A phase I study on the reversal of multidrug resistance (MDR) in vivo: nifedipine plus etoposide

Philip, P. A.; Joel, S.; Monkman, S. C.; Dolega-Ossowski, E.; Tonkin, Katia; Carmichael, J.; Idle, J R; Harris, Adrian L.

doi:10.1038/bjc.1992.53

Cited by 58 publications

(24 citation statements)

References 19 publications

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“…These data, together with the observation that compounds 1 and 2 at equitoxic concentrations affect doxorubicin antiproliferative activity similarly to the parent nifedipine or to the active diltiazem-like compounds [24], may imply the existence of other cytotoxic mechanisms of action different from the inhibition of Pgp-170, still to be determined, and possibly acting sinergistically with the mechanism here studied. On the other hand the fact that both 1 and 2 do not increase the doxorubicin activity reaching that observed in A2780 cells, in terms of MTT activity and drug accumulation, is in part counteracted by the observation that also nifedipine, an active compound that has reached the clinical phase studies [18,19], has a similar activity in our experimental conditions.…”

Section: Discussioncontrasting

confidence: 69%

“…Among these, nifedipine has been tested at different doses in clinical trials as an MDR reversing agent without reaching objective responses and observing the expected doselimiting toxicity due to the cardiovascular activity of this Ca ++ antagonist [18,19]. About the other compounds, in general, they have not reached the experimentation in clinical trials.…”

Section: Introductionmentioning

confidence: 97%

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Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: an in vitro analysis

et al. 2009

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We report herein the reversal of multidrug resistance-1 (MDR1) in A2780/DX3 cells by the two nifedipine-like compounds 1 and 2 that are part of a library of 1,4-dihydropyridines (1,4-DHPs) calcium-channel modulators bearing in C-4 a different substituted imidazo[2,1-b]thiazole system. By methylthiazol tetrazolium (MTT) assay, cytofluorimetry, and fluorescence microscopy we evaluated their ability to reverse MDR in our cell system. Moreover, together with compound 3 (the diltiazem-like 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one) we analyzed their ability to potentiate the triggering of apoptosis after exposure to doxorubicin, through the nuclear morphological analysis after 4',6-diamidino-2-phenylindole (DAPI), the fluorescein isothiocyanate (FITC)-Annexin-V/propidium iodide (PI) staining and the caspase activity determination. Our results demonstrate that compounds 1 and 2, at concentrations showing a very low (5%) or absent inhibition of cell proliferation, in combination with doxorubicin enhance its antiproliferative activity (from 30% to 54% IC(50) reduction) in A2780/DX3 cells through an increase of doxorubicin intracellular accumulation. These compounds together with compound 3, which has already been demonstrated to act as a potent inhibitor of MDR1 function, were also able to significantly potentiate the activation of the apoptosis machinery triggered by the exposure to doxorubicin. In conclusion, our results identify two new molecules structurally related to the calcium-channel blocker nifedipine, but characterized by a very low LTCC blockers activity, able to potentiate the antiproliferative and apoptotic activities of doxorubicin through an increase of its intracellular concentration likely caused by the inhibition of MDR1 function.

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Section: Discussioncontrasting

confidence: 69%

Section: Introductionmentioning

confidence: 97%

Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: an in vitro analysis

et al. 2009

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“…In clinical trials promising results have been observed in patients with multiple myeloma, lymphoma and leukemia (Dalton et al 1989;Solary et al 1992;Sonneveld et al 1992;List et al 1993). In studies with solid tumours chemosensitizers showed less efficacy with responses in a minority of the patients only (Miller et al 1988;Bissett et al 1991;Philip et al 1992;Verweij et al 1991). Besides, some authors have reported on enhancement of toxic side-effects, like myelosuppression, by the addition of chemosensitizers to the therapeutic regimen (Fiqueredo et al 1990;Verweij et al 1991; Yahanda et al 1992).…”

Section: Introductionmentioning

confidence: 91%

The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat

Vrie

Jonker²,

Marquet

et al. 1994

J Cancer Res Clin Oncol

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Abstract:The feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubicin without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%-33% higher doses, because of the enhanced toxicity of the combination treatment.

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“…Cells were plated in 96-well tissue culture dishes and assayed after 3 days exposure to doxorubicin in a concentration range from 5 x 10"8 to 5 x 10"12 M (30). achieved in patients because the agents chosen were developed for other indications (9)(10)(11)(12)(13). Responses have often been few in number, and short-lived.…”

mentioning

confidence: 97%

Reversal of Multidrug Resistance

Se¹,

Zhan²,

Dickstein³

et al. 1994

Journal of Hematotherapy

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Bone marrow transplantation arose from the realization that dose intensification could improve the response to cytotoxic chemotherapy in some patients. Likewise, experiments evaluating cytotoxicity in the laboratory often demonstrate a steep dose-response curve, in which a threefold increase in drug concentration can result in a major decrease in cell survival. If all cancer cells fell within the same range of sensitivity, then the dose intensity achieved by the addition of bone marrow transplantation would provide effective treatment for all cancers.In truth, broad variations exist in chemosensitivity, both within a given type of cancer and among different tumor types. Figure 1 displays doxorubicin dose response curves from the National Cancer Institute (NCI) drug screen database. In vitro cytotoxicity assays are performed simultaneously in an automated fashion on 60 cell lines and are displayed in disease-oriented panels. The IC50s (the concentration at which 50% of cells are growth inhibited) for doxorubicin vary over a 1000-fold concentration range. These major variations in chemosensitivity in cancer cell lines, derived principally from patients who had received no prior therapy, are most likely caused by a diverse assortment of drug resistance mechanisms, which will ultimately limit the success of the dose intensification achieved by bone marrow transplantation.One mechanism of drug resistance that has been studied intensively is that mediated by P-glycoprotein (Pgp), a 170 kilodalton membrane glycoprotein known to transport certain chemotherapeutic agents out of the cell (1,2). Pgp, which is encoded by the mdr-1 gene, mediates resistance in vitro to important chemotherapeutic agents, including doxorubicin, paclitaxel, daunorubicin, vinblastine, vincristine, VP-16 (etoposide), and mitoxantrone, by active efflux of the chemotherapeutic agent (1). In vitro, multidrug resistance can be reversed by the addition of agents that are also recognized by Pgp but are less toxic and, in large concentrations, block the efflux of chemotherapy. These agents include verapamil, cyclosporine, phenothiazines, and dihydropyridines (3). Even cells with very high levels of Pgp and several-hundredfold resistance can have efflux blocked by the concurrent addition of a Pgp antagonist with the chemotherapy. An example of Pgp antagonism is shown in Fig. 2 in SW620 Ad5, a multidrug-resistant human colon carcinoma subline with relatively low levels of Pgp, derived from SW620 parental cells by selection in Adriamycin. Rhodamine fluorescence is measured by fluorescenceactivated cell sorting analysis as an assay of Pgp function (4-8). An initial incubation with rhodamine is followed by a 120 minute incubation in rhodamine-free media to allow the Pgp-mediated efflux of rhodamine. A decrease in rhodamine fluorescence is observed after the efflux period, which is consistent with Pgp-mediated efflux. Both verapamil and cyclosporine A prevent the decrease in fluorescence by impeding efflux. There is no doubt that in laboratory models Pgp is ab...

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A phase I study on the reversal of multidrug resistance (MDR) in vivo: nifedipine plus etoposide

Cited by 58 publications

References 19 publications

Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: an in vitro analysis

Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: an in vitro analysis

The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat

Reversal of Multidrug Resistance

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