33%, respectively. Untreated animals with H460-GFP tumors had a 30-day survival of 0% and 33%, respectively. The retrovirus-mediated gene transfer of METase decreased the intracellular methionine level of tumor cells and consequently enhanced the efficacy of treatment with the rMETase protein. We have thus demonstrated a new strategy of combination tumor therapy with the gene and gene product of MET.
Miki
K
K
AntiCancer, Inc., and Department of Surgery, University of California, San Diego, California 92103, USA.
Xu
M
M
An
Z
Z
Wang
X
X
Yang
M
M
Al-Refaie
W
W
Sun
X
X
Baranov
E
E
Tan
Y
Y
Chishima
T
T
Shimada
H
H
Moossa
A R
AR
Hoffman
R M
RM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D013437:Carbon-Sulfur Lyases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012190:Retroviridae / Q000235:genetics; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase