A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.     

Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha.

OBJECTIVE: We investigated whether monocyte-derived factors could stimulate the growth of ovarian cancer cells. STUDY DESIGN: Human peripheral blood monocytes or human monocyte-like cell lines THP-1 and U-937 were cultured with or without macrophage colony-stimulating factor, lipopolysaccharide, or phorbol myristate acetate. Culture supernatants or recombinant cytokines were assayed for growth stimulation of ovarian cancer cell lines by tritium-thymidine incorporation and direct cell counts followed by statistical analysis with Student t test. RESULTS: Conditioned medium from peripheral blood monocytes or from THP-1 or U-937 cells stimulated ovarian cancer cell growth. Interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 also stimulated ovarian cancer cell growth, whereas macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factor did not. Concentrations of tumor necrosis factor, interleukin-1, and interleukin-6 in conditioned medium could not account for all the growth stimulation, and activity remained after neutralization of tumor necrosis factor, interleukin-1, and interleukin-6 with antibodies. CONCLUSIONS: Interleukin-1, interleukin-6, tumor necrosis factor, and additional monocyte factor(s) could provide paracrine growth stimulation when monocytes are attracted to ovarian cancers that produce macrophage colony-stimulating factor.     

Relation of 5'-nucleotidase and phosphatase activities with immunophenotype, drug resistance and clinical prognosis in childhood leukemia.

Ecto-5'-nucleotidase (ecto-5'NT) catalyzes the extracellular dephosphorylation of nucleotides like IMP. Cytoplasmic 5'NT (cyto-5'NT) and non-specific (e.g. acid- and alkaline) phosphatases (AP) regulate the intracellular degradation of nucleotides. High NT and AP activities might cause a resistance to the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We studied the relation between these enzymes and immunophenotype, drug resistance and prognosis in 77 children with acute lymphoblastic leukemia (ALL). Enzyme activities were assessed radiochemically; in vitro drug resistance was measured with the MTT assay. AP activities were higher in T-ALL and B-ALL than in precursor B-ALL. Cyto-5'NT activity was very low in all phenotypes and accounted for a significant proportion of total IMPase activity only in the very immature CD10- c mu- precursor B-ALL. CD10+ ALL cases with high ecto-5'NT activities showed a trend (p = 0.065) for a lower probability of continuous complete remission than those with a low activity. Ecto-5'NT activity was not related to in vitro drug resistance to 6-TG. A weak correlation was found between in vitro 6-TG resistance and cyto-5'NT and AP activities. We conclude that high ecto-5'NT activities do not cause a resistance to 6-thiopurines in childhood ALL. Some patients have high cyto-5'NT and AP activities associated with 6-thiopurine resistance.     

Amphotericin B serum levels in pediatric bone marrow transplant recipients

We studied amphotericin B (AMB) serum levels (n = 590) in 41 pediatric patients, who underwent allogeneic (21) or autologous (20) bone marrow transplantation (BMT). All patients received AMB orally as part of a total gut decontamination; 30/41 patients (73%) had AMB i.v. either for prophylaxis or therapy of fungal infections. Rapid initial dose escalation of AMB and the infusion over 1 h only were well tolerated by the children. Serum level monitoring allowed AMB long-term treatment safely to be administered in children suffering from transplantation-related complications (veno-occlusive disease of the liver, graft-versus-host disease of the liver). An h.p.l.c. method was used for monitoring AMB serum trough levels to avoid levels exceeding 2 mg/l. One lethal fungal infection was observed in 41 pediatric BMT recipients (2.4%). Rapidly increasing doses of AMB at start of therapy and drug monitoring by h.p.l.c. might help to reduce fungal mortality and renal toxicity by a dose sparing effect in BMT recipients.     

Effects of chronic ethanol consumption and pair feeding on rates of protein synthesis and nucleic acid composition in rat tibia.

An investigation was made into the chronic effects of ethanol feeding on bone (represented by the tibia). Treated rats were fed a liquid diet containing ethanol as 36% of total calories, and controls were pair-fed identical amounts of the same diet in which ethanol was substituted by isocaloric glucose. Bone DNA and RNA contents in ethanol-fed rats were not significantly different from glucose-fed controls at days 3, 7, 14, 28 and 42 of treatment. Fractional rates of bone protein synthesis were measured with [43H]-phenylalanine. At 3, 7, 14, 28 and 42 days, ethanol feeding had no effect on free and protein-bound specific radioactivities, nor on fractional or absolute rates of protein synthesis. Synthesis rates relative to RNA (RNA activities) and DNA (cellular efficiencies) were also not significantly altered by ethanol feeding at these time points. Comparisons were made between rats fed a standard solid laboratory diet ad libitum (i.e. normal rats), and those fed restricted amounts of glucose-containing liquid diet (i.e. dietary-restricted rats) for 42 days. In normal rats, there was an increase in tibial mass and accretion of total collagen content, but in dietary-restricted rats, this accretion was markedly impaired. Furthermore, whilst RNA and DNA contents were increased in tibia of normal rats, the contents of these nucleic acids were reduced in bones of dietary restricted rats. Fractional rates of bone protein synthesis in normal rats were unaltered after 42 days, but reduced by feeding the control liquid diet in restricted amounts.(ABSTRACT TRUNCATED AT 250 WORDS)     

NMR Microscopy of Single Neurons Using Spin Echo and Line Narrowed 2DFT Imaging

NMR microimages of single neural cells were acquired at 500 MHz using a conventional spin echo pulse sequence and a line-narrowing sequence that eliminates susceptibility effects. The data show that any contribution to the measured T₂ relaxation rate arising from diffusion in local field inhomogeneities using spin echo sequences at high fields and high spatial resolution is relatively small. We conclude that the measured T₂ difference between the nucleus and cytoplasm in these cells represents primarily a true T₂ relaxation effect arising from the interactions of water with macromolecules in the two compartments and does not result from microsusceptibility differences. These observations have implications regarding water compartmentation in single cells and the interpretation of the MR characteristics of tissues in vivo.     

The effect of combinations of qinghaosu (artemisinin) with standard antimalarial drugs in the suppressive treatment of malaria in mice

Artemisinin is a novel antimalarial drug isolated in China from the wormwood plant Artemisia annua L. Studies with rodent malaria were carried out to detect antagonism and synergism with a variety of antimalarial drugs. Isobolograms of drug interaction were plotted at the ED90 level. With a normally susceptible strain of Plasmodium berghei, marked potentiative synergism was found with mefloquine, tetracycline and spiramycin. There was some synergism also with primaquine. Combinations of artemisinin with dapsone, sulfadiazine, sulfadoxine, pyrimethamine, pyrimethamine/sulfadoxine and cycloguanil showed antagonism. A high degree of potentiation was shown between artemisinin and primaquine with a primaquine-resistant strain, whilst the combination with mefloquine showed enhanced potentiation with a mefloquine-resistant strain. Combinations of artemisinin with mefloquine, primaquine, tetracycline or clindamycin showed marked potentiation with an artemisinin-resistant strain. The mechanisms underlying the drug interactions observed are discussed.     

Effects of cholinergic modulation on serum insulin-like growth factor4 and its binding proteins in normal and diabetic subjects*

OBJECTIVE We wished to study alterations In serum Insulin-like growth factor-I (IGF-I) and its binding proteins in subjects with insulin dependent diabetes mellitus (IDDM) and possible relations with metabolic and GH secretory status, before and after cholinergic modulation. In addition, we have Investigated whether cholinergic modulation exerts any effects on IGF-I secretion, Independently of any actions on GH secretory status. DESIGN All subjects received OH releasing hormone (GHRH) 1-44; 80 μg i.v.) alone and 60 minutes following 120mg of pyridostigmine orally or 200 mg of plrenzepine orally. The three tests were carried out In random order at least one week apart. Blood was sampled at 15-mInute Intervals over 120 minutes. PATIENTS Twelve male subjects with IDDM and no clinical evidence of complications were selected on the basis of HbA₁ levels to provide a wide range of metabolic control. SIX normal male subjects were also studied. MEASUREMENTS Serum IGF-I, IGF-binding protein 1 (IGFBP-1) and IGFBP-3 were measured at regular intervals throughout the study. Fasting plasma glucose and HbA₁ were measured before each study to provide measures of metabolic control. RESULTS Serum IGF-I and IGFBP-3 levels were significantly lower while serum IGFBP-I levels were significantly higher In the diabetic subjects. Plrenzepine had no effect on serum IGF-I, IGFBP-1 or IGFBP-3 In diabetic subjects but caused a significant Increase In serum IGF-I and IGFBP-3 levels in normal subjects. Pyridostigmine had no effect on IGF-I, IGFBP-1 or IGFBP-3 In either diabetic or normal subjects. IGFBP-1 levels were significantly correlated with fasting plasma glucose but no correlation was demonstrated between measures of diabetic control and serum IGF-I or IGFBP-3 levels In diabetic subjects, nor was there any correlation between OH responses to GHRH alone or after plrenzepine or pyridostigmine pretreatment and serum levels of IGF-I, IGFBP-1 or IGFBP-3. CONCLUSION These data confirm that subjects with IDDM have reduced serum IGF-I and IGFBP-3 and Increased IGFBP-1 levels, the latter being directly related to the fasting plasma glucose concentrations. The absence of any relation between changes In the IGF-I system and altered GH neuroregulation after cholinergic modulation suggests that changes In IGF-I are not the sole contributors to the altered GH neuroregulation which occurs In IDDM. We have also shown an acute stimulatory effect of pirenzepine on serum IGF-I and IGFBP-3 In normal subjects which Is not present in IDDM although the underlying mechanism Is unknown.