Cytotoxicity, factors affecting

The three pharmacological factors affecting the cytotoxicity of platinum... 

Myers, R.A. and Stella, V.J. 1992. Factors affecting the lymphatic transport of penclomedine (NSC-338720), alipophilic cytotoxic drug Comparison to DDT and hexachlorobenzterteJ. Pharm., 80 51-62. 

The role of GSH in DEB toxicity provides a plansible background to envisage oxidative stress-dependent GSH depletion and, especially, decreased GST activity as possible contributory factors affecting the detoxification potential of cells and in vidual susceptibihty to DEB toxicity. This view was corroborated by a study in which pretreatment with phorone, a well-known intracellular glutathione depletor, was foimd to enhance DEB cytotoxicity, consistent with an active role played in vivo by the GSH-detoxifying system. 

Factors that affect drug metabolism will influence the development of serious adverse effects. TPMT, one of the three enzymes that metabolize 6-MP, is encoded by a gene on chromosome 6 that contains functional polymorphisms. Multiple variants have been described ( 2, 3A, 3B, 3C, 3D, 4, 5, 6, 7, 10 31,32) that result in lower TPMT activity, leading to preferential metabolism of 6-MP by the HGPRT enzyme. This results in an increase in the amount of cytotoxic thioguanine nucleotides and greater myelotoxicity. There appears to be an allele dose-dependent... 

The inhibitors available for human use, azacitidine and decitabine, have been approved for the treatment of myelodysplastic syndrome (MDS) [98, 99[. MDS summarizes a set of different conditions that affect the maturation of blood cells. It is a group of bone marrow stem cell malignancies that have a pathogenetic overlap with acute myeloid leukemia, show peripheral blood cytopenias and, in more advanced subtypes, varied degrees of maturation arrest [100]. Both drugs are approved for all subtypes of MDS. Response rates are usually around 30%. The question whether the clinical benefit results more from epigenetic effects and re-activation of silenced maturation factors or more from cytotoxic effects on the immature hyperproliferative cells remains open. 

The third factor is that PAs are extremely effective broad-spectrum feeding deterrents. Numerous species spanning 11 plant families have made use of this attribute (Hartmann and Ober, 2000). Arctiids and other PA-pharmocophagous insects have converted antiherbivore defenses to antipredator defenses. We know little about the mechanisms by which PAs affect their unpalatability. It seems unlikely that the long-term cytotoxic and genotoxic effects of PAs are relevant to their fast-acting deterrency. Recent work has indicated that some PAs bind to acetylcholine receptors (Schmeller et al., 1997) however, further study is required to understand the mode of action of the PAs. 

Interleukin-4 (IL-4), cooperating with IL-21,227a stimulates growth of activated B cells, T lymphocytes, and mast cells, induces formation of cytotoxic CD8+ T cells, and enhances formation of IgG 228/229 The transforming growth factor-P (TGF-P) is another cytokine that modulates the development of the immune system. It affects a very broad range of tissues and is discussed in Chapter 32. 

Adenosine 3, 5 -cyclic monophosphate (cAMP) has been shown to reduce pulmonary edema and lung toxicity caused by factors other than asbestos. An in vitro study by Vatche and coworkers (Israbian et al. 1994) found that cAMP diminished asbestos-induced cytotoxicity by maintaining intracellular ATP levels and inhibiting cellular replication rather than by affecting asbestos-induced oxygen radical production. 

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