In vivo human carboxylesterase cDNA gene transfer to activate the prodrug CPT-11 for local treatment of solid tumors.
To evaluate the concept that in vivo transfer of the human carboxylesterase gene will confer sensitivity of a solid tumor to the prodrug CPT-11 (irinotecan), we constructed an adenovirus vector (AdCMV.CE) carrying the human carboxylesterase gene driven by the cytomegalovirus (CMV) promoter, infected A549 human lung adenocarcinoma cells in vitro and in vivo, and evaluated cell growth over time. AdCMV.CE produced a functional carboxylesterase protein in A549 cells in vitro and in vivo as evidenced by ability of lysates from the infected cells to convert CPT-11 to its active metabolite SN-38. The AdCMV.CE vector effectively suppressed A549 cell growth in vitro in the presence of CPT-11. Cell mixing studies demonstrated that when as few as 10% of cells expressed the human carboxylesterase gene, there was bystander growth suppression in the presence of CPT-11. Consistent with these in vitro observations, when AdCMV.CE was directly injected into established subcutaneous A549 tumors in nude mice receiving CPT-11, there was 35% reduction in tumor size at day 27 compared to controls, and a 41% reduction at day 34 (P < 0.01, both comparisons to controls). Similar observations were made with the cell line H157 and HeLa. These observations suggest that local gene transfer of the human carboxylesterase gene and concomitant local administration of CPT-11 may have potential as a strategy for control of the growth of solid tumors.
Kojima
A
A
Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center, New York 10021, USA.
Hackett
N R
NR
Ohwada
A
A
Crystal
R G
RG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*; D011355:Prodrugs / Q000378:metabolism* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; D002166:Camptothecin