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Biomedical subjects

P Grieb

Publications and source records attributed to P Grieb.

At least 37 records · Page 2Linked to original sources
PubMed1996

2-chlorodeoxyadenosine (2-CdA) in 2-hour versus 24-hour intravenous infusion in the treatment of patients with hairy cell leukemia.

Forty one patients with hairy cell leukemia (HCL) were treated with 2-chloro-deoxyadenosine (2-CdA) administered in various schedules. Complete remission (CR) was achieved in 31 (76%) patients and partial remission (PR) in 9 (22%). The mean duration of remission (CR + PR) was 25.2 months (range 9-45 months). One patient did not respond to therapy. Twelve out of 16 patients (75%) achieved CR after 5-day intravenous infusions of 2-CdA and 19 out of 25 patients (76%) after 7-day courses. In 19 out of 23 patients (82.6%) CR was achieved after intermittent 2-hour infusions and in 12 out of 18 (66.7%) after continuous 24-hour infusion. The differences were not statistically significant. Side effects of 2-CdA were similar in both groups except for infections, which were less frequently observed in the group treated for 5 days. The results of our study suggest that 2-CdA can be effectively administered to patients with HCL using 5-day courses and a 2-hour daily infusion.

Adult↗
PubMed1996

Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or previously untreated B-cell chronic lymphocytic leukemia.

The purpose of our study was to determine the effectiveness of 2-CdA in 2-hour intravenous infusions in the treatment of B-CLL. One hundred and ten patients with B-CLL received 1 to 10 courses of 2-CdA (median 2.5) at a dosage of 0.12 mg/kg daily for 5 consecutive days. Eighteen of them were untreated and 92 relapsed or became refractory to previous therapeutic modalities. Complete remission (CR) was achieved in 8 (7.3%) and partial remission (PR) in 35 patients (31.8%) giving an overall response rate of 39.1%. In 3 patients, cross-resistance to fludarabine was noticed. Toxic effects of 2-CdA were more frequently observed in previously treated patients. Hemorrhagic complications due to drug-induced thrombocytopenia were noticed in 25 (22.7%) and severe infections including sepsis in 14 (12.7%) patients.

Adult↗
PubMed1996

Mitochondrial damage following exposure of organotypic cultures of human malignant gliomas to 2-chloro- and 2-bromo-2'-deoxyadenosine.

The effects of 2-chloro-2'-deoxyadenosine (cladribine, 2-CdA) and a closely related compound 2-bromo-2'-deoxyadenosine (2-BdA) on organotypic cultures of human malignant gliomas were studied with the use of electron microscopy. The cultures grown from surgical biopsies included six glioblastomas, three anaplastic astrocytomas and low-grade fibrillary astrocytoma. After 6 to 10 days of the in vitro growth the cultures were exposed to 0.3-10 microM 2-CdA or 2-BdA for 1 to 10 days. Mitochondrial swelling and disappearance of cristae following exposure to the tested substances were observed, but only in highly anaplastic (low-differentiated) tumor cells. The mitochondrial toxicity was dose- and time-dependent, and no difference was found between the effect of 2-CdA and 2-BdA.

Antineoplastic Agents↗
PubMed1996

2-chloro- and 2-bromo-2'-deoxyadenosine have no effect on the morphology of rat neural and glial cells in organotypic culture.

Organotypic cultures of hippocampus and cerebellum, established from brains of 1-3 days old rats, were exposed at different stages of development (3, 14 and 21 DIV) to 2-chloro-2'-deoxyadenosine (cladribine, 2-CdA) and 2-bromo-2'-deoxyadenosine (2-BdA) at concentrations up to 10 microM, for up to 10 days. Normal pattern and dynamics of differentiation and maturation of both neurons and glial cells was found with the use of light and electron microscopy. No ultrastructural abnormalities were induced by the substances tested. We conclude that 2-CdA and its sister compound 2-BdA do not exert cytotoxic effects toward normal rat central nervous system tissues in organotypic culture.

Animals↗
PubMed1996

Antiviral activity of 2-chloro-2'-deoxyadenosine (2-CdA).

The effect of 2-chloro-2'-deoxyadenosine (cladribine, 2-CdA) on replication of herpes simplex type 1 (HSV) virus in Vero cells (green african monkey kidney line) was evaluated and compared with that of acyclovir. 2-CdA up to 600 micrograms/ml was not cytotoxic. ED50 for 2-CdA was approximately 5 micrograms/ml and ED100 was approximately 70 micrograms/ml, compared with 0.16 microgram/ml and 1.6 micrograms/ml for acyclovir, respectively. DNA cell cytometry suggested the progressive S-phase block at concentrations of 2-CdA 0.14 microgram/ml and higher. The results suggest that 2-CdA is not activated by HSV-encoded kinase, and a weak antiviral effect of the drug results from its interference with DNA replication following activation by kinases of host cells.

Acyclovir↗
PubMed1995

Survival and maturation of heterotopic fetal brain stem xenografts after treatment with 2-chlorodeoxyadenosine and cyclosporine A.

Brain stem halves from fetal rabbits were transplanted to the caudate nucleus area of adult rats. The animals were treated postoperatively with cyclosporine A (CsA) and 2-chlorodeoxyadenosine (CdA) for three days, and with CdA alone for the next 13 days. The treatment started at the day of implantation, and in some animals it was repeated starting at day 36 after grafting (at the time when signs of a light inflammatory reaction appeared in some grafts). Grafts survived and matured histologically, and no signs of acute rejection were observed up to the 90th day. In some grafts we recorded phasic neuronal activities similar to the respiratory-related neural activities characteristic for the adult brain stem. Immunosuppressive with CdA and CsA deserves further evaluation in fetal brain grafting.

Animals↗
PubMed1995

DNA protein flow cytometry of dissociated cultures of human anaplastic gliomas. Pattern of proliferation and differentiation, and the effect of a new cytostatic drug cladribine (2-CdA).

A technique of protein-DNA flow cytometry was applied to characterize cell cycling, and to assess the cytotoxicity of cladribine (2-chloro-2'deoxyadenosine) toward seven dissociated cultures of human primary brain tumors (anaplastic astrocytoma and glioblastoma multiforme) grown in vitro from surgical biopsies. Control cytograms were suggestive of that a clonogeneic fraction of the cell population consists mainly of cells with low protein content, which do not require increase in protein content before entering the S phase of the cell cycle. Following 24 or 48 hours exposure to cladribine, 1 nM approximately 1 microM, no cytotoxic effect was evident in 4 cultures, whereas in two cases dose-dependent progressive block of the phase of the cell cycle was noted. In one case a massive cytotoxic effect resulted in disintegration of culture exposed to 100 nM of the drug. However, the treatment with cladribine was ineffective in a patient bearing the tumor which was the source for the last culture, suggesting that cytotoxicity in vitro may not be predictive of clinical response.

Antineoplastic Agents↗
PubMed1995

Effect of repeated treatments with cladribine (2-chlorodeoxyadenosine) on blood counts in multiple sclerosis patients.

We report the results of blood morphology monitoring of 11 remitting-relapsing multiple sclerosis patients who received repeated treatments with cladribine (2-chlorodeoxyadenosine). The drug was given once, daily, subcutaneously (5 mg) or orally (10 mg) for 5 consecutive days, as 6 monthly courses followed by one or two additional courses at 3 or 6 month intervals. The treatments were well tolerated, although many patients suffered from incidental upper respiratory tract infections, most of which occurred during the last 6 months of the observation period. One patient had recurrent infections, including an episode of urosepsis. All infections responded to standard therapy with antibiotics. Progressive lymphocyte reduction to 1000/microliters on average, and clear, but clinically insignificant drop in thrombocytes, was observed. Granulocyte counts were sometimes markedly elevated. A few patients developed macrocytosis, but none required transfusion. With our dosing and schedule, cladribine seems relatively safe in multiple sclerosis patients.

Adult↗
PubMed1994

Depressed immune surveillance against cancer: role of deficient T cell: extracellular matrix interactions.

Although T cells infiltrate malignant tumors, the local immune response is usually inefficient and tumors escape destruction. While extracellular matrix proteins strongly costimulate T cell responses in normal individuals, our studies indicate that peripheral blood T cells from cancer patients and tumor infiltrating cells respond poorly or are resistant to stimulative signals mediated by collagen I and IV and fibronectin. Moreover, the adhesive properties of cancer T cells are markedly depressed. Those functional deficiencies are paralleled by variable deficits in integrin and non-integrin T cell receptors for extracellular matrix. Immunotherapy with BCG causes a dramatic but transient increase in T cell: ECM interactions.

BCG Vaccine↗
PubMed1994

Cladribine (2-chloro-2'-deoxyadenosine): new perspectives in clinical immunosuppression.

Cladribine (2-chloro-2'-deoxyadenosine) has been recently introduced in the treatment of hematologic malignancies. We have shown that CdA has potent inhibitory activity in vitro and in vivo in concentrations readily achievable in the sera of treated patients. The immunosuppressive efficacy of CdA was at least equal to that of cyclosporine. Furthermore, CdA is particularly efficacious inhibitor of B cell activation.

Cladribine↗
PubMed1994

Influence of 2-chloro-2'-deoxyadenosine alone and in combination with cyclophosphamide or methotrexate on murine leukemia L1210.

The influence of 2-CdA administrated alone and in combination with CY or MTX on the survival time of mice bearing L1210 leukemia was investigated. 2-CdA treated mice lived longer than control animals. Survival times of mice receiving combined therapy of 2-CdA and CY were significantly prolonged as compared with mice treated with these agents separately. Survival times of mice treated with 2-CdA and MTX were not significantly prolonged, compared with animals receiving 2-CdA alone.

Animals↗
PubMed1994

2-Chloro-2'-deoxyadenosine (2-CdA) combined with cyclosporine A successfully prevents rejection of fetal brain stem allograft in rabbits.

Allografts of brain stem from 20-day-old fetuses to nucleus caudatus of adult rabbits were performed. To prevent graft rejection immunosuppression with 2-CdA and cyclosporine A was transiently induced. Graft survival were assessed by histological and electrophysiological techniques. Both morphological (synaptogenesis, myelinization) and functional (generation of rhythmic neuronal activity) signs of graft maturation were found after nine weeks. The data suggest that transient immunosuppression used is sufficient to induce tolerance to neural graft, and no interference with maturation of implanted fetal tissue occurs.

Animals↗
PubMed1994

Modulation of lymphocyte-fibroblast interactions by 2-chloro-2'-deoxyadenosine (2-CdA) in subarachnoid hemorrhage.

The adherence to monolayers of human fibroblasts of chromium-51 labelled peripheral blood mononuclear cells (PBMC) from normal subjects, and from patients after single or multiple subarachnoid hemorrhage (SAH), and the effect of 2-CdA on cell adhesion have been quantified. The fraction of cells adhering to fibroblasts were the lowest for multiple SAH patients and the highest for normal subjects, which can be explained by depletion of activated lymphocytes from peripheral blood of SAH patients. 2-CdA decreased the fraction of adhering cells isolated from normal subjects, did not change the adherence of cells from single SAH patients and increased the fraction of adhering cells isolated from multiple SAH patients. We conclude that the influence of 2-CdA on the adherence of PBMC to fibroblasts is inversely related to the degree of immune system activation.

Autoimmunity↗