Normal cells

Enediynes hold substantial promise as anti cancer drugs because of their potency and selectivity Not only do they inhibit cell growth they have a greater tendency to kill cancer cells than they do normal cells The mechanism by which enediynes act involves novel chemistry unique to the C C—C=C—C C unit which leads to a species that cleaves DNA and halts tumor growth... 

Cancer. Cancer is a cellular malignancy characterized by loss of normal controls resulting in unregulated growth, lack of differentiation, and the abihty to invade local tissues and metastasize. Most cancers are potentially curable, if detected at an early enough stage. The ideal antineoplastic agent would destroy cancer cells without adverse effects or toxicities to normal cells. No such dmg exists. 

A 2-h incubation with another PGE2 analogue, nocloprost (9P-chloro-DMPG) protects normal human fibroblasts but has no effect on the survival of colon adenocarcinoma cells exposed to 10 Gy (1000 rad) (218). Nocloprost protects against radiation-induced DSBs in normal cells but not in tumor cells. Moreover, incubation using nocloprost for 2 h after irradiation enhances the rate of DSB rejoining in fibroblasts but not in adenocarcinoma cells. These data possibly reflect a different distribution of PG receptors on the plasma membrane of the two cell types. 

Vaccine development is hampered by the fact that recurrent disease is common. Thus, natural infection does not provide immunity and the best method to induce immunity artificially is not clear. The genome of these vimses is also able to cause transformation of normal cells, thus conferring on them one of the properties attributed to cancerous cells. Vaccine made from herpes vimses must, therefore, be carefully purified and screened to eliminate the possibihty of including any active genetic material. 

Amino-5-iodo-2, 5 -dideoxyuridine [56045-73-9] (13) C2H22IN2O4, was synthesized ia 1975 (27) and was found effective against herpes keratitis ia rabbits (28). This compound is markedly less cytotoxic than IdU, iadicating that it may have a safer and more specific mode of antiviral activity. A potential limitation of this group of nucleosides is their specificity, for they fail to inhibit all strains of herpes vimses. The specific antiviral activity of (13) is considered to be a result of the incorporation of the 5 -Ai-phosphate into both viral and host DNA in infected cells, but not into the DNA of normal cells. Phosphorylation of (13) occurs only in herpes vims-infected cells, brought about by a vims-induced thymidine kinase (29). 

This reaction is accelerated by iacreased temperature, iacreased electrolyte concentration, and by the use of sodium hydroxide rather than potassium hydroxide ia the electrolyte. It is beheved that the presence of lithium and sulfur ia the electrode suppress this problem. Generally, if the cell temperature is held below 50°C, the oxidation and/or solubiUty of iron is not a problem under normal cell operating conditions. 

It has been estimated that using available neutron intensities such as 10 neutrons/(cm -s) concentrations of B from 10—30 lg/g of tumor with a tumor cell to normal cell selectivity of at least five are necessary for BNCT to be practical. Hence the challenge of BNCT ties in the development of practical means for the selective deUvery of approximately 10 B atoms to each tumor cell for effective therapy using short neutron irradiation times. Derivatives of B-enriched /oj o-borane anions and carboranes appear to be especially suitable for BNCT because of their high concentration of B and favorable hydrolytic stabiUties under physiological conditions. 

Therapy with L-asparaginase is most successful against tumors exhibiting a deficiency in the synthesis of L-asparagine. Most normal cells exhibit a healthy capacity to synthesize this nonessential amino acid and are not damaged by exposure to L-asparaginase (23). This finding demonstrates that biochemical differences between normal and cancer cells can be exploited for successful cancer chemotherapy. 

A different kind of enzyme, translocase [80700-39-6], which transfers a fragment of NAD to the protein—synthesis factor (elongation factor 2), is catalyzed by diphtheria toxin, thereby inhibiting protein synthesis (43). In tumor cells, the rate of protein synthesis is 100 to 1000 times more sensitive to diphtheria toxin than the analogous process in normal cells (41) therefore, diphtheria toxin is selectively toxic to tumor cells. 

Mammalian Cells Unlike microbial cells, mammalian cells do not continue to reproduce forever. Cancerous cells have lost this natural timing that leads to death after a few dozen generations and continue to multiply indefinitely. Hybridoma cells from the fusion of two mammalian lymphoid cells, one cancerous and the other normal, are important for mammalian cell culture. They produce monoclonal antibodies for research, for affinity methods for biological separations, and for analyses used in the diagnosis and treatment of some diseases. However, the frequency of fusion is low. If the unfused cells are not killed, the myelomas 1 overgrow the hybrid cells. The myelomas can be isolated when there is a defect in their production of enzymes involved in nucleotide synthesis. Mammahan cells can produce the necessary enzymes and thus so can the fused cells. When the cells are placed in a medium in which the enzymes are necessaiy for survival, the myelomas will not survive. The unfused normal cells will die because of their limited life span. Thus, after a period of time, the hybridomas will be the only cells left ahve. 

Noncarcinogenic elTects include all toxicological responses except tumors. Toxicological responses and iiicchanisins vary widely, and e.xamples of these include interference with normal cell processes by displacing elements out of the cell and binding with a cell to reduce membrane penneability. However,... 

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

Cancer is a serious malfunction of normal cell growth. In the years from 1950 through 1970, the major approach to treating this disease had been to target DNA and DNA precursors according to the hypothesis that rapidly dividing cells (cancer cells) are more susceptible to DNA toxicity... 

Fluorouracil (5-fluorouracil, 5-FU, Fig. 5) represents an early example of rational drag design in that it originated from the observation that tumor cells, especially from gut, incorporate radiolabeled uracil more efficiently into DNA than normal cells. 5-FU is a fluorinated pyrimidine analog that must be activated metabolically. In the cells 5-FU is converted to 5-fluoro-2>deoxyuridine-monophosphate (FdUMP). This metabolite inhibits thymidilate synthase which catalyses the conversion of uridylate (dUMP) to thymidilate (dTMP) whereby methylenetetrahydrofo-late plays the role of the carbon-donating cofactor. The reduced folate cofactor occupies an allosteric site of... 

Double stranded (ds) RNA is not a constituent of a normal cells but is produced during replication of many RNA and DNA viruses either as an obligatory intermediate or as a side product. As a foreign molecule, double stranded RNA induce the secretion of interferon (EFN) from lymphocytes, neutrophils and fibroblasts. 

However, the normal cells that line the oral cavity and gastrointestinal tract, and cells of the gonads, bone marrow, hair follicles, and lymph tissue are also rapidly dividing cells and are usually affected by these drugs. Thus, antineoplastic drugs may affect normal as well as malignant (cancerous) cells. 

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