654 research outputs found

    OncoLog Volume 46, Number 03, March 2001

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    Researchers Examine Link Between Stress and Response to Cancer Treatment Emotional Side Effects: Section of Behavioral Medicine in Department of Pediatrics Helps Patients and Their Families Cope with Cancer House Call: Getting the Facts About Clinical Trials DiaLog: Where Patient Care and Research Meet, by Leonard A. Zwelling, MD, MBA, Vice President for Research Administration Moving Toward Recovery: Exercise Video Features Adolescents with Cancerhttps://openworks.mdanderson.org/oncolog/1095/thumbnail.jp

    The karabus affair speaks to larger issues for american academic and medical centers.

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    Finally, on March 12, 2013, a major American newspaper, The Wall Street Journal, reported on the plight of Dr. Cyril Karabus (1,2). Dr. Karabus is the 78 year old pediatric oncologist from Claremont, Capetown, South Africa who is well known as the retired head of the Oncology and Hematology Unit of the Red Cross Children’s Hospital, University of Cape Town, as well as for his devoted service to poor children in the apartheid era. In 2002, he cared for a three-year old Yemeni girl with acute myelogenous leukemia during a locum tenens in the United Arab Emirates (UAE)

    Enhanced etoposide sensitivity following adenovirus-mediated human topoisomerase II α gene transfer is independent of topoisomerase II β

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    The roles that the α and β isoforms of topoisomerase II (topo II) play in anticancer drug action were determined using MDA-VP etoposide-resistant human breast cancer cells and a newly constructed adenoviral vector containing the topo IIα gene (Ad-topo IIα). MDA-VP cells were more resistant to etoposide than to amsacrine and had more resistance to etoposide than did MDA-parental cells. MDA-VP cells also expressed lower topo IIα RNA and protein levels than parental cells but had comparable topo IIβ levels. After infection with Ad-topo IIα, topo IIα, RNA and protein levels increased significantly, as did the cells' sensitivity to etoposide. In contrast, topo IIβ levels remained constant with little alteration in the cells' sensitivity to amsacrine. Band-depletion immunoblotting assays indicated that topo IIα was depleted in etoposide-treated, Ad-topo IIα-transduced MDA-VP cells but not in amsacrine-treated cells. Topo IIβ was depleted in amsacrine-treated, Ad-topo IIα-MDA-VP cells, with little change in the topo IIα levels. These results suggest that topo IIα gene transfer does not alter topo IIβ expression and that enhanced sensitivity to etoposide is therefore secondary to change in topo IIα levels. These studies support the theory that etoposide preferentially targets topo IIα, while amsacrine targets topo IIβ. © 2001 Cancer Research Campaign http://www.bjcancer.co

    Mechanism of the formation of DNA–protein cross-links by antitumor cisplatin

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    DNA–protein cross-links are formed by various DNA-damaging agents including antitumor platinum drugs. The natures of these ternary DNA–Pt–protein complexes (DPCLs) can be inferred, yet much remains to be learned about their structures and mechanisms of formation. We investigated the origin of these DPCLs and their cellular processing on molecular level using gel electrophoresis shift assay. We show that in cell-free media cisplatin [cis-diamminedichloridoplatinum(II)] forms DPCLs more effectively than ineffective transplatin [trans-diamminedichloridoplatinum(II)]. Mechanisms of transformation of individual types of plain DNA adducts of the platinum complexes into the DPCLs in the presence of several DNA-binding proteins have been also investigated. The DPCLs are formed by the transformation of DNA monofunctional and intrastrand cross-links of cisplatin. In contrast, interstrand cross-links of cisplatin and monofunctional adducts of transplatin are stable in presence of the proteins. The DPCLs formed by cisplatin inhibit DNA polymerization or removal of these ternary lesions from DNA by nucleotide excision repair system more effectively than plain DNA intrastrand or monofunctional adducts. Thus, the bulky DNA–protein cross-links formed by cisplatin represent a more distinct and persisting structural motif recognized by the components of downstream cellular systems processing DNA damage considerably differently than the plain DNA adducts of this metallodrug

    Altered expression of topoisomerase IIα contributes to cross-resistant to etoposide K562/MX2 cell line by aberrant methylation

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    KRN 8602 (MX2) is a novel morpholino anthracycline derivative having the chemical structure 3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride. To investigate the mechanisms of resistance to MX2, we established an MX2-resistant phenotype (K562/MX2) of the human myelogeneous leukaemia cell line (K562/P), by continuously exposing a suspension culture to increasing concentrations of MX2. K562/MX2 cells were more resistant to MX2 than the parent cells, and also showed cross-resistance to etoposide and doxorubicin. Topoisomerase (Topo) IIα protein levels in K562/MX2 cells were lower of those in K562/P cells on immunoblot analysis and decreased expression of Topo IIα mRNA was seen in K562/MX2 cells. Topoisomerase II catalytic activity was also reduced in the nuclear extracts from K562/MX2 cells when compared with K562/P cells. Aberrant methylated CpG of Topo IIα gene was observed in K562/MX2 cells when compared with the parent line on methylation-specific restriction enzyme analysis. To overcome the drug resistance to MX2 and etoposide, we investigated treatment with 5-Aza-2′-deoxycytidine (5AZ), which is a demethylating agent, in K562/MX2 cells. 5-Aza-2′-deoxycytidine treatment increased Topo IIα mRNA expression in K562/MX2 cells, but not in K562/P cells, and increased the cytotoxicity of MX2 and etoposide. Methylated CpG was decreased in K562/MX2 cells after 5AZ treatment. We concluded that the mechanism of drug resistance to MX2 and etoposide in K562/MX2 cells might be the combination of decreased expression of Topo IIα gene and increased methylation, and that 5AZ could prove to be a novel treatment for etoposide-resistant cell lines, such as K562/MX2

    Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy

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    Despite high tumour response rates to platinum-based chemotherapy in ovarian cancer survival is poor due to the emergence of drug resistance. Mechanistic studies in clinical material have been hampered by the unavailability of sensitive methods to detect the critical drug-induced effects in individual cells. A modification of the single cell gel electrophoresis (comet) assay allows the sensitive detection of DNA interstrand crosslinking in both tumour and normal cells derived directly from clinical material. Tumour cells isolated from 50 ovarian cancer patients were treated ex vivo with 100 μM cisplatin for 1 h and crosslink formation and repair (unhooking) measured. No significant difference in the peak level of crosslinking in tumour cells was observed between patients who were either newly diagnosed or previously treated with platinum-based therapy, or between tumour and mesothelial cells from an individual patient. This indicates no difference in cellular mechanisms such as drug transport or detoxification. In contrast, the percentage repair (unhooking) of DNA interstrand crosslinks was much greater in the group of treated patients. At 24 h in the 36 newly diagnosed patient tumour samples, only one gave >50% repair and 23 gave <10% repair; however, 19 out of 22 treated patient samples gave >10% repair and 14 showed >50% repair. The estimated median difference (newly diagnosed minus treated) was −52 (95% CI −67 to −28), and the P-value from a Mann–Whitney test was <0.001. In eight patients, it was possible to obtain tumour samples prior to any chemotherapy, and also on relapse or at interval debulking surgery following platinum-based chemotherapy. In these patients, the mean % repair prior to therapy was 2.85 rising to 71.23 following treatment. These data demonstrate increased repair of DNA interstrand crosslinks in ovarian tumour cells following platinum therapy which may contribute to clinical acquired resistance
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