Search PubMed⌕ Search

Biomedical subjects

A Sjoerdsma

Publications and source records attributed to A Sjoerdsma.

At least 37 records · Page 2Linked to original sources
PubMed1987

Antiretroviral activity of castanospermine and deoxynojirimycin, specific inhibitors of glycoprotein processing.

The objective of this study was to investigate the antiretroviral activity of specific inhibitors of glycosidases and mannosidases that are involved in N-linked oligosaccharide processing of glycoproteins. Castanospermine and 1-deoxynojirimycin, potent inhibitors of glucosidases I and II, showed significant activity against Moloney murine leukemia virus (IC50: 1.2 microgram/ml). Deoxymannojirimycin and swainsonine, inhibitors of mannosidase I and II, respectively, did not show any activity. These observations suggest that removal of the outermost glucose residue from high mannose asparagine-linked oligosaccharide may be essential for the replication of mouse leukemia virus. The relative nontoxic nature of these inhibitors and a novel mechanism of action suggest a potential for compounds of this type as chemopreventive and therapeutic agents in the treatment of acquired immune deficiency syndrome (AIDS).

1-Deoxynojirimycin↗
PubMed1987

Difluoromethylornithine, an effective new treatment of Gambian trypanosomiasis. Results in five patients.

Recent studies have shown DL-alpha-difluoromethylornithine (eflornithine), an inhibitor of polyamine biosynthesis, to be curative in various Trypanosoma species infections of laboratory animals. Five patients are described with Gambian trypanosomiasis treated in Belgium with difluoromethylornithine, using various intravenous and oral dosage schedules. Three patients had late-stage and two had early-stage disease. Difluoromethylornithine treatment was associated with clearing of parasites from blood within one to four days, a trend towards normalization of all altered biologic values associated with the disease, and marked amelioration of clinical symptoms. Side effects of difluoromethylornithine, including loose stools in three patients and both anemia, and a decrease in auditory acuity in one patient, were mild, transient, and never required interruption of drug treatment. The presence of difluoromethylornithine in cerebrospinal fluid, determined in three patients, demonstrated that difluoromethylornithine penetrates into the central nervous system. In three patients, follow-up of at least 24 months after treatment demonstrated a continued healthy state without evidence of relapse. These promising, albeit preliminary, results of difluoromethylornithine therapy, even in patients with central nervous system involvement, indicate that extended clinical trials are warranted to determine the optimal dosage regimen in patients with early- and late-stage disease.

Adult↗
PubMed1987

Decarboxylated-S-adenosylmethionine excretion: a biochemical marker of ornithine decarboxylase inhibition by alpha-difluoromethylornithine.

In an attempt to define a biochemical marker of ornithine decarboxylase inhibition in humans, alpha-difluoromethylornithine hydrochloride (DFMO), an irreversible ornithine decarboxylase inhibitor, was infused i.v. in seven cancer patients over 10-day courses at doses of 10-90 g/day and 24-h urinary excretion of polyamines and decarboxylated-S-adenosylmethionine was determined before, during, and after treatment. DFMO produces marked increases in urinary decarboxylated-S-adenosylmethionine excretion, up to 84 times pretreatment values. This response appears to be time dependent, requiring several days to reach a maximum and lasting at least 4-5 days after stopping DFMO. In contrast, urinary excretion of the polyamines putrescine, cadaverine, spermidine, N1-monoacetylspermidine, N8-monoacetylspermidine, and spermine, were not consistently altered by DFMO. We conclude that urinary excretion of decarboxylated-S-adenosylmethionine represents a valid biochemical indicator of ornithine decarboxylase inhibition in humans, whereas urinary polyamines are of no value.

Aged↗
PubMed1987

Plasmodium falciparum and Plasmodium berghei: effects of ornithine decarboxylase inhibitors on erythrocytic schizogony.

Five ornithine decarboxylase inhibitors: alpha-difluoromethylornithine (DFMO) (eflornithine); alpha-monofluoromethyl-3,4-dehydroornithine; alpha-monofluoromethyl-3,4-dehydroornithine methyl ester; alpha-monofluoromethyl-3,4-dehydroornithine ethyl ester; and (2R,5R)-delta-methyl-alpha-acetylenic putrescine were shown to inhibit erythrocytic schizogony of Plasmodium falciparum in vitro and reduced spermidine levels in infected erthrocytes. Only DFMO was effective at limiting erythrocytic schizogony of P. berghei in vivo. Administration of DFMO as a 2% solution in the drinking water for 4 days reduced parasitemia in mice by 50% in a 4-day suppression test but did not increase survival time of infected mice. This is the first demonstration of an effect of DFMO on plasmodial erythrocytic schizogony in vivo and suggests that interference with polyamine biosynthesis may, in fact, be a viable chemotherapeutic target in erythrocytic malaria.

Animals↗
PubMed1987

Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells.

The capacity of blood (trypomastigote) forms of Trypanosoma cruzi to infect mouse peritoneal macrophages or rat heart myoblasts in vitro was inhibited by treatment of the trypomastigotes with DL-alpha-difluoromethylarginine (F2Me Arg), monofluoromethylagmatine, or (E)-alpha-monofluoromethyl-3-4-dehydroarginine--all irreversible inhibitors of arginine decarboxylase. Similar results were obtained when F2MeArg-treated parasites were incubated with rat heart myoblasts. The inhibitory effects were characterized by marked reductions in both the proportion of infected cells and the number of parasites per 100 host cells. The concentrations of the arginine decarboxylase inhibitors that affected infectivity had no detectable effect on either the concentration or motility of the parasite and, therefore, could not have affected the collision frequency. F2MeArg appeared to inhibit the ability of T. cruzi to penetrate the host cells since the drug had no significant effect on the extent of parasite binding to the surface of the host cells. The inhibitory effect of F2MeArg was markedly reduced or abrogated in the presence of either agmatine or putrescine, as would have been expected if F2MeArg acted by inhibiting arginine decarboxylase. Addition of F2MeArg to macrophage or myoblast cultures immediately after infection or at a time when virtually all of the intracellular parasites had transformed into the multiplicative amastigote form, resulted in a markedly reduced parasite growth rate. This effect was also prevented by exogenous agmatine. These results indicate the importance of polyamines and polyamine biosynthesis in the following two important functions of T. cruzi: invasion of host cells and intracellular multiplication. Furthermore, concentrations of the inhibitors tested that affected the parasite did not alter the viability of the host cells, the cellular density of the cultures, or the ability of uninfected myoblasts to grow. Thus, arginine decarboxylase inhibitors may have a potential application in chemotherapy against T. cruzi infection.

Agmatine↗
PubMed1987

Impairment of macrophage function by inhibitors of ornithine decarboxylase activity.

The effects of irreversible inhibition of ornithine decarboxylase on the capacity of murine macrophages to take up a protozoan organism (Trypanosoma cruzi) or inert particles were investigated. Incubation of macrophage cultures with four different ornithine decarboxylase inhibitors, namely, DL-alpha-difluoromethylornithine (DFMO, 0.5 to 20 mM), delta-methyl-acetylenic putrescine (1 to 5 mM), monofluoromethyldehydroornithine ethyl ester (1 to 5 mM), and monofluoromethyldehydroornithine methyl ester (1 to 5 mM), before the addition of the parasites significantly reduced the percentage of macrophages with parasites, indicating that some of the host cells were no longer capable of binding or ingesting the parasite. The average number of trypanosomes per 100 macrophages was also diminished, denoting a lesser phagocytic capacity as a consequence of the treatments. These effects were reversible within 2 h after removal of excess DFMO. No alteration in parasite-macrophage interaction was seen when the trypanosomes were treated with DFMO. That the effects of DFMO on the macrophages probably resulted from a reduction in polyamine levels caused by inhibition of ornithine decarboxylase was indicated by the fact that these effects were not seen when the macrophages were incubated with DFMO in the presence of putrescine, the product of ornithine decarboxylation by ornithine decarboxylase. DFMO treatment of macrophages also inhibited the capacity of these cells to ingest killed parasites or latex beads and thus appeared to generally affect phagocytosis. An effect of DFMO on the susceptibility of macrophages to penetration by the parasites seemed less likely because no significant alteration in cell-parasite association occurred when myoblasts--which, not being phagocytic, can be infected only by membrane penetration--were treated with DFMO. Taken together, these results emphasize a role of ornithine decarboxylase activity and polyamine biosynthesis in macrophage function.

Animals↗
PubMed1987

Effects of the ornithine decarboxylase inhibitors DL-alpha-difluoromethylornithine and alpha-monofluoromethyldehydroornithine methyl ester alone and in combination with suramin against Trypanosoma brucei brucei central nervous system models.

Two ornithine decarboxylase inhibitors, DL-alpha-difluoromethylornithine (eflornithine; DFMO) and a-monofluoromethyldehydroornithine methyl ester (delta MFMO X CH3) were compared in their ability to cure two distinct Trypanosoma brucei brucei central nervous system murine model infections. Both inhibitors cured the TREU 667 and LUMP 1001 isolates if used in combination with a single (20 mg/kg) injection of suramin, a trypanocide in current clinical use. The curative dose of delta MFMO X CH3 in combination with suramin was 1.09 g/kg/day, administered in the drinking water for 14 days; used with suramin, the curative dose of DFMO was 5.3 g/kg/day for 14 days (5 times the delta MFMO X CH3 dose required). In host animals, delta MFMO X CH3 was not toxic and was accumulated by trypanosomes 6-8 times faster than DFMO. Since DFMO by itself has been highly effective against T. b. gambiense infections in humans (12-15 g/day for 6 weeks) the present data suggest that delta MFMO X CH3 might be effective in a shorter regimen and at lower doses.

Animals↗
PubMed1987

Treatment of human late stage gambiense trypanosomiasis with alpha-difluoromethylornithine (eflornithine): efficacy and tolerance in 14 cases in Côte d'Ivoire.

alpha-Difluoromethylornithine (DFMO; eflornithine), an inhibitor of polyamine biosynthesis, was used to treat 14 patients with late stage gambiense sleeping sickness, 12 cases having been previously treated with and considered refractory to melarsoprol. alpha-Difluoromethylornithine was administered intravenously at a dose of 400 mg/kg/day for 14 days followed by oral treatment, 300 mg/kg/day, for 21-28 days. In all patients treatment was associated with rapid disappearance of trypanosomes from body fluids (in several cases within 24 hr) and decreased cerebrospinal fluid white blood cell counts. In all but one patient, who died of a pulmonary infection during treatment, alpha-difluoromethylornithine produced a dramatic reversal of clinical signs and symptoms of the disease. Determination of drug concentrations in serum and cerebrospinal fluid of 5 patients demonstrated that alpha-difluoromethylornithine diffuses into the central nervous system with cerebrospinal fluid levels representing up to 51% of corresponding serum concentrations. Diarrhea, abdominal pain, and anemia were the most frequent side effects associated with therapy, but were reversible and did not necessitate discontinuation of treatment. Four patients have been followed for more than 2 years post-treatment without evidence of relapse.

Administration, Oral↗
PubMed1986

Marked and prolonged inhibition of mammalian ornithine decarboxylase in vivo by esters of (E)-2-(fluoromethyl)dehydroornithine.

(E)-2-(fluoromethyl)dehydroornithine, a new enzyme-activated irreversible inhibitor of ornithine decarboxylase (ODC) is no more effective than alpha-difluoromethylornithine (DFMO) at inhibiting polyamine biosynthesis in rat hepatoma tissue culture (HTC) cells and in rat organs even though its potency is over 15 times higher than that of DFMO in vitro. The methyl, ethyl, octyl and benzyl esters of (E)-2-(fluoromethyl)dehydroornithine were synthesized as potential prodrugs of the amino acid. When tested at concentration equivalent to the Ki value of the amino acid, they are devoid of ODC-inhibitory property. When measured 6 hr after its addition to the HTC cell culture medium, the absorption of methyl ester was 20 times higher than that of the parent amino acid or that of DFMO, and was accompanied by a more marked intracellular accumulation of (E)-2-(fluoromethyl)dehydroornithine than that achieved by the addition of the parent amino acid. The methyl ester used at 10 times lower concentrations is as effective as its parent amino acid or as DFMO at inhibiting polyamine biosynthesis in HTC cells. Similarly, the methyl and the ethyl esters of (E)-2-(fluoromethyl)dehydroornithine used at 10 times lower doses are as effective as the parent amino acid and as DFMO at inhibiting ODC in the ventral prostate of rat, 6 hr after oral administration. All the esters of (E)-2-(fluoromethyl)dehydroornithine produce a particularly long duration of ODC inhibition in the ventral prostate and in the testes. Repeated administration (25 mg/kg given once a day by gavage) of the methyl ester of (E)-2-(fluoromethyl)dehydroornithine for 8 days to rats results in a constant 80% inhibition of ODC over a 24-hr period, accompanied by a 90% decrease of putrescine and spermidine concentrations in the ventral prostate.

Adenosylmethionine Decarboxylase↗
PubMed1986

Necessity of antibody response in the treatment of African trypanosomiasis with alpha-difluoromethylornithine.

The role of the immune system in the clearance of Trypanosoma brucei brucei from the bloodstream during alpha-difluoromethylornithine (DFMO) treatment was studied by determining the effects of dexamethasone on immune and therapeutic responses in rats infected with T.b. brucei. Normal DFMO-treated animals exhibited strong antibody responses to trypanosomes and were cured of T. b. brucei infection by a 7-day regimen of 2% DFMO in drinking water. Animals pretreated with dexamethasone were not cured by the same level of DFMO treatment. Nonetheless, in rats pretreated with dexamethasone, trypanosomes were cleared from blood during treatment with DFMO, but all immunocompromised animals eventually succumbed to relapses of the infection. Athymic (nude) mice were cured of T. b. brucei infection by a 72-hr course of treatment with 2% DFMO in their drinking water. These findings suggest that relatively low levels of T-cell-independent, antitrypanosomal antibodies are adequate to clear the bloodstream of parasites during DFMO therapy but that an intact immune response is necessary for cures of the disease to be obtained.

Animals↗
PubMed1986

Identification of polyamines in the cochlea of the rat and their potential role in hearing.

The occurrence of reversible hearing loss in patients treated with the polyamine biosynthesis inhibitor, alpha-difluoromethylornithine (DFMO), led to the hypothesis that this functional hearing deficit might be due to polyamine depletion in the cochlea. To test this hypothesis the polyamine content (putrescine, spermidine and spermine) of the cochleas of normal rats was measured and compared to that of DFMO-treated rats. For the first time, it was demonstrated that in the cochleas of normal rats there were substantial amounts of spermidine and spermine but no detectable putrescine. There was also no measurable ornithine decarboxylase. The DFMO treatments employed in this study were not effective, however, in depleting the cochlear polyamines to levels generally considered critical for disrupting polyamine-dependent processes in other systems. Thus, it is not surprising that auditory thresholds, which were evaluated using brainstem evoked potentials, remained unaltered in the DFMO-treated rats. Demonstration of a role for polyamines in hearing awaits further investigation with the use of more potent inhibitors or other model systems for hearing.

Animals↗
PubMed1986

Effects of DL-alpha-difluoromethylornithine on Leishmania donovani promastigotes.

Alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, has been demonstrated to be an effective agent against a variety of parasitic protozoa but not against Leishmania spp. In this report, we show that Leishmania donovani promastigotes in continuous culture are sensitive to the growth inhibitory and cytotoxic effects of DFMO. Incubation of the promastigotes with DFMO obliterates intracellular putrescine pools and depletes spermidine concentrations, which correlates with the onset of growth inhibition. The effects of DFMO on the growth and the intracellular polyamine pools can be reversed completely by the addition of 10 microM putrescine to the culture medium. These results suggest that the treatment of leishmaniasis may be amenable to chemotherapeutic manipulation by DFMO.

Animals↗
PubMed1986

Inhibition of polyamine biosynthesis by alpha-difluoromethylornithine in African trypanosomes and Pneumocystis carinii as a basis of chemotherapy: biochemical and clinical aspects.

The symposium provided dramatic evidence of the value of the use of polyamine inhibition via alpha-difluoromethylornithine (DFMO, eflornithine) for advances in chemotherapy of Trypanosoma brucei gambiense sleeping sickness and Pneumocystis carinii pneumonia in acquired immune deficiency syndrome (AIDS) and also for further understanding the metabolic importance of the ubiquitous polyamines in these organisms.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Long-term maintenance therapy of established human small cell variant lung carcinoma implants in athymic mice with a cyclic regimen of difluoromethylornithine.

We report that cyclic p.o. administration of alpha-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, is an effective long-term (1-year) maintenance therapy for established implants of cultured human small cell lung carcinoma in athymic (nude) mice. Human small cell lung carcinoma cells, from a line which exhibited cell death in culture in the presence of DFMO, were inoculated into athymic mice and permitted to grow to palpable tumors (3-5-mm nodules with mean volume of 0.04 cm3). The animals were then randomized into untreated, continuous treatment and cyclic (3 weeks of 4 beginning 1 week after 8 weeks continuous) treatment groups. Treatment consisted of 3% DFMO in the drinking water (5.1 g/kg/day). The tumors in the untreated group grew to 27 cm3 by 8 weeks and the animals had a median survival of 7.6 weeks. Tumor growth was inhibited by 99% (0.3 cm3) in the continuous treatment group in comparison to untreated controls. Survival was prolonged with 93% survival at 10 weeks and a 101% increase in median survival to 15.3 weeks (P less than 0.05). The cyclic DFMO group had a 98.3% inhibition in tumor growth for longer than 1 year (0.56 cm3; P less than 0.05). Survival was also markedly prolonged compared to the untreated group with 100% survival up to 24 weeks and a median survival of 54.3 weeks (P less than 0.05). No significant toxicities were observed in the first 10 weeks of DFMO treatment even though antitumor effects were observed. With continuous DFMO treatment, the animals eventually became debilitated and developed marked weight loss and thrombocytopenia; by 20 weeks, mortality was 79%. With cyclic therapy, the animals resumed weight gain, recovered from thrombocytopenia and, at 20 weeks, had 0% mortality. By 55 weeks, mortality was 50% which, however, was not significantly different (P approximately 0.50) from mortality of a control group of nontumorous, athymic mice that had weekly body weight and skin fold measurements concurrently with the experimental, tumor-bearing animals. Thus, the observed mortality is ascribable to continuous encroachment on the normally sterile environment. These data suggest a role for DFMO in long-term therapy of sensitive human tumors such as small cell lung carcinoma, especially in patients with a low tumor burden. Furthermore, a cyclic regimen might be an important tool in maintaining clinical remissions induced by conventional combination chemotherapy.

Animals↗