Combination efficacy of doxorubicin and adenoviral methioninase gene therapy with prodrug selenomethionine.
We have previously demonstrated an enzyme activation prodrug gene therapy strategy using the methionine alpha,gamma-lyase gene (MET) cloned from Pseudomonas putida, in combination with selenomethionine (SeMET) as a prodrug. MET gene transfer via a recombinant adenovirus (Ad-MET) converts the physiologic compound SeMET to highly toxic methylselenol. In this study, we have developed a combination therapy approach using Ad-MET/SeMET gene therapy and doxorubicin (DOX). The combination significantly delayed the growth of H460, an aggressively-growing human lung cancer cell line, in nude mice. H460 cells were injected intra-dermally in nude mice. Tumor-bearing mice were divided into 12 groups [Control (Ctrl), DOX, SeMET, SeMET + DOX, Ad-Ctrl, Ad-Ctrl + SeMET, Ad-Ctrl + DOX, Ad-Ctrl + SeMET + DOX, Ad-MET, Ad-MET + DOX, Ad-MET + SeMET, and Ad-MET + SeMET + DOX]. DOX (2 mg/kg body weight) was given intra-peritoneally twice at 7-day intervals. SeMET (1 microM/mouse) was given by intra-tumor injection everyday, starting the following day after transfection with adenovirus. Tumor growth in the untreated group showed a 10-fold increase in tumor volume after two weeks. In contrast, the increase was only 2.5-fold in the DOX + Ad-MET/SeMET group. The treatment with DOX alone at the low-dose used showed no effect compared to the control group. There was a 5.8-fold increase in tumor volume in mice treated with Ad-MET/SeMET gene therapy alone. The tumor doubling-time was increased to approximately 10 days with the combination therapy of Ad-MET + SeMET + DOX as opposed to 2-3 days in all other treatment groups.
Gupta
Anshu
A
AntiCancer, Inc., Department of Surgery, University of California at San Diego, San Diego, CA, USA.
Miki
Kenji
K
Xu
Mingxu
M
Yamamoto
Norio
N
Moossa
A R
AR
Hoffman
R M
RM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics*; D001711:Biotransformation; D013437:Carbon-Sulfur Lyases / Q000235:genetics*; D003131:Combined Modality Therapy; D003587:Cytomegalovirus / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005813:Genes, Synthetic; D005822:Genetic Vectors / Q000627:therapeutic use*; D007271:Injections, Intradermal; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D017921:Mastadenovirus / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011401:Promoter Regions, Genetic; D016958:Pseudomonas putida / Q000201:enzymology / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012645:Selenomethionine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D001426:Bacterial Proteins; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D004317:Doxorubicin; D012645:Selenomethionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase