Tumour killing

Interleukin-2 regulates the proliferation of tumour-killing T lymphocytes and natural killer cells. 

NK cells are a subset of lymphocytes found in blood and lymphoid tissues, especially the spleen. They are about 15 an in diameter, possess a kidney-shaped nucleus and have two or three large granules in the cytoplasm. They are derived from the bone marrow. NK cells have the ability to kill certain tumour lines and normal cells infected by virus. Killing by NK cells is not specific for viral antigenic epitopes, and is not restricted by MHC molecules. They do not possess CD3 but do express CD2, CD 16 and CD56, together with a low-affinity receptor for the Fc portion of IgG. 

Polymorphonuclear leucocytes (PMNs) employ a system comprising myeloperoxidase, hydrogen peroxide, and a halide factor to kill microorganisms and tumour cells. This process is sometimes loosely called the respiratory burst , which refers to the sudden rise in oxygen consumption by the phagocytosing neutrophils that is independent of the mitochondrial electron transport chain. 

A third biological activity of IL-2 pertinent to immunostimulation is its ability to promote the growth of NK cells. It also promotes further differentiation of NK cells, forming lymphokine-activated killer (LAK) cells, which exhibit an enhanced ability to kill tumour cells or virally infected cells directly. NK cells express the P and y IL-2 receptor subunits only thus, their stimulation by IL-2 requires elevated concentrations of this cytokine. NK cells are also activated by a variety of additional cytokines, including all interferons and TNF. 

TNF-a elicits a wide range of responses in cells and tissues. Apart from causing the lysis of certain tumours (by mechanisms probably related to the ability of the target to induce the synthesis of the mitochondrial manganese-dependent superoxide dismutase, Mn-SOD), it can also kill normal cells. These effects on normal cells are more apparent when biosynthesis is blocked - for example, by the addition of inhibitors of macromolecular bio-... 

Myeloperoxidase is an extremely potent, antimicrobial protein that is present in neutrophils at up to 5% of the total cell protein. Its role in the killing of a wide range of bacteria, fungi, viruses, protozoa and mammalian cells (e.g. tumour cells) is well established from in vitro studies. It also plays an important role in the inactivation of toxins and the activation of latent proteases, as well as in other functions described in section 5.4.1. In view of this apparent central role in neutrophil function during host defence, one would think that any deficiencies in this enzyme would have disastrous consequences on the ability of the host to combat infections. Until the early 1980s, this key role for myeloperoxidase in host protection seemed substantiated by the extremely low incidence of reports of patients with deficiencies of this enzyme. Indeed, up to this time, only 15 cases from 12 families had been reported worldwide. Sometimes these patients were asymptomatic but often suffered Candida infections, particularly if their myeloperoxidase deficiency was also associated with diabetes mellitus. 

Natural killer cells NK CDS 6 Killing of host cells infected with virus killing of abnormal cells displaying abnormal proteins on their cell surface, e.g. tumour cells... 

The cells are called natural killer cells since they kill without a requirement for MHC class I or class II proteins. This characteristic is sometimes termed the MHC-independent immune response. Their principal role is in defence against virnses and other intracellular microorganisms that is, they kill host cells infected with a vims or other pathogen. They also kill tumour cells. Thus they have a role in the process of immune surveillance for tumour cells. 

There is evidence that stressful conditions decrease the effectiveness of the immune system the loss of a job, a divorce or a bereavement increases the risk of development of cancer. This is due to impairment of the process of immune surveillance carried out by the neutrophils and other immune cells. They kill tumour cells that are migrating from a primary tumour to establish another tumour in a different tissue. The impairment may be due to chronic activation of the sympathetic system, which increases the... 

Understanding cancer involves not only knowledge of the genetic changes that cause a normal cell to develop into a tumour cell but also the response of the whole body to a tumour, factors that increase or decrease the risk of development of a tumour and the current therapies that arrest growth of, or kill, tumour cells. These topics are discussed in this chapter, but some basic information is required first the cell cycle, the growth of a tissue, the fuels used by tumour cells and, finally, the role of genes. 

Radiotherapy is the use of ionising radiation to damage and kill tumour cells. Radical radiotherapy involves using radiotherapy to cure the tumour. It may be combined with chemotherapy before, during or after radiotherapy. Adjuvant radiotherapy, for example following surgery to remove a tumour, is given to eradicate residual tumour... 

Radiotherapy is a local treatment aiming to achieve local control or cure of locally confined tumours. It cannot treat metastases. Radiotherapy may be administered as external beam radiotherapy with X-rays or gamma rays, in sealed radioactive sources (e.g. prostate brachytherapy), or unsealed sources (e.g. orally administered radioiodine for thyroid cancer, intravenous strontium-89 for bone metastases). In external beam radiotherapy, the X-ray or gamma ray beams are targeted at the tumour to damage and kill the tumour cells. Inevitably, surrounding normal tissues are also affected resulting in the early and late side effects of radiotherapy. 

Non-surgical methods of cancer treatment, primarily radiation therapy and chemotherapy, rely almost exclusively on procedures that kill cells. The main problem with these treatments is that they do not provide specificity for cancer cells. In the case of radiation therapy, a degree of specificity is achieved by localizing the radiation to the tumour and its immediate surrounding normal tissue. For anti-cancer drugs, it is primarily the rapid proliferation of many of the cancer cells that makes them more sensitive to cell killing than their normal counterparts. However, both modalities are limited by their cytotoxic effects on normal cells. In the case of radiotherapy, normal tissue surrounding the tumour limits the radiation dose, where-... 

Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly ADP-ribose polymerase. Nature 434 913-917... 

The damaging effects that radioactivity can have on tissues are not all bad. To treat cancers, we want to kill cells - albeit the unhealthy, frantically replicating tumour cells, not healthy cells. If radioisotopes can be localized in tumours, they do their destructive business to good effect. Cobalt-60, made by neutron bombardment of stable cobalt-59, is a radioisotope with a half-life of 5.3 years that is used to treat cancer. 

Liver. Male B6C3Fi mice, four weeks of age, received a single intraperitoneal injection of 80 mg/kg bw TV-nitrosodiethylamine (NDEA) in tricaprylin. Two weeks later, the mice were fed diets containing 0, 3000, 6000 or 12 000 ppm di(2-ethylhexyl) phthalate for up to six months. Groups of 10 mice were killed at two, four and six months after NDEA treatment. Few hepatocellular foci were seen at two, four or six months in mice treated with NDEA alone or di(2-ethylhexyl) phthalate alone, while numerous foci and neoplasms were seen in mice given di(2-ethylhexyl) phthalate after NDEA. No tumours were found at six months in mice receiving NDEA alone. By the end of the study, the number of foci per unit volume of liver was similar in mice at all doses of di(2-ethylhexyl) phthalate, but there was an increase in the volume of the foci (0, 1.4, 0.6, 9.4 mm for the control, 3000-, 6000- and 12 000-ppm groups, respectively) (Ward et al., 1983). 

Urinary system-. Groups of 20 male Fischer 344 rats were given 0.05%7V-ethyl-jV-hydroxyethylnitrosamine (EHEN) for two weeks in the diet followed by di(2-ethyl-hexyl) phthalate [purity unspecified] at a concentration of 0 or 1.2% in the diet for 24 weeks. Rats were killed at 27 weeks. Di(2-ethylhexyl) phthalate increased the numbers of rats with renal (tubular) cell tumours (EHEN + di(2-ethylhexyl) phthalate 65% versus 20% for EHEN alone p < 0.01) and the mean number of tumours per kidney (EHEN + di(2-ethylhexyl) phthalate 1.1 versus EHEN alone 0.2,< 0.01) (Kurokawa etal., 1988). 

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