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Biomedical subjects

A Sjoerdsma

Publications and source records attributed to A Sjoerdsma.

At least 55 records · Page 3Linked to original sources
PubMed1986

Phase II trials of alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, in advanced small cell lung cancer and colon cancer.

alpha-Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, blocks polyamine synthesis and has demonstrated antitumor activity against small cell lung cancer and colon cancer in cell culture and animal tumor models. To evaluate clinical efficacy and further define toxic effects of this new agent, phase II trials of DFMO were performed in previously treated patients with advanced small cell lung cancer and previously untreated patients with metastatic colon cancer. Oral DFMO was administered at a dose of 2.25 g/m2/day every 6 hours continuously to patients with small cell lung cancer. The same dose was given to patients with colon cancer but on a schedule of "3 weeks on, 1 week off" to avoid hearing loss. Evaluation of toxicity indicated that thrombocytopenia was seen only in patients receiving continuous DFMO who had received prior chemotherapy, while reversible hearing loss and gastrointestinal side effects occurred on both intermittent and continuous schedules in previously treated and untreated patients.

Aged↗
PubMed1985

Potentiation by alpha-difluoromethylornithine of the activity of 3,4-dihydroxybenzylamine, a tyrosinase-dependent melanolytic agent, against B16 melanoma.

Continuous exposure for 96 hr of B16 melanoma cells in culture to 2.5 mM alpha-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, resulted in a marked increase in the activity of the enzyme tyrosinase, and also 20% cell kill as assessed by clonogenic assay. A 4-hr exposure to 0.4 mM 3,4-dihydroxybenzylamine (DHBA), a compound which is melanolytic due to its conversion to a cytotoxic quinone by the tumor specific enzyme tyrosinase, was found to be approximately equitoxic to 2.5 mM DMFO. However, a combination of DFMO (2.5 mM) and DHBA (0.4 mM) produced greater than 95% cell kill. This observed cytotoxicity with the combination suggests that induction of tyrosinase by DFMO sensitizes B16 melanoma cells to the melanolytic activity of DHBA. Oral administration of DFMO to mice bearing subcutaneous B16 melanomas also resulted in marked increases in the activity of tyrosinase in the tumor tissue. In mice inoculated intraperitoneally with 10(5) B16 melanoma cells, administration of DFMO via the drinking water (2%) increased the survival time by 8.5 days, whereas intraperitoneal administration of 300 mg/kg of DHBA for 14 days resulted in an increase in life span of 4.5 days compared to untreated controls. A combination of DFMO and DHBA prolonged the survival time by 14.6 days. These results indicate that DFMO in combination with an appropriate tyrosinase-dependent melanolytic agent might be useful in the chemotherapy of malignant melanomas.

Catechol Oxidase↗
PubMed1985

Catalytic irreversible inhibition of Trypanosoma brucei brucei ornithine decarboxylase by substrate and product analogs and their effects on murine trypanosomiasis.

Ornithine decarboxylase from Trypanosoma brucei brucei was inhibited by several substrate (ornithine) and product (putrescine) analogs both in vitro and in vivo. Since alpha-difluoromethylornithine is effective for the treatment of experimental and clinical African trypanosomiasis, it was possible that the more potent ornithine and putrescine analogs might be more active in treating the disease. However, only alpha-monofluoromethyldehydroornithine methyl ester was more potent than alpha-difluromethylornithine against mouse trypanosomiasis and warrants further study in model infections.

Animals↗
PubMed1985

Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial.

Difluoromethylornithine (DFMO), a specific, irreversible inhibitor of polyamine biosynthesis shown to be curative in animal models inoculated with various Trypanosoma spp., was evaluated in the Southern Sudan in a preliminary open clinical field trial in patients infected with Trypanosoma brucei gambiense. 20 patients were studied including 18 with late-stage disease involving the central nervous system, 16 of whom were refractory to arsenical treatment. In late-stage disease monotherapy with oral DFMO doses of about 400 mg/kg/day for five to six weeks was associated with disappearance of parasites from cerebrospinal fluid (CSF), decreased CSF WBC counts and protein concentrations and reversal of clinical signs. Side effects associated with this dose regimen included diarrhoea, abdominal discomfort and anaemia, but were seldom sufficiently severe to prompt discontinuing therapy. In early-stage patients about 200 mg/kg/day for six weeks appears adequate to eliminate parasites and reverse clinical symptoms and is well tolerated. Three cases of late-stage sleeping sickness and two of early-stage disease followed up for approximately one and a half to two years after treatment indicated that DFMO monotherapy can be curative. Additional studies are needed to define optimal posology. Inhibition of polyamine biosynthesis is a promising new approach to therapy of trypanosomiasis.

Adolescent↗
PubMed1985

Plasmodium berghei: inhibitors of ornithine decarboxylase block exoerythrocytic schizogony.

DL-alpha-difluoromethylornithine and DL-alpha-monofluoromethyldehydroornithine methyl ester, inhibitors of ornithine decarboxylase, blocked exoerythrocytic schizogony of Plasmodium berghei in mice and in cultured human hepatoma cells. These effects were reversed by exogenous administration of the polyamine, spermidine. The antimalarial drug, primaquine, the side chain of which is structurally analogous to a natural polyamine, did not enhance the activity of alpha-difluoromethylornithine or alpha-monofluoromethyldehydroornithine methyl ester. These results extend previous observations that polyamines influence the malaria parasite's schizogony outside the red blood cell but not within it.

Animals↗
PubMed1984

Inhibition of growth of Mycoplasma dispar by DL-alpha-difluoromethyllsine, a selective irreversible inhibitor of lysine decarboxylase, and reversal by cadaverine (1,5-diaminopentane).

DL-alpha-Difluoromethyllysine was shown to be a potent inhibitor of lysine decarboxylase from Mycoplasma dispar. The inhibition appeared to be specific since neither difluoromethylornithine nor difluoromethylarginine, known to inhibit other decarboxylases, inhibited the reaction catalyzed by lysine decarboxylase in extracts of M. dispar. Inhibition was irreversible since extensive dialysis could not overcome the inhibitory effect exerted by difluoromethyllysine. Difluoromethyllysine (1 mM) also totally blocked the growth of M. dispar when added at the beginning of the growth period, while 1 mM cadaverine, the product of the reaction, reversed this inhibitory effect when added to the culture medium. When difluoromethyllysine was added during the logarithmic growth phase of Mycoplasma, it inhibited the increase of the growth; 1 mM cadaverine again partially reversed this inhibitory action.

Arginine↗
PubMed1984

Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis.

alpha-Difluoromethylornithine (DFMO), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase, blocks polyamine biosynthesis and has antitumor effects in animal tumor models as well as in athymic mice implanted with human small cell carcinoma. This study was designed to determine the maximally tolerated dose of oral DFMO administered every six hours for 28 days to patients with advanced solid tumors or lymphomas. DFMO levels were measured using an ion exchange chromatographic assay and pharmacokinetic studies were performed in patients treated at each dose level. Twenty-two patients received 24 courses of DFMO. The drug was generally well tolerated. Thrombocytopenia was the dose-limiting toxicity and gastrointestinal side effects were also seen. Thrombocytopenia developed in 11 of 16 patients who had received prior chemotherapy but the four patients who had no prior chemotherapy had no decrease in the platelet count. The steady state level of DFMO achieved at the highest dose (3 g/m2) were found to be within the range needed for inhibition of ornithine decarboxylase in cell-culture systems as well as for the inhibitory activity against various human tumors in vitro. A DFMO dose of 2.25 g/m2 every six hours is recommended for phase II studies in patients previously treated with cytotoxic drugs.

Adult↗
PubMed1984

Biochemical and clinical effects of gamma-vinyl GABA in patients with epilepsy.

In a pilot single-blind study, gamma-vinyl GABA, an enzyme-activated irreversible inhibitor of GABA-transaminase (GABA-T), was administered orally to 10 epileptic patients who were refractory to conventional anticonvulsant therapy. Daily doses of 1 g and 2 g for 2 weeks each as add-on therapy were followed by 2 weeks of placebo treatment. CSF obtained from suboccipital and lumbar punctures demonstrated dose-related increases in concentrations of free and total GABA and homocarnosine with treatment, but no changes in 5-hydroxyindoleacetic acid or homovanillic acid levels, indicating effective and selective CNS GABA-T inhibition. These biochemical changes were associated with decreased seizure frequency in seven patients, decreased seizure severity in one, no change in one, and possible worsening in one. gamma-Vinyl GABA may be useful in the therapy of epilepsy.

Adult↗
PubMed1984

New drug combination for experimental late-stage African trypanosomiasis: DL-alpha-difluoromethylornithine (DFMO) with suramin.

Using a previously described mouse model of late-stage African trypanosomiasis (i.e., involvement of the central nervous system), we demonstrate that a combination of DL-alpha-difluoromethylornithine (DFMO) and suramin is curative. In the curative protocol, DFMO is given as a 2% solution in the drinking water for 14 days and suramin is administered as a single dose (20 mg/kg intravenously) on day 1 of DFMO administration. Since: 1) DFMO has very low toxicity, 2) suramin is one of the least toxic of the presently used trypanocides, and 3) suramin and DFMO act synergistically in mouse models of both acute and late stage trypanosomiasis, we conclude that this combination offers special promise in the treatment of African trypanosomiasis in man.

Animals↗
PubMed1984

Pneumocystis carinii pneumonia treated with alpha-difluoromethylornithine. A prospective study among patients with the acquired immunodeficiency syndrome.

Pneumocystis carinii pneumonia is a protozoal infection that, in the setting of acquired immunodeficiency syndrome (AIDS), is often lethal and unresponsive to conventional therapy with trimethoprim-sulfamethoxazole or pentamidine. In the present study, we have prospectively assessed the use of alpha-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, in the treatment of P carinii pneumonia in patients with AIDS who were intolerant or unresponsive to conventional drugs. Improvement by both clinical and objective criteria was observed in six patients who completed six to eight weeks of DFMO therapy. Expansion of these early trials of DFMO is warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1983

Tumor suppression with a combination of alpha-difluoromethyl ornithine and interferon.

alpha-Difluoromethyl ornithine and mouse type 1 interferon, when administered simultaneously, were highly toxic to B16 melanoma cells in culture. Oral administration of alpha-difluoromethyl ornithine suppressed B16 melanoma development in mice 85 percent whereas interferon given subcutaneously inhibited tumor growth only 24 percent. Total or near total suppression of tumor growth was observed in mice receiving both treatments.

Animals↗
PubMed1983

In vivo effects of alpha-DL-difluoromethylornithine on the metabolism and morphology of Trypanosoma brucei brucei.

The EATRO 110 isolate of Trypanosoma brucei brucei was grown in rats for 60 h and the animals treated with the ornithine decarboxylase inhibitor alpha-DL-difluoromethylornithine 12 h or 36 h prior to sacrifice. Control untreated animals died 72-80 h after infection. Treated parasites were shorter and broader than the predominantly long slender forms found in untreated controls and many had two or more nuclei and kinetoplasts. Trypanosomes were purified from blood and examined for disruption of polyamine metabolism. ODC activity decreased by more than 99% after 12 h treatment and putrescine and spermidine levels also decreased dramatically. Spermine, not normally present in control cells, increased to detectable, low levels (less than 1 nmol mg-1 protein) after 36 h treatment. alpha-DL-Difluoromethylornithine-treated cells were unable to synthesize putrescine from [3H]ornithine but were able to convert [3H]putrescine + methionine to spermidine. 12-h treated parasites responded to polyamine depletion by assimilating radiolabeled polyamines in vitro at 2- to 4-times the rate of untreated cells. The metabolism of S-adenosylmethionine was also altered in treated parasites: decarboxylated S-adenosylmethionine increased more than 1000-fold over untreated cells while S-adenosylmethionine decarboxylase activity, associated with the formation of spermidine and spermine in other eukaryotes, paradoxically declined in treated cells. Synthesis of macromolecules was perturbed in treated parasites: rates of DNA and RNA synthesis declined 50-100%, while protein synthesis increased up to 4-fold in 36-h treated cells. alpha-DL-Difluoromethylornithine treatment progressively limits the parasites' ability to synthesize nucleic acids and blocks cytokinesis while inducing morphological changes resembling long slender leads to short stumpy transformation.

Animals↗
PubMed1983

Polyamine biosynthesis is required for the maintenance of peripheral blood cell elements in the rat.

The specific ornithine decarboxylase inhibitor alpha-difluoromethylornithine, when given to adult rats in vivo for 5 wk, resulted in a decrease in peripheral blood cell elements in normal rats and a marked suppression of marrow recovery in rats with chemotherapy-induced marrow hypoplasia. In normal rats, alpha-difluoromethylornithine resulted in a reduction of the leukocyte count to 73% of control, erythrocyte count to 61% of control, and platelet count to 24% of control. The bleeding time was increased to twice normal and 67% of the animals had epistaxis and 42% had melena. In rats treated with the S phase-specific chemotherapeutic agent 1-beta-D-arabinofuranosylcytosine, the simultaneous administration of alpha-difluoromethylornithine prevented the recovery of the bone marrow. The peripheral blood cell counts remained low--leukocyte count was 10% of control, and erythrocyte and platelet counts were 6% of control. All the animals developed epistaxis and melena and there was a 72% mortality. The administration of putrescine (4 mmol/kg, intraperitoneally, daily), the specific polyamine product of ornithine decarboxylase, reversed these hematologic effects in both normal and recovering marrow and resulted in rapid clinical improvement. Thus, the maintenance of normal, adult rat hematologic parameters, as with the proliferation of neoplastic and transformed cells in culture, is critically dependent on continued polyamine biosynthesis.

Animals↗
PubMed1983

Efficacy of combinations of difluoromethylornithine and bleomycin in a mouse model of central nervous system African trypanosomiasis.

DL-alpha-Difluoromethylornithine, a polyamine biosynthesis inhibitor, and bleomycin, a currently used antineoplastic agent, have each previously been shown to be curative for acute short-term infections of mice with Trypanosoma brucei brucei, an African trypanosome closely related to those that cause the human disease African sleeping sickness. These agents were tested singly and in combination in a previously described mouse model of sleeping sickness with demonstrable brain involvement. The original model is extended by using two additional strains of outbred mice and by demonstrating that melarsoprol, an arsenical and currently the only drug used for human African trypanosomiasis involving the brain, was also curative for these brain infections. Neither difluoromethylornithine nor bleomycin alone was curative for the brain infections; however, many combinations of the two drugs were found to be 100% curative with no evidence of immediate toxicity.

Animals↗