Suicide Gene Therapy
Since conventional cancer treatments are not able to cure approximately 50% of cancers in patients, novel therapies must be developed. A number of different cancer gene therapy protocols are currently underway, including those using suicide genes. Gene th
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SUICIDE GENE THERAPY Scott M. Freeman Schering-Plough Research Institute Clinical Research Oncology Kenilworth, New Jersey
INTRODUCTION The field of cancer therapy has made significant advances in the last three decades, but the overall cancer mortality remains virtually unchanged since the 1960’s. Further, although approximately 70% of cancer patients achieve a remission, 50% of cancer patients relapse and become non-responsive to conventional therapeutic regimens. Patients with advanced cancers, particularly those in replaces, are the least responsive to therapy and have a median life expectancy of only one and a half years (Feldman, 1986; Boring, 1992). The progression of disease is often a result of growth of tumors cells that are resistant to any combination of chemotherapy, surgery, and radiation (Goldstein, 1991; Goldstein, 1992). Thus, effective treatment will depend on the development of new strategies that attack cancers that are resistant to conventional approaches. Advances in molecular biology have allowed the elucidation of many cellular functions involved in tumorigenesis. These tumor cell-specific properties are being exploited in a number of novel therapies in which the cancerous cells themselves are targeted in ways that circumvent their resistance to standard agents. Gene therapy is one approach that allows direct treatment of tumor cells by genetically modifying the malignant cells to alter their drug sensitivity phenotype. A suicide gene is a gene encoding a protein which under appropriate conditions (i.e., exposure to a prodrug) is toxic to the genetically modified cell (i.e., tumor cell). The treatment of cancer is different from treatment of genetic diseases, since an effective cancer therapy requires complete eradication of all tumor cells. Although an effective cancer therapy requires that all tumor cells be killed, a number of studies using suicide genes have shown that when less than 100% of the tumor was genetically modified, the entire tumor mass could be eradicated. Thus, this approach could potentially eliminate a cancer even though the technology to genetically modify an entire tumor is not available. Genetic modification of tumor cells could impart a new drug sensitivity phenotype to chemotherapy resistant tumor cells which would then allow killing of the cells by exposure to a prodrug (Moolten, 1986; Moolten, 1990; Moolten, 1994). Initially, chemosensitization was developed for a theoretical prophylactic clinical application because gene Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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therapy technology could not be used to genetically modify all tumor cells in a tumor mass, a pre-requisite for a therapeutic application. However, further investigation led to the fundamental discovery, termed the “bystander effect”, which allowed a therapeutic application of suicide gene therapy (Freeman, 1992; Freeman, 1992; Freeman, 1993; Freeman, 1995). The “bystander effect” demonstrated
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