Cancer reactivity with proteins

In relation to cancer, there is some evidence that highly oxidized and heated fats may have carcinogenic characteristics. HNE (4-hydroxy-2-frans-nonenal), a secondary lipid peroxidation product derived from linoleic acid oxidation, has assumed particular interest because it has shown cytotoxic and mutagenic properties. Its toxicity, as well other secondary lipid peroxidation products (HHE 4-hydroxy-2-frans-hexenal and HOE 4-h yd roxy-2-trans-oc ten al), is explained through the high reactivity with proteins, nucleic acids, DNA, and RNA. Research links them to different diseases such as atherosclerosis, Alzheimer s, and liver diseases (Seppanen and Csallany, 2006). Research is rapidly progressing, but results are still not conclusive. 

While the effect on tests requiring the interaction of the tumour cells with extra cellular matrix components suggest that the interaction of RAPTA compounds with cell surface molecules may be responsible for part of their activity, the compounds also accumulate within cancer cells and interact to a significant extent with proteins in the cytoplasm. Adduct formation of RAPTA compounds with proteins has been studied using mass spectrometric methods [10, 25, 26]. In general, rapid and irreversible binding has been observed. In a recent study the reactivity of cisplatin and RAPTA-C with a mixture of proteins was probed without using any... 

Vinyl chloride is a simple volatile industrial chemical, which in the liver is converted by an enzyme (cytochrome P450) into a reactive product. The reactive product can interact with proteins and, more importantly, with DNA in the nucleus of liver cells. The metabolite interacts with two of the four bases in the DNA backbone, adenine and cytidine. These bases form both part of the genetic code and pairs with other bases in the DNA. The addition of the vinyl chloride alters the bases and reduces their ability to form pairs, with the result that the code in the DNA is misread which leads to mutations. When the cells of the liver divide or that part of the genetic code is expressed, mistakes, or mutations, creep in. It is now known that after liver cells are exposed to vinyl chloride some of the mutations occur in the oncogenes or cancer genes. Mutant proteins produced from these genes can be detected in the blood of workers who were exposed to vinyl chloride and suffered from the liver cancer. The level of such proteins seems to correlate with the level of exposure to vinyl chloride. 

At high doses the interaction with protein can cause immediate damage to the liver (acute hepatitis). At lower doses interaction with DNA will lead to mutations in the genetic code which can cause cancer. Laboratory studies in experimental animals like rats have revealed that aflatoxin Bi can cause liver cancer, and the products of the reactive metabolites of aflatoxin can be detected in the blood of these animals. Furthermore the same metabolites have also been detected in the blood and urine of humans eating fungus-contaminated food in China, for example. Most recently a correlation has been shown between exposure to these fungal toxins, as indicated by metabolites of aflatoxins bound to protein in blood samples, and liver cancer in humans in China. 

Of 52 patients with colorectal cancer treated with a median of six 3-weekly cycles of raltitrexed 1.5-3.0 mg/m combined with oral carmofur 300-400 mg/m on cycle days 2-14, 39 had a fever on days 2-9 after receiving raltitrexed, 49 had fatigue, and 49 had a raised serum C-reactive protein concentration without a documented infection (6). Median concentrations of C-reactive protein, interleukin-6, interleukm-8, and tumor necrosis factor-alfa were higher 7 days after raltitrexed or raltitrexed + carmofur than at baseline. The authors suggested that patients with colorectal cancer treated with raltitrexed may develop drug-related systemic inflammation, which may be difficult to distinguish from infection. 

Soluble fragments of TNF-Rs were first referred to as TNF-binding proteins, having been discovered in the biological fluids of health volunteers, postmenopausal women, and patients with cancer or chronic renal disease (Olsson et al., 1993). These soluble forms of TNF-Rs are immunologically distinct from one another but demonstrate functional cross-reactivity with the surface receptors (Engelmann et al., 1990b). 

These proteins are called acute phase proteins (or reactants) and include C-reactive protein (CRP, so-named because it reacts with the C polysaccharide of pneumococci), ai-antitrypsin, haptoglobin, aj-acid glycoprotein, and fibrinogen. The elevations of the levels of these proteins vary from as little as 50% to as much as 1000-fold in the case of CRP. Their levels are also usually elevated during chronic inflammatory states and in patients with cancer. These proteins are believed to play a role in the body s response to inflammation. For example, C-reactive protein can stimulate the classic complement pathway, and ai-antitrypsin can neutralize certain proteases released during the acute inflammatory state. CRP is used as a marker of tissue injury, infection, and inflammation, and there is considerable interest in its use as a predictor of certain types of cardiovascular conditions secondary to atherosclerosis. Interleukin-1 (IL-1), a polypeptide released from mononuclear phagocytic cells, is the principal—but not the sole—stimulator of the synthesis of the majority of acute phase reactants by hepatocytes. Additional molecules such as IL-6 are involved, and they as well as IL-1 appear to work at the level of gene transcription. 

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