Effects of Orally Active Taxanes on P-Glycoprotein Modulation and Colon and Breast Carcinoma Drug Resistance

Vredenburg, Michael; Ojima, Iwao; Veith, Jean; Pera, Paula; Kee, Kristin; Cabral, Fernando; Sharma, Amarnath; Kanter, Peter M.; Greco, William R.; Bernacki, Ralph J.

doi:10.1093/jnci/93.16.1234

Cited by 72 publications

(62 citation statements)

References 41 publications

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“…Recently, several epothilones have been developed, which bind a similar site on tubulin but differ from the taxanes in specific binding characteristics, potency, and cross-resistance (28)(29)(30). A number of microtubule-stabilizing drug regimens are under investigation for refractory metastatic disease (31,32). The current report describes a new drug related to the taxanes, TPI-287.…”

Section: Discussionmentioning

confidence: 99%

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

Fitzgerald

Emerson

Qian

et al. 2012

Molecular Cancer Therapeutics

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Brain metastases of breast and other cancers remain resistant to chemotherapeutic regimens that are effective systemically, in part due to the blood-brain barrier. We report that TPI-287, a new microtubule-stabilizing agent, displays in vitro cytotoxic activity similar to taxanes and epothilones. Unlike the taxanes, TPI-287 is permeable through the blood-brain barrier. Brain-to-plasma ratios of TPI-287 after a single injection typically exceeded one and were as high as 63.8 in the rat and 14.1 in the mouse. A brain-tropic derivative of the MDA-MB-231 triple-negative breast cancer cell line, 231-BR, was used to test whether TPI-287 may be efficacious at preventing or treating brain metastases. TPI-287 had growth inhibitory effects comparable with paclitaxel when 231-BR tumor cells were injected into the mammary fat pad. Brain metastatic colonization was determined by intracardiac injection of 231-BR cells, with treatment beginning on day 3 to 4 postinjection, culminating in a histologic count of brain metastases in brains necropsied days 25 to 28 postinjection. In this assay, paclitaxel, ixabepilone, and nab paclitaxel did not have significant inhibitory activity. TPI-287 was ineffective in the same assay using a 6 mg/kg every week schedule; however an 18 mg/kg dose delivered on days 3, 7, and 11 significantly reduced the outgrowth of brain metastases (55% reduction, P ¼ 0.028) and reduced proliferation in brain metastases (16% reduction, P ¼ 0.008). When TPI-287 treatment was delayed until days 18, 22, and 26 postinjection, efficacy was reduced (17% reduction, not significant). These data suggest that TPI-287 may have efficacy when administered early in the course of the disease.

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Section: Discussionmentioning

confidence: 99%

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

Fitzgerald

Emerson

Qian

et al. 2012

Molecular Cancer Therapeutics

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“…Conversely, 2-day PB28 was shown not to modulate the expression level of another ATP-binding cassette transporter, ABCG2, involved in resistance to topoisomerase I inhibitors (30) and of other proteins, such as epidermal growth factor receptor, Akt, and Erk1/2 (data not shown), suggesting a specific action on P-gp expression of this j 2 agonist and not a generalized protein synthesis inhibition. Moreover, the specificity of the PB28-dependent inhibition of P-gp expression has been confirmed in a different tumor cell model, HCT-15, highly expressing P-gp protein (44). In HCT-15, we preliminarily determined the 2-day PB28 IC 50 concentration (10 Amol/L) and then measured the drug-dependent reduction of P-gp expression by flow cytometry, showing that PB28-treated HCT-15 had a reduced expression of this drug efflux pump of f50% with respect to the untreated cells.…”

Section: Pb28-dependent Modulation Of P-gp and Cytotoxic Activity Of mentioning

confidence: 79%

Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer

Azzariti

Colabufo

Berardi

et al. 2006

Molecular Cancer Therapeutics

109

122

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S Ligands have recently been shown to have cytotoxic activity, to induce ceramide-dependent/caspase-independent apoptosis, and to down-regulate P-glycoprotein (P-gp) mRNA levels in some mouse and human models. In this study, we verified whether a mixed S 2 agonist/S 1 antagonist, PB28, was able to have antitumor activity and to enhance anthracycline efficacy in two human breast cancer cell lines, MCF7 and MCF7 ADR, both characterized by significant S 2 receptor expression, by high and low S 1 receptor expression, and low and high P-gp expression, respectively. In both cell lines, PB28 showed high S 2 receptor affinity and low S 1 receptor affinity; furthermore, it inhibited cell growth with a clear effect at 48 hours (IC 50 in nanomolar range), a consistent time exposure-independent increase of G 0 -G 1 -phase fraction (of f20% of both cell lines) and caspase-independent apoptosis (15% increased after 1-day drug exposure). PB28 also reduced P-gp expression in a concentration-and time-dependent manner (f60% in MCF7 and 90% in MCF7 ADR). We showed also a strong synergism between PB28 and doxorubicin by adopting either simultaneous or sequential schedules of the two drugs. We suggest that this synergism could depend on PB28-induced increase of intracellular accumulation of doxorubicin (f50% in MCF7 and 75% in MCF7 ADR by flow cytometry analysis). In conclusion, we suggest that the S 2 agonist PB28 could be an interesting antitumor agent either in monotherapy or in combination with conventional drugs.

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“…For drug treatments, cells were maintained in logarithmic growth and plated 48 h before addition of 0.4 M paclitaxel (diluted from 1 mM stock in Me 2 SO). The final concentration of Me 2 SO in the culture was Ͻ0.01% (47). For IC 50 measurements, cell survival was measured 24 h after addition of paclitaxel, using a commercial 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test kit (Sigma) as described previously (48).…”

Section: Methodsmentioning

confidence: 99%

“…Whereas the two tumor cell lines could differ in any or all of these respects, many of these variables would be predicted to influence the overall efficacy of the drug but not the relationship between microtubule dynamics and cell proliferation. Drug efflux pumps can diminish the local concentration of paclitaxel in the tumor, and up-regulation of drug-resistant tubulin isoforms or mutants would also protect the tumor from the antiproliferative activity of the drug (22,47,76,78,95). Thus, although both factors could increase the IC 50 , neither should alter the relationship between druginduced inhibition of microtubule dynamics and cell turnover.…”

Section: Fig 6 Effect Of Paclitaxel Dose On Microtubule Dynamics Inmentioning

confidence: 99%

In Vivo Measurement of Microtubule Dynamics Using Stable Isotope Labeling with Heavy Water

Fanara

Turner

Busch

et al. 2004

Journal of Biological Chemistry

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Effects of Orally Active Taxanes on P-Glycoprotein Modulation and Colon and Breast Carcinoma Drug Resistance

Abstract: IDN-5109 modulates Pgp activity, resulting in superior tumor growth inhibition against Pgp-expressing tumors as compared with paclitaxel. IDN-5109 may broaden the spectrum of taxane use to include colon tumors.

Cited by 72 publications

References 41 publications

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer

In Vivo Measurement of Microtubule Dynamics Using Stable Isotope Labeling with Heavy Water

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