Tumour destruction

Pseudomonas cytotoxin hybrids destroy cancer cells and have given promising results in tumour destruction. 

TUMOUR DESTRUCTION USING LASER-INDUCED CHEMISTRY (SELECTIVE RELEASE OF SINGLET OXYGEN)... 

The major indication for thermal ablation in bone tumours is pain. Secondarily, local tumour destruction may support destruction of the tumoral matrix, which may enhance repair processes and consequently prolong the process of functional preservation. 

Most transformed cells do not express class II MHC molecules and express lower than normal levels of class I MHC molecules. This renders their detection by immune effector cells more difficult. Treatment with cytokines, such as IFN-y, can induce increased class I MHC expression, which normally promotes increased tumour cell susceptibility to immune destruction. 

Whatever the exact nature of tumour escape, it has been demonstrated, both in vitro and in vivo, that immunostimulation can lead to enhanced tumour detection and destruction. Several approaches to cancer immunotherapy have thus been formulated, many involving application of IL-2 as the primary immunostimulant. 

Antibodies that, by binding to the cell surface antigen, mark the tumour cell for destruction. NK cells and macrophages express cell surface receptors that bind to the antibody Fc region (Box 13.2). Thus, antibody bound to tumour antigens directs these immune elements directly to tumour surface. Antibodies also activate complement, which is capable of directly lysing tumour cells. 

Antibody-based strategies for tumour detection/destruction... 

The antibody preparations could be administered unaltered or (more commonly) after their conjugation to radioisotopes or toxins. Binding of unaltered monoclonal antibodies to a tumour surface alone should facilitate increased destruction of tumour cells (Figure 13.4). This approach, however, has yielded disappointing results, as the monoclonal antibody preparations used to date have been murine in origin. The Fc region of such mouse antibodies is a very poor activator of human immune function. Technical advances, allowing the production of human/humanized monoclonals (see later) may render this therapeutic approach more attractive in the future. 

Figure 13.4 Binding of appropriate antibody to tumour-associated antigens marks the tumour cell for destruction. This is largely due to the presence of a domain on the antibody Fc region (see also Box 13.2), which is recognized and bound by macrophages and NK cells. Therefore, congregation of such cells on the surface of the tumour is encouraged. This greatly facilitates their cytocidal activity towards the transformed cells...

Inserting toxin genes in tumour cells in order to promote tumour cell destruction Inserting suicide genes into tumour cells... 

Yet another strategy that may prove useful is the introduction into tumour cells of a sensitivity gene. This concept dictates that the gene product should harbour the ability to convert a non-toxic pro-drug into a toxic substance within the cells - thus leading to their selective destruction. The model system most used to appraise such an approach entails the use of the thymidine kinase gene of the herpes simplex virus (Figure 14.12). 

The cell metabolism and its existing environment are disturbed severely by the electrochemical treatment, causing the destruction of both normal and tumour cells rapidly and completely. 

Photochemical reaction with organic molecules within the tumour cells, where hydrogen abstraction occurs. This initiates a number of radical reactions, resulting in destruction of the tumour. 

The use of Ti02 as a photosensitiser for the destruction of cancer cells involves topical application of the Ti02 as fine particles to the site of the tumour, which is then irradiated with UV light by means of an optical fibre. 

The process used in the treatment of patients by PDT involves the application of the photosensitiser, either topically or by systemic injection, which then selectively accumulates in the tumour (or lesion). In the next step low energy light is led into the tumour via a fibre optic, where it interacts with the sensitiser and oxygen, causing cell destruction. This is shown schematically in Figure 4.21. 

Despite the scientific elegance of the antibody-mediated approach to tumour detection/ destruction, initial clinical trials proved disappointing. A number of factors contributed to their poor therapeutic performance, particularly against solid tumours. Most such factors relate directly or indirectly to the fact that the first generation of such drugs utilized whole monoclonal antibody preparations of murine origin. These factors include ... 

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