Survival efficacy of the combination of the methioninase gene and methioninase in a lung cancer orthotopic model

Abstract

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 Ͻ .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.

Pharmacokinetics, Methionine Depletion, and Antigenicity of Recombinant Methioninase in Primates

“…The rMETase gene has been shown to be active as an antitumor agent including its use with selenomethionine as a pro-drug (23)(24)(25).…”

Can Dietary Methionine Restriction Increase the Effectiveness of Chemotherapy in Treatment of Advanced Cancer?

“…In laboratory animals with Lewis lung carcinoma, synergistic antitumor activity was demonstrated between methioninase and the chemotherapy drug 5-fluorouracil [30]. In an orthotopic lung cancer model, recombinant methioninase plus methioninase gene therapy was effective in suppressing cancer [34]. The fact that methioninase inhibits tumor growth in preclinical models further supports the concept of dietary methionine restriction as cancer treatment.…”

PLP-Dependent Enzymes: a Potent Therapeutic Approach for Cancer and Cardiovascular Diseases

“…The potentiality of gene therapy for methionine dependent tumors based on deprivation of the tumor cells from the intrinsic L-methionine, so this technique significantly intensified by combination with external L-methioninase, to remove the serum L-methionine. A plausible anti-proliferative activity towards human lung cancer by transduction of P. putida L-methioninase gene via retroviral vectors, in combination with methioninase treatment, was observed (Miki et al, 2000b). Transduction of P. putida Lmethioninase gene to human lung carcinoma using retroviral victors and their therapeutic implications were extensively studied by Tan et al, 1997, Miki et al, 2000a,b, 2001.…”