Cytotoxicity drug exposure

Datta, R, Manome, Y, Taneja, N, Boise, LH, Weichselbaum, R, Thompson, CB, Slapak, CA and Kufe, D (1995) Overexpression of Bcl-XL by cytotoxic drug exposure confers resistance to ionizing radiation-induced intern ucleosomal DNA fragmentation. Gell Growth Differ, 6, 363-370. 

The surface epithelial cells of the small intestine are renewed rapidly and regularly. It takes about two days for the cells of the duodenum to be renewed completely. As a result of its rapid renewal rate, the intestinal epithelium is susceptible to various factors that may influence proliferation. Exposure of the intestine to ionizing radiation and cytotoxic drugs (such as folic acid antagonists and colchicine) reduces the cell renewal rate. 

For anti-tumour drugs, Ozawa et cd. [27] proposed the following models. For cell cycle phase non-specific drugs (type I drug), the cytotoxic activity depends on the drug exposure, as reflected in the area under the intracellular concentration-time profile (AUC), and can be modelled using the following formula [2,28] ... 

The monolayer culture technique is frequently employed in cytotoxicity tests with cancer lines and in studies of chemical sensitivity of different tumor types. This method offers high flexibility with respect to drug exposure and recuperation conditions, as well as to the quantification of any effect. Among all methods, cell culture in a monolayer requires a lower cell number and allows the evaluation of multiple drugs in large concentration ranges. 

The recovery period after drug exposure is important for many reasons. This period permits the re-establishment of metabolic equilibrium when inhibition is used as a pharmaceutical test. In addition, cells can recover from sublethal damage or indicate effects of late cytotoxicity, which are not revealed in alternative tests. 

For example, the differences between CP and Br in complexes of the type [Ru (r 6-arene)(en)Z]+, where arene is biphenyl, indane or benzene, is not dramatic, however, when Z = I the hydrolysis is slower (3- to 7-fold). Other leaving groups such as pyridine or pyridine derivatives can slow down the hydrolysis further and even block it almost completely on biologically-relevant time scales. Such complexes are not cytotoxic towards cancer cells within 24-h drug exposures. There are a few exceptions such as [Ru(ri6-hexamethylbenzene)(en)(SPh)]PF6, where the monodentate ligand is thiophenolate. This complex does not hydrolyse, but intrigu-ingly is active. The mechanism of activation of this complex is different (vide infra). 

The number of cells within each colony depends on the number of cell doublings and can be used as an estimate of the effects, if any, of the drug on the cell doubling time. A clonogenic assay can thus discriminate between cytotoxic (cell kill) and cytostatic (decreased growth rate) effects. Because a cytostatic effect may be lost upon removal of the drug a cytotoxicity assay based on colony formation is also described since this allows continuous drug exposure. 

Cells in exponential phase of growth are exposed to a cytotoxic drug. The duration of exposure is usually determined as the time required for maximal... 

A variety of continuous TV infusion fluorouracil regimens have been developed to increase the duration of drug exposure during the S phase of the cell cycle and increase DNA-dependent cytotoxicity. Some of these schedules involve short (24- to 48-hour) weekly or biweekly or protracted continuous fluorouracil infusions for up to 12 weeks. Doses of fluorouracil employed in 24 to 48 hour infusions generally range from 1000 to 2000 mg/m per day. A regimen utilizing 300 mg/m per day for 10 weeks is considered the maximally tolerated dose for protracted continuous infusion. Based on the assumption that a dose-response relationship exists for colorectal cancer, this approach is one of the most efficacious methods of dose intensification for fluorouracil. The maximum cumulative fluorouracil dose that can be administered via continuous IV infusion in... 

Yu T, Zhang Y, He H, Zhou S, Liu Y, Huang P (2011) Anticancer potency of cytotoxic drugs after exposure to high-intensity focused ultrasoimd in the presence of microbubbles and hmnatoporphyiin. Mol Pharmaceutics 8 1408-1415... 

The immune system is a highly integrated and regulated network of cell types that requires continual renewal to achieve balance and immunocom-petence. The delicacy of this balance makes the immune system a natural target for cytotoxic drugs or their metabolites. Since renewal is dependent on the ability of cells to proliferate and differentiate, exposure to agents that arrest cell division can subsequently lead to reduced immune function or immunosuppression. This concept has been exploited in the development of therapeutic drugs intended to treat leukemias, autoimmune... 

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