General cell toxicants

However, the oldest and still the most commercially valuable group of fungicides are the general cell toxicants. 

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No. Mancozeb is a broad-spectrum fungicide used as a protectant in many economically important crops but, because of its behaviour as a general cell toxicant, its conversion into a systemic would result in an unacceptable piiytotoxic crop response. 

Host-resistance assays can be used to assess the overall immunocompetence of the humoral or cell-mediated immune systems of the test animal (host) to fend off infection with pathogenic microbes, or to resist tumorigenesis and metastasis. These assays are performed entirely in vivo and are dependent on all of the various components of the immune system to be functioning properly. Thus, these assays may be considered to be more biologically relevant than in vitro tests that only assess the function of cells from one source and of one type. Since these assays require that the animal be inoculated with a pathogen or exogenous tumor cell, they cannot be performed as part of a general preclinical toxicity assessment, and are thus classified as Type 2 tests in the revised Redbook. These assays are also included as Tier II tests by the NTP. 

The chemistry of RNOS has been largely studied in vitro and has been found to generally elicit toxic responses. The relevance of extrapolation of these results to higher organisms is essentially unknown. Clearly, the cell-to-cell communication and balanced production and consumption pathways in whole organisms cannot be duplicated in vitro. 

An important question in cell uptake of DNA is the potential toxicity of the dendrimer nucleotide complexes. In general, the toxicity has been found to be lower for dendrimer-nucleotides than for other transfection systems including polylysine [154-156]. 

The alternative approach is to use non-viral vectors, such lipid-based, peptide-based and polymer-based delivery systems, as described in detail in Chapter 14. Liposomes are relatively easy to manufacture, are generally non-toxic and are devoid of the capability to cause an infection (see Section 5.3.1). However, a number of limitations are associated with their use. For example, it is difficult to direct liposomes to a particular type of cell. Liposome/DNA complexes which may be internalized by the target cells are... 

The inherent features of monoclonal antibodies (mAbs), i.e., high specificity and generally low toxicity, make them ideal for targeting transformed cell surfaces. Upon binding, the mAbs could induce homo- or hetero-dimerization of the receptors, which in turn stimulate internalization into the target cells... 

Figure 2.12 A conceptual physiologically based pharmacodynamic (PBTD) model for CC14 and kepone interaction. KMIT = rate constant for mitosis KREP Rate constant of inj. cells repair KBIR = rate constant for cell birth KINJ = rate constant for cell injury by toxicants KDIEI = rate constant for general cell death KDIE-1 = rate constant for cell death due to injury KPH = rate constant for phagocytosis. (Redrawn from El-Masri et al. [1996a], with permission.)...

Cytotoxic cancer chemotherapeutic agents are immunosuppressive because they interfere with mononuclear cell multiplication and function. But they are generally too toxic for the above purposes and the following are principally used for intended immunosuppression ... 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

While combination chemotherapy and high-dose therapy (with or without stem cell transplantation) can increase cancer response rates, they generally increase toxicity significantly and sometimes in unanticipated ways when drugs interact with each other. Hence, the toxicity of each combination chemotherapy protocol and each high-dose therapy protocol must be considered individually. 

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