The relationship between cisplatin sensitivity and drug uptake into mammalian cells in vitro

Eichholtz-Wirth, H.; Hietel, B.

doi:10.1038/bjc.1986.168

Cited by 53 publications

(16 citation statements)

References 6 publications

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“…We found that cisplatin accumulation was not saturable up to 500 gM which agrees with other studies in a variety of tissue types (Eichholtz-Wirth & Hietel, 1986;Hecquet et al, 1986;Hromas et al, 1987;Andrews et al, 1988). Although this suggests that transport of cisplatin may occur Figure 5 Loss of cisplatin over a 120 min period from 41M (0) and 41McisR6 (A) cell lines preincubated with cisplatin.…”

Section: Accumulation Of Novel Platinum (Iv) Complexessupporting

confidence: 80%

Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes

Loh

Mistry²,

Kelland³

et al. 1992

Br J Cancer

157

103

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SummaryAcquired resistance to cisplatin (cis-diamminedichloroplatinum (II)) has been generated in vitro in the 41M The 4lMcisR6 cells were not found to be cross-resistant to ouabain, a postulated specific inhibitor of sodium-potassium adenosine triphosphatase (Na+, K+-ATPase), suggesting that decreased cisplatin accumulation in these cells is probably not regulated by alterations in their Na+, K+-ATPase levels, and Na+ potential across the plasma membrane. Cellular accumulation of a novel class of platinum (IV) ammine/cyclohexylamine dicarboxylates, which exhibit enhanced cytotoxicity over cisplatin and completely circumvent resistance to cisplatin in the 41McisR line, was also examined. The data suggests that increased accumulation of these compounds, as a result of their enhanced lipophilicity, could account for the dramatic increase in their potency over cisplatin.

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Section: Accumulation Of Novel Platinum (Iv) Complexessupporting

confidence: 80%

Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes

Loh

Mistry²,

Kelland³

et al. 1992

Br J Cancer

157

103

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“…Although both cisplatin and carboplatin contain a platinum backbone, cisplatin is a predecessor of carboplatin with a 100-fold faster rate of intracellular activation and a significantly higher rate of side-effects [42][43][44]. Furthermore, cell lines used in this study have varying cell cycle/ doubling times, and varying sensitivity toward platinum agents has been reported in different mammalian cell lines [45]. Taken together, we hypothesize that these different variables contribute to the differences observed in this study between cell lines and platinum-based chemotherapy regimens.…”

Section: Discussionmentioning

confidence: 96%

Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption

Lysov

Swystun

Kuruvilla³

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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Lung cancer patients undergoing chemotherapy have an elevated risk for thrombosis. However, the mechanisms by which chemotherapy agents increase the risk for thrombosis remains unclear. The aim of this study was to determine the mechanism(s) by which lung cancer chemotherapy agents cisplatin, carboplatin, gemcitabine, and paclitaxel elicit increased tissue factor activity on endothelial cells, A549 cells, and monocytes. Tissue factor activity, tissue factor antigen, and phosphatidylserine exposure were measured on chemotherapy-treated human umbilical vein endothelial cells (HUVEC), A549 cells, and monocytes. Cell surface protein disulfide isomerase (PDI) and cell surface free thiol levels were measured on HUVEC and A549 non-small cell lung carcinoma cells. Treatment of HUVECs, A549 cells, and monocytes with lung cancer chemotherapy significantly increased cell surface tissue factor activity. However, elevated tissue factor antigen levels were observed only on cisplatin-treated and gemcitabine-treated monocytes. Cell surface levels of phosphatidylserine were increased on HUVEC and monocytes treated with cisplatin/gemcitabine combination therapy. Chemotherapy also resulted in increased cell surface levels of PDI and reduced cell surface free thiol levels. Glutathione treatment and PDI inhibition, but not phosphatidylserine inhibition, attenuated tissue factor activity. Furthermore, increased tissue factor activity was reversed by reducing cysteines with dithiothreitol. These studies are the first to demonstrate that lung cancer chemotherapy agents increase procoagulant activity on endothelial cells and A549 cells by tissue factor decryption through a disulfide bond formation in a PDI-dependent mechanism.

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“…Little information has so far been provided, however, on the approach with combination chemotherapy at the tumour mass level. Sensitivity of a cell to DXR and DDP is known to be highly related to the intracellular drug concentration (Eichholtz-Wirth & Hietel, 1986;Iliakis & Lazor, 1987). Any means to increase the drug penetration into MTS should improve drug concentration within the cells in the MTS core.…”

Section: Discussionmentioning

confidence: 99%

Interactions of doxorubicin and cis-platin in squamous carcinoma cells in culture

Kohno

Ohnuma²,

Kaneko³

et al. 1988

Br J Cancer

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Summary Doxorubicin (DXR) has a positive inoculum effect and penetrates poorly into the core of multicellular tumour spheroids (MTS). Cis-platin (DDP) displays neither of these characteristics. We evaluated whether combining these 2 agents would influence the cell kill effect at a tumour mass level. MTS were produced from a PC-10 squamous lung carcinoma cell line. MTS were exposed to either drug first for h with different intervals between exposure. Cells were then trypsinized to a single cell suspension and subjected to clonogenic assay. Combination effects were analyzed by median effect plot analysis. The more MTS ml-' medium, the lower the cell kill effect of DXR. Simultaneous exposure to the 2 drugs was synergistic. DXR exposure first followed by DDP was less efficacious than, or the same as, the simultaneous exposure. In contrast, DDP followed by DXR was more efficacious with the best cell kill at a 1 h interval between each drug. This phenomenon was observed even at non-toxic doses of DDP. The fluorescent microscopic study of DXR indicated that prior exposure of MTS to DDP resulted in increased DXR penetration into the MTS core leading to heightened synergism with this sequence. These data suggest that the proper combination of DXR plus DDP should be in sequence with DDP first. Clinical, toxicological and pharmacological trials of DDP administration first, followed by DXR, are warranted.Doxorubicin (DXR) and cis-platin (DDP) are both highly active anticancer agents widely used in the treatment of human cancer. We introduced a combination of these 2 agents, termed A & P (adriamycin and platinum) (Vogl et al., 1976), which has become the basis, by adding more drugs, for the treatment of patients with ovarian cancer, small cell lung cancer and other neoplasms. Recently, we have demonstrated that DXR has a positive inoculum effect in vitro and loses efficacy at high cell densities, whereas DDP does not (Ohnuma et al., 1986). Moreover, we have shown that DXR penetrates poorly into the core of multicellular tumour spheroids (MTS) whereas DDP shows no such penetration gradient (Inoue et al., 1985). These pharmacological differences at the tumour mass level indicate that DXR should be best used when tumour size is small and cell density low. Therefore, we hypothesized that the proper sequence of A & P should be DDP first, followed by DXR, rather than vice versa. This communication sets forth the experimental proof of our hypothesis and elucidates a possible mechanism for this effect. Materials and methodsHuman tumour cell line PC-10 squamous lung carcinoma cell line was used in these experiments (Kinjo et al., 1979). Cells were maintained as a monolayer in RPMI-1640 medium (GIBCO, Grand Island, NY), supplemented with 10% (v/v) heat-inactivated foetal bovine serum (FBS) (Gibco) at 37"C in a 5% CO2/95% humidified air atmosphere. These cells were subcultured after trypsinization with 0.2% trypsin (Type III from Conditions of drug exposure and determination of cell survival After 3 weeks of culture, MTS with a diame...

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The relationship between cisplatin sensitivity and drug uptake into mammalian cells in vitro

Cited by 53 publications

References 6 publications

Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes

Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes

Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption

Interactions of doxorubicin and cis-platin in squamous carcinoma cells in culture

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