Vincristine accumulation

Kobayashi, J. Hosoyama, H. Wang, X.-X. Shigemori, H. Koiso, Y. IwasaM, S. Sasaki, T Naito, M. Tsumo, T. Effects of taxoids from Taxus cuspidata on microtubule depolymerization and vincristin accumulation in MDR cells. Bioorg. Med Chem. Lett., 1997, 7 393-398. 

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). 

Vincristine a severe polyneuropathy is a particularly common side effect, but in some patients a painful autophagic myopathy is also present. Abnormal lysosomal complexes are also formed which function as virtually indigestible lipid accumulations. 

Thimmaiah, K.N., Horton, J.K., Qian, X.D., Beck, W.T., Houghton, J.A. and Houghton, J. (1990) Structural determinants of phenoxazine type compounds required to modulate the accumulation of vinblastine and vincristine in multidrug-resistant cell lines. Cancer Communications, 2, 249-259. 

Treatment of cells with concentrations of vincristine or vindesine that produce relatively little effect on cell viability results in an accumulation of cells in the M and Gj (gap after DNA synthesis) phases of the cell cycle. The cellular effects, as measured by techniques such as flow... 

Cells that exhibit high (several hundredfold) levels of resistance to vinblastine, vincristine, and vindesine have an extremely limited capacity to accumulate radiolabeled vinblastine for example, essentially no increase in radioactivity associated with human leukemic lymphoblastic cells resistant to vinblastine could be detected over a 60-min incubation period in the presence of concentrations of tritiated vinblastine that were cytotoxic to parent cells. The parent cells, highly sensitive to vinblastine, were observed to accumulate vinblastine to levels seven-fold higher than those observed for the resistant cells (76). 

Vincristine has been shown to enhance the accumulation of the folate antagonist methotrexate in murine leukemia cells, and the enhancement has been shown to involve inhibition of a specific efflux route for methotrexate (25) the suggestion has been made that the effect of vincristine on methotrexate efflux may be related to alterations of cell membrane electrical activity that appear to occur when cells are treated with vincristine. In this connection, it is worth mentioning that association of tubulin with membrane structures from bovine brain has been described 25a). Both vinblastine and vincristine have been reported to enhance the accumulation of the folate antagonist methotrexate in human leukemic cells (S) there is no evidence, however, to indicate that this interaction has significance in a clinical setting. 

In vitro studies with several tumor cell lines have shown vitamin C to enhance the cytotoxic activity of doxorubicin, cisplatin, paclitaxel, dacarbazine, 5-FU, and bleomycin. Vitamin C has also been shown to increase drug accumulation and to partially reverse vincristine resistance of human nonsmall-cell lung cancer cells. 

TFP (5) was the first phenothiazine demonstrated to modulate MDR in drug-resistant P338 murine leukemia cells. TFP (5) enhanced intracellular accumulation of vincristine and adriamycin (77) in resistant tumor cells by inhibiting outward transport of these anticancer drugs [167]. Studies per-... 

Tsuruo T, Iida H, Kitatani Y, et al. Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells. Cancer Res 1984 44(10) 4303 4307. 

Sako, M. Suzuki, H. Yamamoto, N. Hirota, K. Highly increased cellular accumulation of vincristine, a useful hydrophobic antitumor-dmg, in multidmg-resistant solid cancer cells induced by a simply reduced taxinine. Bioorg. Med. Chem. Lett., 1999, 9 3403-3406. 

Some information on environmentally relevant reversal agents is available from aquatic invertebrates. P-gp-related dye exclusion in the mussel M. califomianus was inhibited by the moderately hydrophobic pesticides pentachlorophenol, dacthal, chlorbenside and sulfallate, but not by DDT, DDD, DDE or the PCB Arochlor 125432. Similarly, Diesel-2 oil water-extracts increased the accumulation of vincristine in the gills of M. galloprovincialis91. In the freshwater mussel Dreissena polymorpha, water from the polluted Sava River increased the accumulation of fluorescent P-gp... 

When incubated with human hepatocytes, vinorelbine was the most rapidly and intensely accumulated Vinca alkaloid followed by vinblastine, vindesine and vincristine, as would be suggested by the lipophilicities of the molecules [187]. Vinflunine is even more lipophilic than vinorelbine and accumulates taster inside cells [23]. 

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