Cancer and Metastasis Reviews 24: 147–164, 2005. C  2005 Springer Science + Business Media, Inc. Manufactured in The Netherlands. Gene therapy for head and neck cancer Kevin J. Harrington 1,2,∗ , Christopher M. Nutting 2 and Hardev S. Pandha 3 1 Targeted Therapy Laboratory, Cancer Research UK, Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London SW3 6JB; 2 Head and Neck Unit, Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ; 3 St George’s Hospital Medical School, Department of Oncology, 2nd Floor Jenner Wing, Cranmer Terrace, London SW17 0RE Key words: gene therapy, head and neck cancer, promoter, vector, virus Abstract The prognosis of patients with advanced head and neck cancer has not changed significantly in the last twenty years, despite concerted efforts to optimize treatment using conventional modalities such as surgery, radiother- apy and chemotherapy. Novel therapeutic approaches based on our increasing understanding of the molecular changes that underlie the development of cancer have the potential to alter this situation. Gene therapy involves the delivery of genetic sequences in to tumour or normal cells for a therapeutic purpose. A number of viral and non-viral vectors have been developed that have the ability to deliver therapeutic genes specifically to tu- mours. These therapeutic genes can exert their effects by correcting existing genetic abnormalities, by killing cells directly or indirectly through recruitment of the immune system. In this review, the various gene therapy strategies that are under development are presented with particular reference to the treatment of head and neck cancer. 1. Introduction Globally, head and neck cancer (HNC) is common with more than 500000 new diagnoses per annum. Early stage (AJCC Stage I and II) disease has a relatively good prognosis but many patients present with late stage (AJCC Stage III and IV) disease or experience incurable locoregional recurrence [1]. Advances in conventional cancer treatments (surgery, radiotherapy and chemotherapy) have failed to make a significant impact on the outlook of this disease in the last few decades [2]. Therefore, there is a pressing need to develop novel therapies that may complement or even replace current conventional treatments. Cancer gene therapy (CGT) is the delivery of spe- cific genetic sequences in to cells or tissues to achieve a therapeutic effect against malignant tumours. This def- inition generally implies that the goal is to kill cancer cells directly by transducing them with genes mediating a cytotoxic effect. Alternatively, indirect approaches ∗ Corresponding author. E-mail: kevinh@icr.ac.uk can involve introducing genetic material in to normal tissues to direct the patient’s immune system against the tumour. HNC is an ideal model system in which to develop CGT strategies. HNC is usually a loco-regional disease at presentation in which the tumour is restricted to the primary site and/or the regional cervical lymph nodes. Even at relapse, the disease generally remains in the head and neck region and presents with disease at or close to the body surface. It is, therefore, amenable to intratumoural injection of gene delivery vectors and/or tissue biopsy to monitor gene expression and therapeutic efficacy. The hurdles that have to be overcome before CGT can become a clinical reality can be described in terms of: (1) designing ways to deliver genetic sequences to the target tissue at high concentrations; (2) selecting the most efficacious therapeutic genetic sequence to be introduced; and (3) having controls that restrict the expression of the therapeutic genes to target tissues. In this review, the progress that has been made in each of