title: Progress and problems with the use of suicide genes for targeted cancer therapy.
abstract: Among various gene therapy methods for cancer, suicide gene therapy attracts a special attention because it allows selective conversion of non-toxic compounds into cytotoxic drugs inside cancer cells. As a result, therapeutic index can be increased significantly by introducing high concentrations of cytotoxic molecules to the tumor environment while minimizing impact on normal tissues. Despite significant success at the preclinical level, no cancer suicide gene therapy protocol has delivered the desirable clinical significance yet. This review gives a critical look at the six main enzyme/prodrug systems that are used in suicide gene therapy of cancer and familiarizes readers with the state-of-the-art research and practices in this field. For each enzyme/prodrug system, the mechanisms of action, protein engineering strategies to enhance enzyme stability/affinity and chemical modification techniques to increase prodrug kinetics and potency are discussed. In each category, major clinical trials that have been performed in the past decade with each enzyme/prodrug system are discussed to highlight the progress to date. Finally, shortcomings are underlined and areas that need improvement in order to produce clinical significance are delineated.
authors.affiliation: Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08855, United States.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Karjoo
authors.affiliation: Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08855, United States.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08855, United States; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, United States. Electronic address: ahatefi@pharmacy.rutgers.edu.
authors.forename: Arash
authors.initials: A
authors.lastname: Hatefi
mesh_terms: D000818:Animals; D004798:Enzymes / Q000008:administration & dosage; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D011355:Prodrugs / Q000008:administration & dosage
chemical_list: D004798:Enzymes; D011355:Prodrugs
keywords: Bystander effect; Cancer Gene therapy; Cytosine deaminase; Enzyme prodrug; GDEPT; Ganciclovir; Nitroreductase; Thymidine kinase