遗传学实验技术

Suicide genes (SG) can be viewed as negatively selectable marker genes. Their gene products convert otherwise nontoxic prodrugs (PD) into cytotoxic metabolites. The enzymatic conversion leads to high levels of the activated toxic drug within genetically modified cells and ultimat ...

Many types of cancer become resistant to current chemotherapeutic and radiotherapeutic interventions. To overcome this situation, applications of gene therapy may be promising. Whereas many types of transgene, such as tumor suppressor genes and cytokine genes, have potential tu ...

Chemotherapy is widely used with surgery and radiotherapy for the treatment of malignant disease. Selectivity of most drugs for malignant cells remains elusive. Unfortunately, an insufficient therapeutic index, a lack of specificity, and the emergence of drug-resistant cell subp ...

Tumors are known to have an abnormal and chaotic vascular network, unable to effectively or reliably supply the whole tumor with oxygen and nutrients. Over the past years direct evidence has accumulated showing that reduced oxygen tension (hypoxia) is a common feature of both experimental a ...

Radiotherapy (RT) is a primary treatment modality for the majority of solid tumors. The objective is to destroy the tumor mass by exposure to ionizing radiation (IR) from an external beam or isotopic source. IR causes DNA damage directly and indirectly via the production of reactive oxygen inter ...

The vectors currently available for gene therapy of cancer rarely achieve expression of therapeutic genes in more than a small fraction of the cells in solid tumors. This makes therapeutic success critically dependent on secondary events, known as bystander effects, by which transgene e ...

Charaterization of a variety of genomic defects in malignant cells (1) has led to attempts to treat cancer by gene therapy. Gene therapy is a therapeutic approach in which therapeutic nucleic acids are transferred into the affected organs. Although the ideal concept would be the replacement of ...

One of the major goals for cancer therapies is to target toxic agents to tumor cells in a selective and specific manner, avoiding damage to normal tissues. One approach is to use “suicide” gene therapy or GDEPT (gene-directed enzyme-prodrug therapy) where the gene delivered encodes an enzyme that c ...

The prodrug CB1954 (5--2,4-dinitrobenzamide) is a weak monofunctional alkylating agent originally synthesized at the Chester Beatty Laboratories in the late 1960s (1). The antitumor activity of CB1954 was determined by screening a panel of aziridines for cytotoxicity against the r ...

The efficacy of standard chemotherapy tends to be limited by an inability to achieve sufficiently high drug concentrations to tumor cells without inducing concomitant toxicity elsewhere. If the tumor itself were induced to produce the drug, the efficacy would be increased. This strate ...

Over a century ago, Paul Ehrlich proposed the magic bullet theory of targeting therapeutic agents to specific tissues in order to increase their efficacy and reduce systemic toxicity. Because of their selectivity and the rapid development of hybridoma technology in the 1980s, monoclon ...

This chapter will review a particular class of antitumor prodrugs that are designed to exploit the ability of solid cancers to carry out reductive metabolism. These so-called bioreductive prodrugs are constructed in such a way that metabolic reduction leads to the production of a cytotoxic ...

Suicide gene therapy requires vectors or vehicles capable of efficient and selective gene delivery of the therapeutic genes to tumor cells. A number of vector systems has been proposed for gene therapy. These include: the viral vectors, adenoviruses (see Chapters 4 and 5), adeno-associated ...

The engineering of tumor-targeting Salmonella strains bearing a high degree of both attenuation and tumor inhibition is a recently developed approach to vector-based treatment of cancer (1,2). Tumor-targeted Salmonella have many desirable features for a tumor-selective deliv ...

Nonreplicative DNA viral vectors (i.e., adenovirus, herpes simplex virus, adeno-associated virus) have been widely used for suicide gene therapy against cancer because their strong and temporary expression of the transgene fit this purpose. Particularly, nonreplicating “ade ...

Replication-selective oncolytic viruses are being developed as novel, targeted anticancer agents (virotherapy) (1,2). Viruses have evolved to infect cells, replicate, induce cell death, release viral particles, and, finally, to spread in human tissues. Replication in tumor tiss ...

A recombinant retroviral vector is one of many available options for effecting gene transfer. To date, this type of vector has been most widely used and is involved in more than a third of current gene therapy trials, many of which are for delivery of suicide genes in the context of cancer treatment (1). Many i ...

The goal of suicide gene therapy is the specific expression of a toxic gene in cancer cells. In order to achieve this objective, vehicles and transfection strategies must be designed to specifically deliver suicide genes to the desired cells. Up to now, the use of bacteria and other micro-organisms, ...

Cationic liposome/micelle-based systems have come closer to providing clinically effective gene delivery than any other chemical nonviral delivery systems to date. These systems are formed from either a single synthetic cationic amphiphile (known as a cytofectin; cyto for cell and ...

A major problem for cancer treatment is the presence of toxic side effects associated with chemotherapeutic agents that limit their efficacy. Alternatively, this can be regarded as the limitation of the dose of drug available to a patient before major general toxicity occurs, with consequ ...