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  • 1
    Electronic Resource
    Electronic Resource
    Antitumour evaluation of dolastatins 10 and 15 and their measurement in plasma by radioimmunoassay (1996)
    Springer
    Cancer chemotherapy and pharmacology 38 (1996), S. 225-232 
    Details
    ISSN: 1432-0843
    Keywords: Key words Dolastatins ; Radioimmunoassay ; Cytotoxicity ; Xenograft ; P-glycoprotein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Dolastatins 10 and 15 are small peptides isolated from the marine sea hare Dolabella auricularia that have been shown to interact with tubulin. Their growth-inhibitory properties were compared using panels of human ovarian and colon-carcinoma cell lines. Both agents were very potent inhibitors of cell growth, with dolastatin 10 being an average of 9.1-fold more potent than dolastatin 15 [mean 50% inhibitory concentrations (IC50 values) 2.3×10–10 and 2.1×10–9 M, respectively; P 〈0.05] and more potent than paclitaxel or vinblastine. While neither dolastatin exhibited marked cross-resistance in cisplatin- or etoposide-resistant cell lines, contrasting effects were observed using an acquired doxorubicin-resistant (CH1doxR, 100-fold resistant, P-glycoprotein overexpressing) cell line. Resistance was significantly higher to dolastatin 15 (12.7-fold) than to dolastatin 10 (only 3.2-fold; P 〈0.05) and was reversible in both cases by verapamil. In vivo, using a s. c. advanced-stage human ovarian carcinoma xenograft and equitoxic doses, greater activity was observed with dolastatin 10 (6.1-day growth delay) versus 0.4 days for dolastatin 15. A radioimmunoassay for dolastatin 10 (limit of detection in mouse plasma 5 ng/ml) was developed. The rabbit antiserum also cross-reacted by 65% with dolastatin 15. Comparative mouse pharmacokinetics following i. v. administration of 1 mg/kg showed that both compounds are rapidly eliminated, but with a shorter second-phase half-life (t 1 /2 β) being observed for dolastatin 15 (being detectable for only up to 4 h post-administration), the t 1 /2 β being 3 times longer for dolastatin 10. In addition, areas under the plasma concentration-time curve (AUC values) were 1.6-fold higher for dolastatin 10 (333 versus 208 ng ml–1 h). Plasma binding of dolastatin 10 exceeded 90%. The highly sensitive RIA will be useful for pharmacokinetic studies in conjunction with the planned phase I clinical trials of these novel, extremely potent, tubulin-binding agents, of which dolastatin 10 appears to possess the more promising preclinical features.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050475
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  • 2
    Electronic Resource
    Electronic Resource
    Immunomodulation in patients receiving intravenous Bryostatin 1 in a phase I clinical study: comparison with effects of Bryostatin 1 on lymphocyte function in vitro (1994)
    Springer
    Cancer immunology immunotherapy 39 (1994), S. 223-230 
    Details
    ISSN: 1432-0851
    Keywords: Bryostatin I ; Clinical study ; Cancer ; LAK ; Interleukin-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Bryostatin 1 is a protein kinase C activator that inhibits growth of tumour cells and activates lymphocytes in vitro, properties that have encouraged its use in phase 1 clinical studies as an anticancer agent. We investigated interleukin-2(IL-2)-induced proliferation and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMC) from cancer patients receiving Bryostatin intravenously. After Bryostatin administration both LAK generation and proliferation were enhanced when patients' PBMC were stimulated with IL-2 in vitro. However, when normal donors' PBMC were cultured in vitro in the presence Bryostatin and IL-2, LAK induction was inhibited while IL-2-driven proliferation was increased. These effects were also seen following only 2 h exposure to Bryostatin and could be elicited by conditioned medium from Bryostatin-pretreated cells. Neither IL-4 nor interferon γ was detected in the conditioned medium. Bryostatin in vitro was found to increase expression of IL-2 receptors on CD4+, CD8+ and CD56+ cells and augment the proportion of CD8+ cells in conjunction with IL-2. We conclude that Bryostatin in combination with IL-2 in vitro enhances proliferation and IL-2 receptor expression on lymphocytes, favouring CD8+ cells while suppressing the generation of LAK activity. Intravenous administration of Bryostatin increases the potential of IL-2 to induce proliferation and LAK activity in lymphocytes which, taken together with its putative direct antitumour effect, makes Bryostatin an interesting candidate for clinical trials in combination with IL-2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01525985
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  • 3
    Electronic Resource
    Electronic Resource
    Immunomodulation in patients receiving intravenous Bryostatin 1 in a phase I clinical study: comparison with effects of Bryostatin 1 on lymphocyte function in vitro (1994)
    Springer
    Cancer immunology immunotherapy 39 (1994), S. 223-230 
    Details
    ISSN: 1432-0851
    Keywords: Key words: Bryostatin 1  –  Clinical study  –  Cancer  –  LAK  –  Interleukin-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Bryostatin 1 is a protein kinase C activator that inhibits growth of tumour cells and activates lymphocytes in vitro, properties that have encouraged its use in phase 1 clinical studies as an anticancer agent. We investigated interleukin-2(IL-2)-induced proliferation and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMC) from cancer patients receiving Bryostatin intravenously. After Bryostatin administration both LAK generation and proliferation were enhanced when patients’ PBMC were stimulated with IL-2 in vitro. However, when normal donors’ PBMC were cultured in vitro in the presence Bryostatin and IL-2, LAK induction was inhibited while IL-2-driven proliferation was increased. These effects were also seen following only 2 h exposure to Bryostatin and could be elicited by conditioned medium from Bryostatin-pretreated cells. Neither IL-4 nor interferon γ was detected in the conditioned medium. Bryostatin in vitro was found to increase expression of IL-2 receptors on CD4+, CD8+ and CD56+ cells and augment the proportion of CD8+ cells in conjunction with IL-2. We conclude that Bryostatin in combination with IL-2 in vitro enhances proliferation and IL-2 receptor expression on lymphocytes, favouring CD8+ cells while suppressing the generation of LAK activity. Intravenous administration of Bryostatin increases the potential of IL-2 to induce proliferation and LAK activity in lymphocytes which, taken together with its putative direct antitumour effect, makes Bryostatin an interesting candidate for clinical trials in combination with IL-2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01525985
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  • 4
    Electronic Resource
    Electronic Resource
    Bryostatin 1 induces productive Epstein-Barr virus replication in latently infected cells: implications for use in immunocompromised patients (1993)
    Springer
    Cancer chemotherapy and pharmacology 33 (1993), S. 89-91 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bryostatin 1 is a novel anti-tumor agent currently undergoing clinical trial. We investigated the effect of this drug on B-lymphocyte cell lines that carry the Epstein-Barr virus and found that it induces these latently infected cells into the production of transforming virus particles over a wide range of concentrations. These results may have clinical implications, particularly with regard to the use of the drug in the immunocompromised patient.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686030
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  • 5
    Electronic Resource
    Electronic Resource
    Comparison of the antitumor activity of bryostatins 1, 5, and 8 (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 271-278 
    Details
    ISSN: 1432-0843
    Keywords: Bryostatin analogs ; Protein kinase C ; Tumor necrosis factor ; Bryostatin blood levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bryostatin 1, a macrocyclic natural lactone isolated from a marine Bryozoan, has undergone phase I testing in humans. Side effects of treatment have included muscle pain and joint aches, a transient decrease in platelets, and the release of tumor necrosis factor alpha (TNFα) and IL-6 into the blood stream. In animals, anticancer activity has been demonstrated against murine leukemias, lymphomas, melanomas, and sarcomas. The mechanism of action of this compound depends in part on its ability to activate protein kinase C. To determine the biologic activity and toxicity of other members of the family of bryostatin compounds, we studied the ability of bryostatins 5 and 8 to inhibit the growth of murine melanoma K1735-M2. Bryostatins 1, 5, and 8 induced equivalent inhibition of melanoma growth, but bryostatins 5 and 8 induced less weight loss than bryostatin 1 (P〈0.001). Neither the injection of an antimurine TNFα antibody nor an adenovirus, which produces a mutated TNF receptor inhibiting TNFα activity, into mice had any effect on either bryostatin-induced weight loss or melanoma tumor growth inhibition. Using a novel competition assay, the levels of bryostatin in the plasma were measured. The approximate half-life (t1/2) of bryostatin was 8.62 min, the clearance (Cl) 3.53 ml/min and the AUC 322.20 nmol/l min. A similar result was obtained with each bryostatin analog. These results suggest that human testing of additional bryostatin analogs may yield compounds with similar antitumor activity but decreased side effects. A novel assay to measure the level of all bryostatins in the plasma of patients undergoing treatment is described.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00688328
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  • 6
    Electronic Resource
    Electronic Resource
    Activity of dolastatin 10 against small-cell lung cancer in vitro and in vivo: induction of apoptosis and bcl-2 modification (1999)
    Springer
    Cancer chemotherapy and pharmacology 43 (1999), S. 507-515 
    Details
    ISSN: 1432-0843
    Keywords: Key words Dolastatin ; Lung cancer ; Apoptosis ; Xenografts ; Experimental therapeutics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Dolastatin 10 is a natural cytotoxic peptide which acts through the inhibition of microtubule assembly. Studies have suggested that such agents can induce apoptosis in association with bcl-2 phosphorylation. Since bcl-2 overexpression is common in small-cell lung cancer (SCLC), we evaluated the activity of dolastatin 10 in SCLC cell lines and xenografts. Methods: In vitro growth inhibition was evaluated with a standardized MTT assay and apoptosis with fluorescent microscopy and a TUNEL assay. Immunoblot analysis and phosphatase digestion were used to determine bcl-2 modification. In vivo activity was evaluated in subcutaneous and metastatic SCLC xenograft models in SCID mice. Results: Dolastatin 10 had growth inhibitory activity against four SCLC cell lines (NCI-H69, -H82, -H446, -H510) with IC50 values ranging from 0.032 to 0.184 nM. All four cell lines exhibited evidence of apoptosis after 48 h of exposure to 1.3 nM dolastatin 10. Immunoblot analysis revealed that 1.3 nM dolastatin 10 altered the electrophoretic mobility of bcl-2 in NCI-H69 and -H510 cells within 16 h of treatment. Incubation of protein extract from dolastatin 10-treated NCI-H69 and -H510 cells with calcineurin resulted in the disappearance of the altered mobility species, suggesting dolastatin 10-induced bcl-2 phosphorylation. In in vivo studies, 450 μg/kg of dolastatin 10 IV × 2 given after intravenous injection of NCI-H446 cells completely inhibited tumor formation. In established subcutaneous NCI-H446 xenografts, 450 μg/kg of dolastatin 10 IV induced apoptosis in the majority of tumor cells within 96 h, resulting in a log10 cell kill of 5.2 and an increase in median survival from 42 to 91 days. Conclusions: These findings suggest that dolastatin 10 has potent activity against SCLC and that the modulation of apoptotic pathways deserves further evaluation as an anticancer strategy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050931
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  • 7
    Electronic Resource
    Electronic Resource
    Positron emission tomography of murine liver metastases and the effects of treatment by combretastatin A-4 (1999)
    Springer
    European journal of nuclear medicine 26 (1999), S. 231-238 
    Details
    ISSN: 1619-7089
    Keywords: Key words: Positron emission tomography ; Fluorodeoxyglucose ; Liver ; Metastasis ; Combretastatin A-4
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract . There are major potential advantages in non-invasive measurement of preclinical tumour biology and therapeutic response in clinically relevant, internal body sites, notably the ability to follow outcome in individual animals rather than averaging results from groups. We have exploited positron emission tomography (PET) to determine the feasibility of detecting liver metastases in B6D2F1 mice using fluorine-18 fluorodeoxyglucose ([18F]FDG) both before and after treatment by the novel cytotoxic agent, combretastatin A-4. The normal distribution of [18F]FDG in the absence of disease was characterised, with the clear delineation of the brain, the heart and the urinary bladder in all studies. In untreated mice with liver metastases, a strong correlation (r 2 = 0.98) was found between the quantitative estimates of [18F]FDG uptake obtained by analysis of PET images, and those obtained from ex vivo assay of liver plus metastases excised immediately after imaging. In this first series, the effective limit of resolution was in livers containing a number of small metastases (range 8–14) with a single volume equivalent of approximately 200 mm3. PET image analysis was concordant with histological measurements in showing that single intraperitoneal doses of combretastatin A-4 resulted in an average 30% volume destruction of metastatic mass by 24 h following administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002590050382
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