TRAIL enhances efficacy of radiotherapy in a p53 mutant, Bcl-2 overexpressing lymphoid malignancy.
OBJECTIVE
Resistance to apoptosis is a contributing factor in the response to radiotherapy. Aim of this study was to evaluate whether TRAIL--in a soluble isoleucine zippered form--enhances the cytotoxic effect of irradiation on tumour cells with a blockade in the mitochondrial apoptosis route and/or a dysfunctional p53 pathway.


METHODS
The p53 mutant human T acute lymphoblastic leukemia line Jurkat transduced with the Bcl-2 gene was used as model system in vitro and in a subcutaneous transplant setting in immunodeficient mice. Sensitivity to single and combined treatment was read out by apoptosis hallmarks and clonogenic survival in vitro, and by bioluminescence and palpation in vivo.


RESULTS
Jurkat cells overexpressing Bcl-2 did not undergo apoptosis after irradiation, but the combination with TRAIL synergistically induced apoptosis without breaking mitochondrial resistance. TRAIL also reduced clonogenic survival after irradiation. In vivo, radiotherapy or TRAIL alone delayed tumour outgrowth, but combination treatment had the most profound effect.


CONCLUSIONS
Isoleucine zippered TRAIL can strongly enhance the efficacy of tumour therapy with ionising radiation in an unfavourable setting of p53 mutation and Bcl-2 overexpression.
Wissink
Esther H J
EH
Division of Immunology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Verbrugge
Inge
I
Vink
Stefan R
SR
Schader
Manuela B
MB
Schaefer
Uta
U
Walczak
Henning
H
Borst
Jannie
J
Verheij
Marcel
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007532:Isoleucine