Cellular pharmacodynamics of several anthracycline antibiotics

Nr, Bachur; M, Steele; Wd, Meriwether; Rc, Hildebrand

doi:10.1021/jm00227a015

Cited by 94 publications

(14 citation statements)

References 3 publications

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“…Using flow cytometry, we demonstrated rapid accumulation of all the anthracyclines in both cell types within minutes of incubation, which is in agreement with previous in vitro and in vivo findings of rapid influxes of anthracyclines across cellular membranes (Meriwether & Bachur, 1972;Egorin et al, 1974;Bachur, 1976). In both hepatoma cell lines, the fluorescence of DNR and ACL reached a plateau within 15 min.…”

Section: Discussionsupporting

confidence: 91%

Human hepatoma cells rich in P-glycoprotein are sensitive to aclarubicin and resistant to three other anthracyclines

Lehne

Angelis²,

Clausen³

et al. 1996

Br J Cancer

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Summary Drug resistance is a major obstacle to successful chemotherapy of primary liver cancer, which is associated with high expression of the multidrug resistance (MDR) gene product P-glycoprotein (Pgp), a multidrug efflux transporter. The most effective single agents in treatment of primary liver carcinoma belong to the anthracycline family, yet several anthracyclines are known to be substrates for Pgp. In the present study, we compared four anthracycines with respect to cell growth inhibition, intracellular accumulation and cellular efflux using the HB8065/R human hepatoma cell line which is rich in Pgp, and the Pgp-poor parental line HB8065/S. The anthracyclines were also administered in conjunction with the Pgp-modifying agents verapamil and SDZ PSC 833 to assess modulation of resistance. The HB8065/R cells were sensitive to aclarubicin (ACL) and highly resistant to epirubicin (EPI), doxorubicin (DOX) and daunorubicin (DNR). SDZ PSC 833 enhanced accumulation, decreased efflux and increased cytotoxicity of EPI, DOX and DNR in the HB8065/R cells, but none of these effects was seen with ACL. In conclusion, ACL is apparently not transported by Pgp and retains its activity in a multidrug-resistant human hepatoma cell line; such properties can be exploited for clinical purposes.

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Section: Discussionsupporting

confidence: 91%

Human hepatoma cells rich in P-glycoprotein are sensitive to aclarubicin and resistant to three other anthracyclines

Lehne

Angelis²,

Clausen³

et al. 1996

Br J Cancer

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“…At identical doses, daunorubicin caused considerably less histamine release in the dog than did doxorubicin. This variation in response might be explained by the differences in structural characteristics of doxorubicin and daunorubicin, since the slight difference in structure between the 2 compounds leads to differences in membrane transport, intracellular accumulation and physiologic handling [16]. The reason a quantitative difference was not detected in the present studies is not known, but could be related to a difference in the route of administration or in the responsiveness of the mast cells of the 2 species.…”

Section: Discussionmentioning

confidence: 55%

Anthracycline-induced histamine release from rat mast cells

et al. 1982

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Comparisons were made of the ability of doxorubicin, daunorubicin, rubidazone and aclacinomycin A to release histamine from rat peritoneal mast cells. Preliminary in vitro experiments indicated that doxorubicin (10(-6) to 2.5 X 10(-4) M), in contrast to compound 48/80 and the calcium ionophore A23187, did not produce significant release under any condition tested when purified or unpurified rat mast cells were used. In in vitro experiments, released histamine was measured in the cell-free supernatant of peritoneal fluid of rats after intraperitoneal injection of the agents. The time course of doxorubicin-induced histamine release from the peritoneum was rapid, with maximal release occurring within 4 to 6 min. Dose-response curves of the 4 agents over the range 10(-5) to 3.3 X 10(-3) M revealed that all caused histamine release, with 10(-3) M concentrations of each causing maximal release of comparable magnitude to that produced by 9.5 X 10(-6) M A23187. Treated mast cells recovered from the peritoneal cavity showed degranulation and vacuolization when examined by electron microscopy. Increased vascular permeability by the Evans-blue test was also noted with all 4 agents, and zones were of comparable size after injection of the highest concentration of each agent. The results indicate that in vivo, doxorubicin, daunorubicin, rubidazone and aclacinomycin A cause a rapid release of histamine from rat mast cells and an increase in vascular permeability in rat sin. There also appeared to be a reasonable correlation between the blueing reaction and histamine release in the peritoneal cavity in that the doses that did not cause skin blueing also failed to cause histamine release. The lack of histamine release by doxorubicin from mast cell preparations in vitro suggests that alterations to the doxorubicin molecule or the presence of other critical substances may be necessary for this activity to commence.

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“…Eichholtz-Wirth [2], Andersson et al [12] and other authors [4,6,8] have also observed that the incorpora tion of anthracyclines into cells was not linear with time, except in some cases during the first 30 min. However, different results have been obtained con cerning the relationship between cytotoxicity and total drug exposure.…”

Section: Discussionmentioning

confidence: 95%

“…Numerous experimental systems have been de veloped in order to understand its cellular pharmaco logy and that of daunorubicin, a related anthracycline mostly active in vivo against leukemias. Those anti cancer drugs, or their derivatives, have been studied especially on HeLa cells [2], CHO cells [3], L 1210 cells [4], P388 cells [5,6], Friend leukemia cells [7], Ehrlich ascites tumor cells [8,9] and sarcoma 180 cells [10]. Cellular pharmacology studies of these drugs have also been conducted on normal cells such as fibro blasts [11] or bone marrow cells [12].…”

Section: Introductionmentioning

confidence: 99%

“…The intracellular con centration of the drugs seems to play an important role in determining the activity of these drugs [2,8,10,12]. This intracellular concentration is thought to be the result of a passive influx of the drugs into the cells, which depends on the amphiphilic properties of the molecules [4], and an active efflux of the drugs out of the cells, which is an energy-requiring process [5,19]. One of the possible causes of resistance of tumors to anthracyclines is ovcractivity of the active efflux process, which prevents the intracellular concentra tion to become high enough to damage the DNA [19].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cellular Pharmacokinetics of Doxorubicin in Cultured Mouse Sarcoma Cells Originating from Autochthonous Tumors

Nguyen-Ngoc¹,

Vrignaud²,

Robert³

1984

Oncology

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We have studied the cellular pharmacology of doxorubicin in a line of mouse sarcoma cells isolated from a dimethylbenzanthracene-induced autochthonous tumor. We have studied the cytotoxicity of the drugs as a function of the exposure dose and of the exposure time to the drug. Cytotoxicity was evaluated as the inhibition of the incorporation of [³H-methyl]-thymidine in the cellular nucleic acids. Intracellular drug concentrations were measured by spectrofluorometry. We have shown that the intracellular drug concentration was a linear function of the extracellular drug concentration up to 5 μg/ml; the cytotoxicity was an exponential function of the exposure dose up to 1 μg/ml, but it was not an exponential function of the exposure time: the cytotoxicity may therefore be very different for similar total drug exposures. Incubation with a low dose for a long time did not provide a cytotoxicity as high as that obtained with a high dose for a short period of time. These results emphasize the role of the peak concentration of doxorubicin for its maximal action in the target cell.

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Cellular pharmacodynamics of several anthracycline antibiotics

Cited by 94 publications

References 3 publications

Human hepatoma cells rich in P-glycoprotein are sensitive to aclarubicin and resistant to three other anthracyclines

Human hepatoma cells rich in P-glycoprotein are sensitive to aclarubicin and resistant to three other anthracyclines

Anthracycline-induced histamine release from rat mast cells

Cellular Pharmacokinetics of Doxorubicin in Cultured Mouse Sarcoma Cells Originating from Autochthonous Tumors

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