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  • 1
    Electronic Resource
    Electronic Resource
    Clinical pharmacology of the biological response modifier maleic anhydride divinyl ether copolymer (MVE-2) (1986)
    Springer
    Cancer chemotherapy and pharmacology 18 (1986), S. 243-246 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The anionic pyran copolymers represent a novel class of high molecular weight biological response modifiers with antitumor activity. Clinical pharmacology studies were performed on MVE-2, a polymer with an average molecular weight of 15.5 Kd. MVE-2 was analyzed in plasma and urine by HPLC. In addition, pharmacology studies were also performed using [14C] labeled MVE-2. The clearance of unlabeled MVE-2 from plasma was monophasic and the t1/2 for MVE-2 was extremely short (between 10 and 26 min). The apparent volume of distribution (Vd) varied from 12–18 l. Both the t1/2 and the Vd did not appear to be dose-dependent. The plasma clearance for [14C] labeled MVE-2 was studied in seven patients. The clearance of [14C] labeled MVE-2 fit a biphasic mathematical model. The alpha phase half-life was between 11 and 18 min while the beta phase half-life was between 70 and 85 min. Urinary excretion for either unlabeled drug or the [14C] label was between 30 and 45% of the administered dose. These studies show that, in man, the polyanionic macromolecule MVE-2 is cleared rapidly from plasma and excreted extensively in urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00273395
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and tissue disposition of the biological response modifier BAY i 7433 (copovithane) in patients with cancer (1986)
    Springer
    Cancer chemotherapy and pharmacology 18 (1986), S. 247-251 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Copovithane is an uncharged, water-soluble, synthetic polymer with an average molecular weight of 5800 daltons. It demonstrates antitumor activity in vivo against a variety of tumors in animal models but is inactive in vitro. This agent has been found to have immunorestorative activity in man. In concert with its phase I clinical trial, copovithane concentrations were analyzed by HPLC in plasma, urine, and autopsy and in tumor biopsy specimens obtained from patients. Copovithane was cleared from plasma biphasically with a mean t1/2α of 11.1±4 min and a t1/2β of 246±78 min at the dose of 1 g/m2, while the plasma half-lives increased to 57.7±12 and 718±149 for the alpha and beta phases, respectively, at the 10 g/m2 dose, demonstrating clear, dose-dependent pharmacokinetics. There were no significant differences between dose 1 and dose 4 pharmacokinetics. The apparent volume of distribution (Vd) was 14.5±1. at the 1 g/m2 dose and increased to 73 1. at the 33 g/m2 dose. The calculated mean clearance rate for copovithane in plasma was between 2.4 and 5.4 mg/kg x min and did not appear to be dose-dependent. The urinary excretion of copovithane was approximately 5% of the administered dose over 120 h at the 1 g/m2 dose and decreased to 1% at the 33 g/m2 dose. In seven tumor biopsy samples, concentrations of drug in tumor varied from 1- to 1000-fold higher than that found in concurrent plasma samples. In three autopsy samples, the highest concentrations were found in kidney, intestine, and liver, in decreasing order. These studies show that copovithane exhibits dose-dependent changes in pharmacokinetics at doses between 1 and 33 g/m2. However, copovithane does penetrate well to tumor tissues, achieving high tumor/plasma ratios. In addition, copovithane concentrations were highest in kidney tissue, which may be a site for potential organ toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00273396
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  • 3
    Electronic Resource
    Electronic Resource
    Growth inhibitory effect of recombinant α and β interferon on human glioma cells (1987)
    Springer
    Journal of neuro-oncology 5 (1987), S. 323-330 
    Details
    ISSN: 1573-7373
    Keywords: recombinant interferon ; glioma cells ; in vitro
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Growth inhibitory activity of recombinant α and β interferon on two human glioma cell lines, EFC-2 and KE cells, was determined by two different growth assays. Recombinant β interferon showed β slight growth inhibitory effect on EFC-2 cells at day 3, and maximum inhibition was seen on day 6 with an ID50 of 50 U/ml. Recombinant α interferon showed no significant growth inhibition at any concentration. KE cells were resistant to both recombinant α and β interferon. The growth inhibitory activity of recombinant β interferon on EFC-2 cells was not blocked by recombinant α interferon, although recombinant α and β interferons shared same receptors on EFC-2 cells. Addition of DFMO (α-difluoromethylornithine) to interferon in the media showed additive effect rather than synergistic effect in growth inhibition of glioma cells. Out of 7 glioma cell lines tested, 4 showed heterogeneous sensitivity to recombinant β interferon, and all were resistant to recombinant α interferon. These results suggest β differential sensitivity of EFC-2 cells to recombinant β interferon, as well as a heterogeneous sensitivity to recombinant β interferon among different glioma cell lines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00148389
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  • 4
    Electronic Resource
    Electronic Resource
    Phase I study of cancer therapy with recombinant interleukin-2 administered by intravenous bolus injection (1989)
    Springer
    Biotherapy 1 (1989), S. 215-226 
    Details
    ISSN: 1573-8280
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Sixty-six patients with disseminated malignancy were treated with recombinant interleukin-2 (IL-2) on a three times a week (M, W, F) IV-bolus injection schedule. Doses ranged from 0.001 to 14.0 × 106 units/M2 body surface area. Consecutive groups of 3-5 patients were placed on each dose level and were maintained on that level except for dosage de-escalation for toxicity. Toxicity to all major organ systems were noted with major toxicity including fever and chills, anorexia, fatigue and malaise, arthralgias and arthritis as well as hepatic and renal toxicity. All toxicity reversed within one week of drug cessation. Renal toxicity manifested by azotemia, arthritis and fatigue were the common dose limiting toxicities and the maximally tolerated dose was 12 × 106 units/M2. Pharmacokinetic studies indicated a short half-life (T 1/2α = 7–23 minutes). At doses over 0.5 × 106 units/M2 increases in absolute lymphocytes and eosinophil counts were noted. All T lymphocyte subsets increased. Maximal increases were seen at 4–8 × 106 units/M2 with a lesser increase at 10–14 × 106 units/M2 dosage level. Circulating NK cells also increased while circulating LAK cells were detected during therapy. Partial responses were noted in 3 patients with melanoma. These lasted 4, 6 and 16 months and involved pulmonary, pulmonary plus mesenteric and retro-orbital plus hepatic metastases respectively in these patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02170890
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  • 5
    Electronic Resource
    Electronic Resource
    Early events in the antiproliferative action of tumor necrosis factor are similar to the early events in epidermal growth factor growth stimulation (1989)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 41 (1989), S. 139-157 
    Details
    ISSN: 0730-2312
    Keywords: epidermal growth factor receptor ; tyrosine kinase activity ; phosphorylation ; c-myc ; control of cell growth ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The process of TNF-induced cytotoxicity is complex but appears to be mediated through a TNF-specific cell surface receptor. Recent evidence suggests that TNF action on tumor cells may be antagonized by epidermal growth factor (EGF) and other EGF-receptor modulatory peptides implicating a role for EGF-R in the process of TNF-induced cytotoxicity. In the present report, we investigated the biochemical actions of TNF of several biochemical events known to occur in the process of EGF signal transduction in intact cells. The actions of TNF were compared directly to those of EGF in both TNF-sensitive and -resistant tumor cell lines.In TNF-sensitive ME-180 cervical carcinoma cells, TNF (20 ng/ml) stimulated the tyrosine protein kinase activity of the EGF-receptor (EGF-R) fivefold when measured by receptor autophosphorylation in an immune complex kinase assay. TNF activation of EGF-R kinase activity in ME-180 was measurable 10 min after TNF incubation and enzymatic activity remained elevated 20 min after TNF addition. Activition of the receptor by TNF correlated with increased 32P incorporation into EGF-R protien when receptor was immunoprecipitated from 32P-equilibrated cells following a 20 min incubation with TNF. Acid hydrolysis of EGF-R protein isolated from TNF-treated ME-180 cells demonstrates an increase in the phosphotyrosine content of EGF-R when compared to receptor isolated from untreated cells. The results suggest that TNF increased EGF-R tyrosine protein kinase activity and the state of EGF-receptor tryosine phosphorylation in a manner similar to that reported for EGF. However, TNF does not appear to be structurally related to EGF since TNF was unable to directly activate EGF-R when incubated with extensively washed immunoprecipitates of EGF-R.In TNF-resistant T24 bladder carcinoma cells, TNF failed to alter EGF-R tyrosine protein kinase activity although both EGF and phorbol ester were shown to modulate the enzymatic activity of the receptor in these cells. These results indicate that the ability of TNF to modulate EGF-R kinase in target cells may correlate with its cytotoxic actions on TNF-sensitive tumor cells.Other biochemical activities associated with the induction or regluation of cellular growth were examined in TNF- or EGF-treated tumor cells. EGF stimulated a rapid 8-16-fold increase in the expression of the proto-oncogene c-myc when analyzed by dot-blot analysis of total cellular RNA or Northern blot hybridization of polyadenylated RNA. TNF treatment failed to alter c-myc expression in ME-180 cells when analyzed by either technique. The two structurally distinct peptides, TNF and EGF, induced similar patterns of ornithine decarboxylase activity (the rate-limiting enzyme in polyamine biosynthesis) in ME-180 cells but differed in their relative magnitude of maximal induction. Similar results were obtained in TNF- or EFG-treated T24 cells, suggesting the effects of TNF on polyamine biosynthesis are not related to its cytotoxic mechanism of action. These results indicate that TNF shares some of the early biochemical actions of EGF in tumor cells and some of these effects may be related to the mechanism of TNF-induced cytotoxicity.
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240410305
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