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  • 1
    Electronic Resource
    Electronic Resource
    Factors Affecting Topotecan Sensitivity in Human Leukemia Samples (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 803 (1996), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1996.tb26382.x
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  • 2
    Electronic Resource
    Electronic Resource
    MAMMALIAN CASPASES: Structure, Activation, Substrates, and Functions During Apoptosis (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 68 (1999), S. 383-424 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: (a) Zymogen gene transcription is regulated; (b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and (c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.68.1.383
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  • 3
    Electronic Resource
    Electronic Resource
    Effect of adding the topoisomerase I poison 7-ethyl-10-hydroxycamptothecin (SN-38) to 5-fluorouracil and folinic acid in HCT-8 cells: elevated dTTP pools and enhanced cytotoxicity (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. 391-399 
    Details
    ISSN: 1432-0843
    Keywords: Key words Irinotecan ; Deoxynucleotide pools ; Thymidylate synthase ; Fluoropyrimidines ; Colon cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To determine the effect of combined treatment with 7-ethyl-10-hydroxycamptothecin (SN-38, the active metabolite of irinotecan) and 5-fluorouracil/folinic acid (5FU/FA) in vitro using HCT-8 human intestinal adenocarcinoma cells. Methods: Cell survival was examined using colony forming assays. Cell cycle distribution before and after treatment was assessed by flow microfluorimetry. Levels of thymidylate synthase (TS) and topoisomerase I (topo I) in untreated and treated cells were determined by immunoblotting. Changes in deoxynucleotide pools were examined by high-performance liquid chromatography. Results: Clonogenic assays revealed that colony formation was decreased by 50% after a 24-h exposure to 8 ± 2 nM SN-38 or 12 ± 3 μM 5FU, the latter being assayed in the presence of 2 μM FA. When treatment with 5FU/FA was followed by SN-38, the cytotoxicity was similar to that observed with 5FU/FA alone. In contrast, when HCT-8 cells were exposed to both agents simultaneously or to SN-38 followed by 5FU/FA, the cytotoxicity was greater than that of SN-38 or 5FU/FA treatment alone. Investigation of the mechanistic basis for this sequence dependence revealed that SN-38 treatment was associated with a dose- and time-dependent decrease in conversion of [5-3H]-2′-deoxyuridine to [3H]-H2O and thymidylate in intact cells. Immunoblotting failed to reveal any decrease in TS protein that could account for the decreased activity. High-performance liquid chromatography revealed that SN-38 treatment was associated with increased levels of the deoxynucleotide dTTP and decreased levels of dUTP. Flow microfluorimetry revealed that a 24-h treatment with 10 nM SN-38 resulted in accumulation of HCT-8 cells in late S and G2 phases of the cell cycle, with a further increase in the G2 fraction during the 24 h after SN-38 removal. Conclusions: These observations are consistent with a model in which SN-38 sequentially induces diminished DNA synthesis, elevated dTTP pools, inhibition of dUMP synthesis and enhanced toxicity of 5FU/FA. Accordingly, sequencing of irinotecan and 5FU/FA might be important in combining these agents into an effective treatment for colorectal cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050835
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  • 4
    Electronic Resource
    Electronic Resource
    Camptothecin analogues: studies from The Johns Hopkins Oncology Center (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. S53 
    Details
    ISSN: 1432-0843
    Keywords: Topoisomerase I ; Camptothecin ; Cancer chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The camptothecin analogues topotecan and irinotecan (CPT-11) are active anticancer drugs. This article reviews the accumulated results of clinical and laboratory studies performed with these agents at The Johns Hopkins Oncology Center. In a phase I clinical and pharmacology trial of topotecan given as a 30-min infusion daily for 5 days every 3 weeks, profound neutropenia precluded dose escalation above 1.5–2.0 mg/m2 per day, the maximum tolerated dose (MTD). The daily ×5 schedule has been developed further with dose escalation using granulocytecolony-stimulating factor support in patients who have kidney or liver dysfunction and given in combination with cisplatin. In addition, a phase I trial of topotecan given as a 5-day continuous intravenous infusion to patients with refractory leukemia has had promising antileukemic responses. A separate series of in vitro studies indicates that a modest degree of resistance to the cytotoxicity of topotecan can be mediated by P-glycoprotein. A phase I and pharmacology study of irinotecan given as a 90-min infusion every 3 weeks has defined an MTD of 240 mg/m2, with dose escalation being limited by several toxicities. These included an acute treatment-related syndrome of flushing, warmth, nausea, vomiting, and diarrhea; a subacute combination of nausea, diarrhea, anorexia, and weight loss; and/or neutropenia. Antitumor activity has been observed with topotecan and irinotecan in patients with a variety of solid tumors and refractory leukemia in our studies, which supports the widespread enthusiasm for this group of compounds.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00684864
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  • 5
    Electronic Resource
    Electronic Resource
    Apparent cleavage of poly(ADP-ribose) polymerase in non-apoptotic mouse LTA cells: An artifact of cross-reactive secondary antibody (1998)
    Springer
    Molecular and cellular biochemistry 178 (1998), S. 245-249 
    Details
    ISSN: 1573-4919
    Keywords: poly(ADP-ribose) polymerase ; apoptosis ; word ; antibody cross-reactivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Proteolytic cleavage of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) to fragments of 89 kD and 24 kD is widely observed during apoptotic cell death. In the present study, labelling of a Mr ∼89000 polypeptide was demonstrated in untreated mouse LTA cells during probing of immunoblots with C-2-10 monoclonal anti-PARP antibody. The source of the labeling was traced to the secondary antibody preparation, which labeled a Mr ~89000 polypeptide in murine LTA cells but not in human cells. These observations indicate that assessment of PARP cleavage must be (1) performed with appropriate controls when new cell lines are investigated and (2) carefully interpreted in light of additional biochemical or morphological data demonstrating apoptotic changes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006808001462
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  • 6
    Electronic Resource
    Electronic Resource
    Evaluation of 2,6-Diamino-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl) hexanamide (NPC 15437), a protein kinase C inhibitor, as a modulator of P-glycoprotein-mediated resistancein vitro (1995)
    Springer
    Investigational new drugs 13 (1995), S. 285-294 
    Details
    ISSN: 1573-0646
    Keywords: P-glycoprotein ; protein kinase C
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We assessed the effect of the protein kinase C inhibitor 2,6-diamino-N-([1-(1-oxotridecyl)-2-piperidinyl] methyl)hexanamide (NPC 15437) on the action of anthracyclines, epipodophyllotoxins and vinca alkaloids in P-glycoprotein (Pgp)-expressing CHRC5 hamster ovary and MCF-7/AdriaR human breast cancer cells. Flow microfluorimetry revealed that treatment of CHRC5 cells with 75 μM NPC 15437 for 1 h resulted in a 6- to 10-fold increase in the nuclear accumulation of daunorubicin. Colony forming assays revealed that treatment with 75 μM NPC 15437 was associated with a 4-fold decrease in the LD90 for etoposide and a 2.5-fold decrease in the LD50 for vincristine. At higher concentrations of NPC 15437, greater modulation of anthracycline accumulation was observed; but NPC 15437 itself inhibited subsequent colony formation. Similar effects on drug accumulation and cytotoxicity were observed in MCF-7/AdriaR cells. Experiments designed to investigate the mechanism by which NPC 15437 exerts these effects revealed that treatment with the protein kinase C activator phorbol-12-myristate 12-acetate partially reversed the effect of NPC 15437, suggesting that NPC 15437 was exerting an effect through protein kinase C. Photoaffinity labeling experiments revealed that NPC 15437 also inhibited the binding of [3H]-azidopine to Pgp in isolated membrane vesicles. These results identify NPC 15437 as the prototype of a new class of potential Pgp modulators but indicate that the effects of this agent as a modulator are potentially limited by its cytotoxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873134
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