Anthracyclines accumulation

Nooter, K., Sonneveld, P., Oostrurn, R., Herweijer, H., Hagenbeek, T., and Valerio, D. (1990) Overexpression of the mdrl gene in blast cells from patients with acute myelocytic leukemia is associated with decreased anthracycline accumulation that can be restored by cyclosporin-A. Int. J. Cancer 45, 263-268. 

Confocal scanning microspectrofluorometry reveals specific anthracycline accumulation in cytoplasmic organelles of multi-drug resistant cancer cells. Journal of Histochemistry Cytochemistry, 46 (12), 1369-1376. ). 

Tab. 5.19 Effect of charge and I ipoph ilicity of anthracyclines on their accumulation in cardiac muscle and non muscle (fibroblast) cells. (Reprinted from Tab. 1 of ref. 126 with permission from the American Chemical Society)...

The detection of the anthracycline daunomycin by accmnulation at MWCNTs-modified GCE was also reported [81]. Daunomycin was accumulated at open circuit for 3 min and then it was reduced by differential pulse voltammetry... 

An important improvement of these assays is the use of fluorescent Pgp substrates with a much higher sensitivity than the anthracyclines. Many of these are dyes that had other applications to monitor cellular functions, such as viability, mitochondrial potential, or pH. We and others have compared extensively many of these dyes for their sensitivity and specificity to detect Pgp function in tumor cell lines (8,11), hematopoietic progenitor cells (12) and AMLs (13). We have chosen to use rhodamine 123 as dye and have validated its use by direct comparison with radiolabeled daunorubicin and vincristine accumulation in AMLs (14). 

Etoposide and teniposide are similar in their actions and in the spectrum of human tumors affected. Unlike podophyllotoxin, but like the anthracyclines, they form a ternary complex with topoisomerase 11 and DNA and prevent resealing of the break that normally follows topoisomerase binding to DNA. The enzyme remains bound to the free end of the broken DNA strand, leading to an accumulation of DNA breaks and cell death. Cells in the S and G2 phases of the cell cycle are most sensitive to etoposide and teniposide. Resistant cells demonstrate ampMcation of the mdr-1 gene that encodes the P-glycoprotein drug efflux transporter, mutation or decreased expression of topoisomerase 11, or mutations of the p53 tumor suppressor gene, a required component of the apoptotic pathway. 

Daunorubicin, doxorubicin, epirubicin, and idarubicin usually are administered intravenously. Careful infusion over 10-15 minutes is recommended to prevent extravasation, since severe local vesicant action may result. The drugs are cleared by a complex pattern of hepatic metabolism and biliary excretion. The plasma disappearance curve for doxorubicin is multipha-sic, with elimination half-lives of 3 hours and - SO hours. All anthracyclines are converted to an active alcohol intermediate that plays a variable role in their therapeutic activity. Idarubicin has a tj of 15 hours, and its active metabolite, idarubicinol, has a tj of - 40 hours. There is rapid upt e of the drugs in the heart, kidneys, lungs, liver, and spleen. They do not cross the blood-brain barrier. Daunorubicin and doxorubicin are eliminated by metabolic conversion to a variety of aglycones and other inactive products. Idarubicin is primarily metabolized to idarubicinol, which accumulates in plasma and likely contributes significantly to its activity. Clearance is delayed in the presence of hepatic dysfunction, and at least a 50% initial reduction in dose should be considered in patients with elevated serum bilirubin levels. 

The first C-labeled compound synthesized for functional imaging of MDR was the anthracycline daunorubidn (DNR) which is a well-known substrate of Pgp. In vitro experiments with human ovarian carcinoma cell lines showed a 16-fold higher accumulation of [ C]DNR in sensitive cells (A2780) as compared with the resistant Pgp-overexpressing counterpart (A2780AD) [116]. After treatment with verapamil, the accumulation of ["C]DNR in Pgp-overexpressing cells increased to the levels found in sensitive cells further demonstrating the influence of Pgp on transport kinetics of ["C]DNR. The ability of [ C]DNR, in tracer... 

Uncertain. One reason may be that the ciclosporin affects the P-glycopro-tein of the biliary tract so that the clearance of these anthracyclines in the bile is reduced. An additional reason may be that ciclosporin inhibits the metabolism of metabolites, such as doxorubicinol, so that they accumulate. The increased levels of both would explain the increases in toxicity. It is not clear why such severe neurotoxicity was seen in one patient. 

Figure S Redrawn and modified model of topoisomerase 11 catalysis as proposed by Roca and Wang (159). Doxorubicin, daunorubicin, other 10-descarbomethoxy anthracyclines, and other topoisomerase 11 poisons" inhibit topoisomerase II activity by stabilization of the "cleavable com-ptex" (i.e., freezing the catalytic cycle between steps 3 and 4), which results in an accumulation of DNA strand breaks, and ultimately, DNA degradation. Aclarubicin and possibly other anchracy-dines possessing the 10-carbomethoxy moiety inhibit topoisomerase II by inhibiting reaction 1, namely, the complexaiion of DNA and the enzyme.

A complex array of properties contribute to the in vivo antitumor activity and toxicity of anthracyclines, including ability to bind DNA, accumulation in tissues (dbtribution), elimination, and metabolic fate of the drugs. In an effort to find anthracyclines with higher efficacy to toxicity ratios, more than 2000 analogs of daunombicin, doxorubicin, and other anthracyclines have been synthesized and tested (1). From these tests, some ivoad generalizations can he made concerning structure-activity relationships. 

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