Combining radiotherapy with APO010 in cancer treatment.
OBJECTIVE
Various proapoptotic agents are currently being explored to improve the outcome of radiotherapy. We have evaluated whether APO010-a novel recombinant ligand of the Fas/CD95 death receptor-enhanced the cytotoxic effect of radiation on lymphoid and solid tumor cell types.


METHODS
A Bcl-2-overexpressing T-leukemic cell line (Jurkat), a colon carcinoma cell line (HCT116), and a mesothelioma cell line were used as model systems 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 tumor growth delay using bioluminescence and palpation in vivo.


RESULTS
Whereas the three cell lines resisted apoptosis induction by irradiation and APO010 alone, combined treatment greatly enhanced their apoptotic response. In clonogenic survival assays, APO010 reduced the outgrowth of Jurkat-Bcl-2 and HCT116 cells and sensitized the mesothelioma cell line to radiation. In vivo, systemic treatment with APO010 alone caused tumor growth delay in Jurkat-Bcl-2 and HCT116 cells. However, APO010 did not improve the efficacy of radiotherapy in any of the model systems at the selected single dose, which had moderate and reversible systemic toxicity.


CONCLUSIONS
Although APO010 and radiation had a clear combined cytotoxic effect on tumor cells in vitro, a combined therapeutic effect was not achieved on the same cells subcutaneously grafted in mice, at APO010 doses approximating the maximally tolerable level. These findings suggest that it will be difficult to identify a therapeutic window for this combined modality approach in a clinical setting.
Verbrugge
Inge
I
Divisions of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Wissink
Esther H J
EH
Rooswinkel
Rogier W
RW
Jongsma
Johan
J
Beltraminelli
Nicola
N
Dupuis
Marc
M
Borst
Jannie
J
Verheij
Marcel
M
D052242:Adiponectin / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D053222:Fas Ligand Protein / Q000494:pharmacology* / Q000633:toxicity; D045325:HCT116 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D052242:Adiponectin; D053222:Fas Ligand Protein; D011993:Recombinant Fusion Proteins