Dividing cells, vulnerable

Rapidly dividing cells require an abundant supply of thymidylate for the synthesis of DNA. The vulnerability of these cells to the inhibition of TMP synthesis has been exploited in cancer chemotherapy. Thymidylate synthase and dihydrofolate reductase are choice targets of chemotherapy (Figure 25.14). 

Acute exposure of large doses may cause radiation poisoning or radiation burns. Chronic exposure may result in cancer or mutations in one s children due damage to DNA. Organs with rapidly dividing cells such as bone marrow, intestines, and gonads are most vulnerable. Some effects do not appear until several years have passed. 

Many other examples of this concept exist. A recent example is methotrexate, a derivative of folic acid that has been used successfully in treating certain carcinomas as well as rheumatoid arthritis. Just as in the case above, methotrexate, because of its resemblance to folic acid, can enter into some of the same chemical reactions as folic acid, but it cannot ultimately serve the same inherent biological function. Here that role is involvement in reactions critical to cellular division. Although methotrexate is toxic to all dividing cells, those cells that divide most rapidly—cancer cells—are most vulnerable to its effect. 

A relatively new use for radioactive isotopes/radiopharmaceuticals is in the detection and treatment of cancer. This branch of radiology is often used to help diagnose and treat abnormalities very early in the stages of a disease, such as thyroid cancer. Since rapidly dividing cells like those present in cancer are more vulnerable to radiation than slow-growing normal cells, treatment using medical isotopes works well. 

The nervous system is vulnerable to attack from several directions. Neurons do not divide, and, therefore, death of a neuron always causes a permanent loss of a cell. The brain has a high demand for oxy gen. Lack of oxygen (hypoxia) rapidly causes brain damage. This manifests itself both on neurons and oligodendroglial cells. Anoxic brain damage may result from acute carbon monoxide, cyanide, and hydrogen sulfide poisonings. Carbon monoxide may also be formed in situ in the metabolism of dichloromethylene. 

The vulnerability of the conceptus is viewed as due to qualitative or quantitative characteristics of both structure and function (1) it is composed of a small number of rapidly dividing undifferentiated cells with absent or limited metabolic capabilities to alter or detoxify xenobiotics, repair lesions, etc. (2) there is a necessity for precise temporal and spatial localization of specific cell numbers and types, as well as specific cell products, for normal differentiation, including programmed cell death (3) sensitivities of certain cell types to certain insults may be unique to specific periods of cell movement, induction, or differentiation (i.e., transient vulnerability during the period of formation of tissues or organs) and (4) the immunosurveillance system (to provide recognition of self and detection of xenobiotics or lesions) is absent or immature in the prenatal or perinatal individual. 

Cancer cells often have two characteristics that make them especially vulnerable to agents that damage DNA molecules. First, they divide frequently, and so their DNA replication pathways are more active than they are in most cells. Second, as already noted, cancer cells often have defects in DNA-repair pathways. Several agents widely used in cancer chemotherapy, including cyclophosphamide and cisplatin, act by damaging DNA. 

During fetal development, there are critical periods of vulnerability to environmental impacts, the critical periods occurring at various times in different tissues. Cells rapidly dividing to form tissues and organs are at greatest risk, and it s reasonable that fetal programming is more likely to occur in such tissues. 

Studies on brain development during malnutrition have continued to demonstrate the vulnerability of the developing brain to nutritional insult. Winick (1968) has emphasized that nutritional deficiency occurring while cells of the central nervous system are actively dividing results in a permanent decrease in central nervous system cell number. Later nutritional deficiency which results in decrease in cell size appears to be recoverable. Perhaps even more important than effects of malnutrition on brain cell number is the effect on brain protein synthesis and rayelination. 

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