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Thomas Litman - One of the best experts on this subject based on the ideXlab platform.
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use of peptide antibodies to probe for the Mitoxantrone resistance associated protein mxr bcrp abcp abcg2
Biochimica et Biophysica Acta, 2002Co-Authors: Thomas Litman, Patricia Fetsch, Andrea Abati, Zhirong Zhan, Ulla Jensen, Alastair Hansen, Kuangming Covitz, Paul R Hansen, Thomas Horn, Torben SkovsgaardAbstract:Recent studies have characterized the ABC half-transporter associated with Mitoxantrone resistance in human cancer cell lines. Encoded by the ABCG2 gene, overexpression confers resistance to camptothecins, as well as to Mitoxantrone. We developed four polyclonal antibodies against peptides corresponding to four different epitopes on the Mitoxantrone resistance-associated protein, ABCG2. Three epitopes localized on the cytoplasmic region of ABCG2 gave rise to high-affinity antibodies, which were demonstrated to be specific for ABCG2. Western blot analysis of cells with high levels of ABCG2 showed a single major band of the expected 72-kDa molecular size of ABCG2 under denaturing conditions. Immunoblot analysis performed under non-reducing conditions and after treatment with cross-linking reagents demonstrated a molecular weight shift from 72 kDa to several bands of 180 kDa and higher molecular weight, suggesting detection of dimerization products of ABCG2. Evidence of N-linked glycosylation was also obtained using tunicamycin and N-glycosidase F. Finally, both by light, fluorescence and electron microscopic immunohistochemical staining, we demonstrate cytoplasmic and predominantly plasma membrane localization of ABCG2 in cell lines with high levels of expression. Plasma membrane staining was observed on the surface of the chorionic villi in placenta. These results support the hypothesis that ABCG2 is an ABC half-transporter that forms dimers in the plasma membrane, functioning as an ATP-dependent outward pump for substrate transport.
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a functional assay for detection of the Mitoxantrone resistance protein mxr abcg2
Biochimica et Biophysica Acta, 2001Co-Authors: Robert W Robey, Keisuke Miyake, Thomas Litman, Yasumasa Honjo, Anne Van De Laar, Joanna Regis, Susan E BatesAbstract:The fluorescent compounds rhodamine 123, LysoTracker Green DMD-26, Mitoxantrone, and BODIPY-prazosin were used with the antagonist fumitremorgin C (FTC) in order to develop functional assays for the half-transporter, MXR/BCRP/ ABCP1. A measure of FTC-inhibitable efflux was generated for each compound in a series of MXR-overexpressing drugselected cell lines and in ten unselected cell lines which were used to determine if the four fluorescent compounds were sensitive enough to detect the low MXR levels found in drug-sensitive cell lines. FTC-inhibitable efflux of Mitoxantrone and prazosin was found in four of the ten cell lines, SF295, KM12, NCI-H460, and A549, and low but detectable levels of MXR mRNA were also observed by Northern analysis in these cells. FTC-inhibitable Mitoxantrone and prazosin efflux in both selected and unselected cell lines was found to correlate well with MXR levels as determined by Northern blotting, r 2 = 0.89 and r 2 = 0.70 respectively. In contrast, rhodamine and LysoTracker were not able to reliably detect MXR. Cytotoxicity assays performed on two of the four unselected cell lines confirmed increased sensitivity to Mitoxantrone in the presence of FTC. FTC was found to be a specific inhibitor of MXR, with half-maximal inhibition of MXR-associated ATPase activity at 1 WM FTC. Short term selections of the SF295, KM12, NCI-H460 and A549 cell lines in Mitoxantrone resulted in a small but measurable increase in MXR by both Northern blot and functional assay. These studies show that flow cytometric measurement of FTC-inhibitable Mitoxantrone or prazosin efflux is a sensitive and specific method for measuring the function of the MXR half-transporter in both selected and unselected cell lines. fl 2001 Elsevier Science B.V. All rights reserved.
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overexpression of the atp binding cassette half transporter abcg2 mxr bcrp abcp1 in flavopiridol resistant human breast cancer cells
Clinical Cancer Research, 2001Co-Authors: Robert W Robey, Keisuke Miyake, Thomas Litman, Douglas D Ross, Wilma Y Medinaperez, Kenryu Nishiyama, Tyler Lahusen, Adrian M Senderowicz, Susan E BatesAbstract:We sought to characterize the interactions of flavopiridol with members of the ATP-binding cassette (ABC) transporter family. Cells overexpressing multidrug resistance-1 (MDR-1) and multidrug resistance-associated protein (MRP) did not exhibit appreciable flavopiridol resistance, whereas cell lines overexpressing the ABC half-transporter, ABCG2 (MXR/BCRP/ABCP1), were found to be resistant to flavopiridol. Flavopiridol at a concentration of 10 μm was able to prevent MRP-mediated calcein efflux, whereas Pgp-mediated transport of rhodamine 123 was unaffected at flavopiridol concentrations of up to 100 μm. To determine putative mechanisms of resistance to flavopiridol, we exposed the human breast cancer cell line MCF-7 to incrementally increasing concentrations of flavopiridol. The resulting resistant subline, MCF-7 FLV1000, is maintained in 1000 nm flavopiridol and was found to be 24-fold resistant to flavopiridol, as well as highly cross-resistant to Mitoxantrone (675-fold), topotecan (423-fold), and SN-38 (950-fold), the active metabolite of irinotecan. Because this cross-resistance pattern is consistent with that reported for ABCG2-overexpressing cells, cytotoxicity studies were repeated in the presence of 5μ m of the ABCG2 inhibitor fumitremorgin C (FTC), and sensitivity of MCF-7 FLV1000 cells to flavopiridol, Mitoxantrone, SN-38, and topotecan was restored. Mitoxantrone efflux studies were performed, and high levels of FTC-reversible Mitoxantrone efflux were found. Northern blot and PCR analysis revealed overexpression of the ABCG2 gene. Western blot confirmed overexpression of ABCG2; neither P-glycoprotein nor MRP overexpression was detected. These results suggest that ABCG2 plays a role in resistance to flavopiridol.
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the multidrug resistant phenotype associated with overexpression of the new abc half transporter mxr abcg2
Journal of Cell Science, 2000Co-Authors: Thomas Litman, Keisuke Miyake, Douglas D Ross, Mariafiorella Brangi, Eric A Hudson, Patricia Fetsch, Andrea Abati, James H Resau, Susan E BatesAbstract:Mechanisms of drug resistance other than P-glycoprotein are of increasing interest as the list of newly identified members of the ABC transport family has grown. We sought to characterize the phenotype of the newly discovered ABC transporter encoded by the Mitoxantrone resistance gene, MXR, also known as ABCP1 or BCRP. The pharmacodynamics of Mitoxantrone and 12 other fluorescent drugs were evaluated by confocal microscopy in four multidrug-resistant human colon (S1) and breast (MCF-7) cancer cell lines. We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein- and MRP-mediated resistance. High levels of cross-resistance were observed for Mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of Mitoxantrone, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression. Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells. Thus, the multidrug-resistant phenotype due to MXR expression is overlapping with, but distinct from, that due to P-glycoprotein. Further, cells that overexpress the MXR protein seem to be more resistant to Mitoxantrone and topotecan than cells with P-glycoprotein-mediated multidrug resistance. Our studies suggest that the ABC half-transporter, MXR, is a potent, new mechanism for conferring multiple drug resistance. Definition of its mechanism of transport and its role in clinical oncology is required.
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reversal of resistance by gf120918 in cell lines expressing the abc half transporter mxr
Cancer Letters, 1999Co-Authors: Michiel De Bruin, Keisuke Miyake, Thomas Litman, Robert W Robey, Susan E BatesAbstract:Abstract The emergence of several newly identified members of the ABC transporter family has necessitated the development of antagonists that are able to inhibit more than one transporter. We assessed the ability of the chemosensitizer GF120918 to function as a multispecific antagonist using cytotoxicity assays, rhodamine and calcein efflux assays, and confocal microscopy in cell lines expressing different multidrug resistance transporters. At a concentration of 1 μM in cytotoxicity assays, GF120918 was able to sensitize both S1-B1-20, a subline expressing P-glycoprotein (Pgp), and S1-M1-80, a subline expressing a newly identified Mitoxantrone transporter, MXR. GF120918 was ineffective in sensitizing MRP-overexpressing MCF-7 VP-16 cells to etoposide as determined by cytotoxicity studies. In flow cytometry experiments, rhodamine 123 efflux in S1-B1-20 cells was decreased at GF120918 concentrations as low as 25–50 nM, with 250 nM giving complete inhibition of rhodamine efflux. Complete inhibition of rhodamine efflux in Mitoxantrone-resistant S1-M1-80 cells required 10 μM. Examination of intracellular Mitoxantrone accumulation by confocal microscopy confirmed higher levels of Mitoxantrone in S1-B1-20 and S1-M1-80 cells when incubated in the presence of GF120918 than when incubated with Mitoxantrone alone. Thus, GF120918 appears to fit the paradigm of a multispecific blocker and is able to block rhodamine and Mitoxantrone efflux by the newly identified Mitoxantrone transporter. Further studies of this compound should be pursued to determine its feasibility for use in the clinic.
Paul Oconnor - One of the best experts on this subject based on the ideXlab platform.
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evidence report the efficacy and safety of Mitoxantrone novantrone in the treatment of multiple sclerosis report of the therapeutics and technology assessment subcommittee of the american academy of neurology
Neurology, 2010Co-Authors: James J Marriott, Janis Miyasaki, Gary S Gronseth, Paul OconnorAbstract:Objective: The chemotherapeutic agent Mitoxantrone was approved for use in multiple sclerosis (MS) in 2000. After a review of all the available evidence, the original report of the Therapeutics and Technology Assessment Subcommittee in 2003 concluded that Mitoxantrone probably reduced clinical attack rates, MRI activity, and disease progression. Subsequent reports of decreased systolic function, heart failure, and leukemia prompted the US Food and Drug Administration to institute a “black box” warning in 2005. This review was undertaken to examine the available literature on the efficacy and safety of Mitoxantrone use in patients with MS since the initial report. Methods: Relevant articles were obtained through a review of the medical literature and the strength of the available evidence was graded according to the American Academy of Neurology evidence classification scheme. Results: The accumulated Class III and IV evidence suggests an increased incidence of systolic dysfunction and therapy-related acute leukemia (TRAL) with Mitoxantrone therapy. Systolic dysfunction occurs in 12% of patients with MS treated with Mitoxantrone, congestive heart failure occurs in 0.4%, and leukemia occurs in 0.8%. The number needed to harm is 8 for systolic dysfunction and 123 for TRAL. There is no new efficacy evidence that would change the recommendation from the previous report. Conclusions: The risk of systolic dysfunction and leukemia in patients treated with Mitoxantrone is higher than suggested at the time of the previous report, although comprehensive postmarketing surveillance data are lacking. Neurology ® 2010;74:1463–1470
Ian F Tannock - One of the best experts on this subject based on the ideXlab platform.
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survival and psa response of patients in the tax 327 study who crossed over to receive docetaxel after Mitoxantrone or vice versa
Annals of Oncology, 2008Co-Authors: Dominik Berthold, Gregory R Pond, R De Wit, Mario A Eisenberger, Ian F TannockAbstract:textabstractBackground: The TAX 327 study compared 3-weekly docetaxel, weekly docetaxel or 3-weekly Mitoxantrone, each with prednisone, for 1006 patients with metastatic hormone-refractory prostate cancer. Survival and symptom control were superior following 3-weekly docetaxel as compared with Mitoxantrone. At progression, many patients were treated with the other drug. Here, we provide a retrospective report of survival and prostate-specific antigen (PSA) response after second-line therapy. Methods: The TAX 327 database provided information about treatment after progression on first-line therapy, and survival has been updated. Investigators were asked to provide information about crossover treatment and serial PSA values. Results: We identified 232 crossover patients. Median survival after crossover was 10 months and did not depend on direction of crossover. Data on PSA response are available for 96 patients: PSA response (≥50% reduction) occurred in 15% of 71 men receiving Mitoxantrone after docetaxel and in 28% of 25 men receiving docetaxel after Mitoxantrone. Median PSA progression-free survival was 3.4 months for Mitoxantrone after docetaxel and 5.9 months for docetaxel after Mitoxantrone. Conclusions: One quarter of men received crossover therapy and survival was similar in the crossover groups. The PSA response rate to docetaxel after Mitoxantrone was higher than that for Mitoxantrone after docetaxel.
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docetaxel plus prednisone or Mitoxantrone plus prednisone for advanced prostate cancer
The New England Journal of Medicine, 2004Co-Authors: William R Berry, Ian F Tannock, Stephane Oudard, Kim N Chi, Ronald De Wit, Jozsef Horti, Anna Pluzanska, Christine Theodore, Nicholas D JamesAbstract:As compared with the men in the Mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P = 0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the Mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with Mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. conclusions When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with Mitoxantrone plus prednisone.
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Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or Mitoxantrone and prednisone.
Journal of Clinical Oncology, 1999Co-Authors: David Osoba, Ian F Tannock, D. Scott Ernst, Alan J. NevilleAbstract:PURPOSE: A combination of Mitoxantrone plus prednisone is preferable to prednisone alone for reduction of pain in men with metastatic, hormone-resistant, prostate cancer. The purpose of this study was to assess the effects of these treatments on health-related quality of life (HQL). PATIENTS AND METHODS: Men with metastatic prostate cancer (n = 161) were randomized to receive either daily prednisone alone or Mitoxantrone (every 3 weeks) plus prednisone. Those who received prednisone alone could have Mitoxantrone added after 6 weeks if there was no improvement in pain. HQL was assessed before treatment initiation and then every 3 weeks using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the Quality of Life Module–Prostate 14 (QOLM-P14), a trial-specific module developed for this study. An intent-to-treat analysis was used to determine the mean duration of HQL improvement and differences in improvement duration between groups of patients...
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use of palliative end points to evaluate the effects of Mitoxantrone and low dose prednisone in patients with hormonally resistant prostate cancer
Journal of Clinical Oncology, 1994Co-Authors: Malcolm J Moore, Ian F Tannock, David Osoba, Alan J. Neville, K Murphy, A Armitage, B Findlay, C M L Coppin, Peter Venner, J WilsonAbstract:PURPOSEThis phase II study was designed to assess the effects of Mitoxantrone with prednisone in patients with metastatic prostate cancer who had progressed on hormonal therapy. The methods of assessment included quality-of-life analyses, pain indices, analgesic scores, and the National Prostatic Cancer Project (NPCP) criteria.PATIENTS AND METHODSPatients received Mitoxantrone 12 mg/m2 intravenously every 3 weeks plus prednisone 10 mg orally daily. All had a castrate serum testosterone and Eastern Cooperation Oncology Group (ECOG) performance status or = 50% or a decrease i...
Katherine A Skorupski - One of the best experts on this subject based on the ideXlab platform.
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randomized phase iii trial of piroxicam in combination with Mitoxantrone or carboplatin for first line treatment of urogenital tract transitional cell carcinoma in dogs
Journal of Veterinary Internal Medicine, 2015Co-Authors: S D Allstadt, Carlos O Rodriguez, B Boostrom, Robert B Rebhun, Katherine A SkorupskiAbstract:Background Reported response rates of transitional cell carcinoma (TCC) in dogs to piroxicam in combination with either Mitoxantrone or carboplatin are similar; however, it is unknown whether either drug might provide superior duration of response. Hypothesis/Objectives To determine if the progression-free interval (PFI) of dogs with TCC treated with Mitoxantrone and piroxicam was different than that of dogs receiving carboplatin and piroxicam. The hypothesis was that the efficacy of Mitoxantrone is no different from carboplatin. Animals Fifty dogs with TCC without azotemia. Methods Prospective open-label phase III randomized study. Either Mitoxantrone or carboplatin was administered every 3 weeks concurrently with piroxicam with restaging at 6-week intervals. Twenty-four dogs received carboplatin and 26 received Mitoxantrone. Results Response was not different between groups (P = .56). None of the dogs showed complete response. In the Mitoxantrone group, there were 2 (8%) partial responses (PR) and 18 (69%) dogs with stable disease (SD). In the carboplatin group, there were 3 PR (13%) and 13 (54%) dogs with SD. The PFI was not significantly different between groups (Mitoxantrone = 106 days; carboplatin = 73.5 days; P = .62; hazard ratio 0.86; 95% confidence interval 0.47–1.56). Dogs with prostatic involvement experienced a shorter survival (median, 109 days) compared to dogs with urethral, trigonal, or apically located tumors; this difference was significant (median 300, 190, and 645 days, respectively; P = .005). Conclusions and Clinical Importance This study did not detect a different in outcome in dogs with TCC treated with either Mitoxantrone or carboplatin in combination with piroxicam.
Ilan G Ron - One of the best experts on this subject based on the ideXlab platform.
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cmf cyclophosphamide methotrexate 5 fluorouracil versus cnf cyclophosphamide Mitoxantrone 5 fluorouracil as adjuvant chemotherapy for stage ii lymph node positive breast cancer results by demographic and clinical subgroups
American Journal of Clinical Oncology, 2002Co-Authors: Ilan G Ron, N Wigler, Riva Borovik, Shulamith Rizel, Adi Shani, Joseph Brenner, Hannan Farbstein, Tamar Peretz, Harold J Brenner, Samario ChaitchikAbstract:A multicenter phase III randomized study comparing the efficacies of two adjuvant polychemotherapeutic regimens in 145 patients with stage II node-positive breast cancer: the standard chemotherapy combination, CMF (cyclophosphamide, methotrexate, 5-fluorouracil), and an experimental protocol, CNF (cyclophosphamide, Mitoxantrone [Novantrone], 5-fluoroura-cil) in which Mitoxantrone replaced methotrexate. The finding of a significant advantage (p = 0.04) in the disease-free survival for those receiving Mitoxantrone (mean survival 4.4 years for CNF versus 2.7 years for CMF) led the authors to break the data down in subpopulations to determine exactly which groups of women responded more favorably to CNF than CMF. An advantage in disease-free survival was found, most notable in four subgroups: Sephardic women, women less than 45 years of age, premenopausal women, and women with 4 to 10 positive axillary lymph nodes. Although the small numbers of women in each of these subgroups rule out drawing definitive conclusions, the trend merits further study to confirm these observations.
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cmf cyclophosphamide methotrexate 5 fluorouracil versus cnf cyclophosphamide Mitoxantrone 5 fluorouracil as adjuvant chemotherapy for stage ii lymph node positive breast cancer a phase iii randomized multicenter study
American Journal of Clinical Oncology, 2001Co-Authors: Ilan G Ron, N Wigler, Riva Borovik, G Brufman, Shulamith Rizel, Adi Shani, Joseph Brenner, Hannan Farbstein, Ari DaleAbstract:A multicenter phase III randomized study compared the efficacies of two adjuvant polychemotherapeutic regimens in 145 patients with stage II node-positive breast cancer. The standard chemotherapy combination, CMF (cyclophosphamide, methotrexate, 5-fluorouracil), was administered to 77 women. The experimental protocol, CNF (cyclophosphamide, Mitoxantrone, 5-FU), in which Mitoxantrone (Novantrone) replaced methotrexate, was given to 68 patients. Follow-up of the 145 patients by six participating hospitals showed no statistically significant difference (p = 0.6) between the two treatment regimens during a median follow-up of 4.5 years in terms of overall survival. There was, however, a significant advantage (p = 0.04) in the disease-free survival for those receiving Mitoxantrone (mean survival 4.4 years for CNF versus 2.7 years for CMF). Toxic side effects associated with CNF (particularly alopecia and myelotoxicity) were relatively more frequent but acceptable and did not lead to dose reduction. In light of its association with improved disease-free survival in this study, larger studies should be undertaken on the role of Mitoxantrone as adjuvant treatment in stage II breast cancer.
