Tumour regression in a ligand inducible manner mediated by a chimeric tumour suppressor derived from p53

The p53 tumour suppressor induces cell cycle arrest and apoptosis in respon se to cellular stresses. p53 is inactivated by various cellular and viral f actors. We set out to generate regulatable p53 derivatives that are highly inducible by synthetic ligands, escape inactivation and efficiently induce apoptosis. We have generated Ligand Inducible Chimeric Tumour Suppressors ( LICTS), that are inactive unless provided with artificial ligands. They are resistant to inactivation, due to the replacement of domains that mediate p53 inhibition by heterologous sequences. LICTS are activated by micromolar concentrations of ligand in a variety of cell lines. Following ligand addi tion, they translocate to the nucleus, activate p53 inducible genes and ind uce apoptosis. We have established human head and neck squamous cell carcin oma lines that stably express LICTS, which are inducible. These lines form tumours in nude mice in the absence of ligand. Addition of ligand inhibits tumour formation, and moreover, regresses established tumours by apoptosis. Although regulatable p53 expression has been achieved previously, our stud y provides the first demonstration of regulatable in vivo regression of tum ours in a p53 based approach. Regulated inhibition and regression of tumour s with a ligand inducible chimeric tumour suppressor could provide a novel approach to p53 based gene therapy.