2002 CTOS Annual Meeting Posters — Biology

SYNERGISTIC ACTION OF DOXORUBICIN AND TRAIL IN TNF-ALPHA RESISTANT RHABDOMYOSARCOMA CELLS
[Abstract ID: 75]

Category: Biology

Authors: Rudy Komdeur¹, Coby Meijer¹, Harald J Hoekstra¹, Martine van Zweeden¹, Steven de Jong¹, Jelle Wesseling¹, Eva van den Berg¹, Winette TA van der Graaf¹

Author Institutions: ¹Groningen University Hospital, Netherlands

Presenter: Harald J Hoekstra
h.j.hoekstra@chir.azg.nl

Correspondent: Rudy Komdeur
r.komdeur@chir.azg.nl
Groningen Netherlands 9713 GZ
Ph: +31-50-3612877
Fax: +31-50-3614873

Objectives: TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells. Apoptosis by TRAIL is mediated by two death receptors, DR4 and DR5, while two decoy receptors, DcR1 and DcR2, interrupt apoptosis. Contrary to TNF-α, approved for regional perfusion of extremity soft-tissue sarcomas, TRAIL might be applicable for systemic administration (Lancet 356:2014, 2000). TRAIL plus chemotherapy has shown to sensitize cancer cells to apoptosis.

Methods: The embryonal rhabdomyosarcoma cell line KYM-1 (TNF-α sensitive) and sub-lines KD4 (increased TNF-α sensitivity) and 37B8R (TNF-α resistant) were treated with TRAIL single-agent and with doxorubicin (DOX) or 4-hydroxy-ifosfamide (4OH-IFO). Cytotoxicity was assessed by a tetrazolium-dye assay after 96h drug exposure. DR4, DR5, DcR1 and DcR2 expression were assessed by flow cytometry.

Results: For IC50 values of TRAIL, DOX and 4OH-IFO, see Table. DR4, DR5 and DcR1 expression of KD4 and 37B8R were similar to KYM-1 (ratio 1-2). Only 37B8R had detectable DcR2 expression. TRAIL plus DOX or 4OH-IFO had additive effect in KYM-1 and KD4. TRAIL plus DOX (but not 4OH-IFO) acted synergistically in 37B8R, leading to a 5-fold higher cytotoxicity than single-agent TRAIL or DOX.

Conclusions: In this panel of cell lines, resistance to TRAIL may be mediated by DcR2. TRAIL with DOX or 4OH-IFO acted at least additively in all cell lines. DOX sensitized TRAIL-induced cytotoxicity in the TNF-α resistant 37B8R cells, suggesting a therapeutic potential for this combination.