Cytosine deaminase/5-fluorocytosine gene therapy and Apo2L/TRAIL cooperate to kill TRAIL-resistant tumor cells.
The death ligand Apo2L/TRAIL (Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand) eradicates many tumor types while sparing most normal tissues. However, some tumors are resistant to TRAIL. We therefore determined if TRAIL cooperates with cytosine deaminase/5-fluorocytosine (CD/5-FC) gene therapy and investigated the mechanisms involved. Transfection of human LAN-5 neuroblastoma cells with CD rendered the cells (LAN-5-CD) sensitive to 5-FC-induced, caspase-dependent apoptosis. Mediated by caspase-3, CD/5-FC and TRAIL cooperated to induce apoptosis in these TRAIL-resistant cells and to cleave X-linked inhibitor of apoptosis protein (XIAP). In established LAN-5-CD tumors growing subcutaneously in mice, intratumorally applied TRAIL did not decrease tumor growth and systemically administered 5-FC only attenuated tumor growth. In contrast, 5-FC together with TRAIL dramatically decreased tumor growth and eradicated a tumor. Assuming sufficient gene transfer of CD in situ, CD/5-FC with TRAIL may be useful for the therapy of tumors resistant to TRAIL.
Wei
J
J
University Children's Hospital, Ulm, Germany.
Wahl
J
J
Knauss
H
H
Zeller
S
S
Jarmy
G
G
Fitze
G
G
Debatin
K-M
KM
Beltinger
C
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D043525:Cytosine Deaminase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics; D005260:Female; D005437:Flucytosine / Q000494:pharmacology*; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009447:Neuroblastoma; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*
D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C499308:Rag2 protein, mouse; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D005437:Flucytosine; D020169:Caspases; D043525:Cytosine Deaminase