PD6-1-5: Dose-response relationships in extensive small cell lung cancer and implications for resistance mechanisms.

Abstract

Copyright © 2007 by the International Association for the Study of Lung Cancer S426 Restoration of the tumor suppressor genes P53, Retinoblastoma, FHIT and FUS1 had only minimal effect on cell death, although the tumor suppressors are functional defective in >80 % of SCLC. Modulating the oncogene activity of Bcl-2 was attempted by introducing a truncated version of Bax, with increased apoptotic activity. Inhibition of Hsp70-mediated cancer survival was attempted by the introduction of Hsp40 J domain, a dominant negative gene inhibiting Hsp70 activity. Although the gene products activated cellular death pathways in transfected cells, no significant cell death was observed. In contrast suicide gene strategies showed great potential for SCLC gene therapy. The suicide gene system herpes simplex virus thymidine kinase (HSVtk) with the prodrug ganciclovir (GCV) had already been tested and implemented at the laboratory showing >50 % cell death in vitro and tumor regression in vivo. HSVtk efficacy was improved by the replacement of GCV with penciclovir (PCV), which demonstrated significant less toxicity to untransfected cells. Another suicide gene system was implemented for testing: the yeast cytosine deaminase (YCD)gene either alone or fused with the yeast uracil phosphoribosyltransferase (YUPRT) gene and combined with the prodrug 5-FC. The YCD/YUPRT fusion gene showed superior efficacy, mediating 90 % SCLC cell death. This dual suicide gene strategy targets in contrast to HSVtk/GCV or PCV, both DNA and RNA synthesis, also causing cell death to non-proliferating, dormant cancer cells. The strategy demonstrated significant bystander cytotoxicity due to the diffusion of toxic metabolites to nearby cancer cells, showing potential to overcome the low transfection efficiency currently characterizing in vivo gene therapy. An update will be presented.