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Biomedical subjects

P Sonneveld

Publications and source records attributed to P Sonneveld.

11 recordsLinked to original sources
PubMed1992

Modulation of multidrug-resistant multiple myeloma by cyclosporin. The Leukaemia Group of the EORTC and the HOVON.

Resistance to chemotherapy in refractory multiple myeloma is frequently associated with expression of multidrug resistance (MDR). In resistant cells, intracellular accumulation of doxorubicin and vincristine does not occur because the MDR-1 gene product, a membrane glycoprotein (PgP), is an energy-dependent efflux pump. Cyclosporin is one of several non-cytotoxic drugs that can block the function of PgP. In a prospective study, we assessed the possibility that cyclosporin could be used clinically to modulate MDR. We studied 21 patients with multiple myeloma; disease had progressed during primary chemotherapy in 6 and was resistant to VAD (vincristine, doxorubicin, dexamethasone) in 15. The patients received cyclosporin by continuous infusion during VAD treatment; there were three cyclosporin dosage groups (5, 7.5, 10 mg/kg daily). Serum cyclosporin concentrations adequate for MDR modulation were reached in all patients receiving 7.5 or 10 mg/kg daily. 47% (7) of the VAD-refractory patients and 48% (10) of the whole group responded to VAD. Before treatment, MDR-1 expression was present in 12 patients. After VAD plus cyclosporin, no MDR-1-positive plasma cells were present in 6 of 8 patients tested. The response rate in MDR-1-positive patients was 58% compared with 33% in all our patients. Toxic effects were mild and reversible and did not include nephrotoxic or serious cardiovascular side-effects. 12 months after the start of treatment, survival was 85%, and disease-free survival at a median of 9 months after the response was 65%. Thus, in multiple myeloma clinical resistance to VAD can be circumvented by cyclosporin, which enables the cytotoxic drugs to eliminate resistant myeloma cells.

Adult↗
PubMed1992

High expression of the mdr3 multidrug-resistance gene in advanced-stage chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by an often indolent course with a poor therapeutic response at advanced stage. We investigated the expression of the human multidrug resistance genes mdr1 and mdr3 in 31 patients with CLL. Using specific probes for mdr1 and mdr3 mRNA, respectively, expression of both genes could be found in 29 of 31 patients. Of those, nine had high expression of mdr1 and 13 of mdr3. Although 29 of 31 patients showed coexpression of mdr1 and mdr3, the mRNA levels were not interrelated. Prior treatment did not significantly influence the level of mdr1 or mdr3 expression. In patients with advanced CLL (Rai stage 3 + 4) the mdr3 expression was significantly higher than in early-stage CLL (Rai stage 0 to 2) (mean +/- SEM, 25.4 +/- 4.2 U v 4.2 +/- 1.1 U; P less than .0001). Such a difference was not present for mdr1 expression (21.5 +/- 4.3 U v 10.7 +/- 3.1 U; P = .09). These data indicate that advanced-stage CLL is associated with an increased mdr3 expression, which may concur with a decreased sensitivity to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Intrathecal administration of etoposide in the treatment of malignant meningitis: feasibility and pharmacokinetic data.

Two patients presenting with malignant meningitis resulting from small-cell carcinoma of the lung and with lymphoblastic leukemia, respectively, were treated by intrathecal administration of etoposide. In both cases, this treatment was well tolerated and produced relief of the central nervous system symptoms. Pharmacokinetic data showed that cerebrospinal fluid drug levels of up to 5.2 micrograms/ml were achieved, which were considerably higher than those obtained after i.v. administration of high-dose etoposide.

Adult↗
PubMed1992

Reversal of typical multidrug resistance by cyclosporin and its non-immunosuppressive analogue SDZ PSC 833 in Chinese hamster ovary cells expressing the mdr1 phenotype.

The new non-immunosuppressive cyclosporin derivative SDZ PSC 833 (PSC) is a potent agent used to overcome typical multidrug resistance (MDR) associated with overexpression of the mdr1 gene encoding for a P-170 glycoprotein. In the present study, the efficacy of PSC as compared with cyclosporin was determined in Chinese hamster ovary cell lines exhibiting different levels of resistance to colchicine (0, 0.1, 0.2 and 10 micrograms/ml, respectively). Low concentrations of PSC (8.2 nM) increased the cytotoxicity of colchicine in cell lines expressing low levels of drug resistance. The concentration resulting in 50% cell survival (LC50 value) found for colchicine alone or in combination with PSC in the CHO-A3 cell line that was resistant to 100 ng colchicine/ml decreased from greater than 500 to 200 ng/ml at 8.2 nM PSC and to less than 100 ng/ml at 82 and 820 nM PSC. In the CHO-A3 cell line that was resistant to 200 ng colchicine/ml, the LC50 values decreased from greater than 500 ng/ml for colchicine alone to 500 ng/ml for colchicine used in combination with 8.2 nM PSC and to less than 100 ng/ml for colchicine combined with 82 or 820 nM PSC. At a concentration of 82 nM PSC, the maximal effect in MDR reversal was observed in the cell lines exhibiting moderate resistance. In the highly resistant cell line, PSC (820 nM) also reversed colchicine resistance. In drug-accumulation experiments, we obtained a 4-fold increase in intracellular doxorubicin accumulation using 820 nM PSC. A comparison of PSC with cyclosporin revealed that a cyclosporin concentration 20-fold that of PSC was required to obtain the same sensitising effect. On the basis of these data, it may be concluded that PSC is a most promising chemosensitiser.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Treatment of myelodysplastic syndromes (MDS) and high leukaemic risk with low-dose cytosine arabinoside (LD-AraC) plus granulocyte-macrophage colony-stimulating factor (rh GM-CSF). The EORTC Leukaemia Group.

Symptomatic patients with myelodysplastic syndromes (MDS) and 10-30% blasts in the bone marrow were treated with low-dose AraC (2 x 10 mg/m2 subcutaneously (sc) days 1-14) and GM-CSF (fully glycosylated, Sandoz/Schering-Plough, 2 x 150 micrograms protein/day sc) given either subsequently (days 15-21) or simultaneously (days 8-14 and one week rest). Evaluations were carried out after three courses (nine weeks); responding patients could be continued for two further cycles. Eighty-two patients with refractory anaemia and excess of blasts (RAEB), with (RAEBt) or without transformation, were evaluable: 45 RAEB and 37 RAEBt, mean age 64 years (range 17-80 years). A complete remission was achieved in 14 cases (17%), 11 had a good response (13%), and 12 a partial response (15%). Stable disease was found in 21 cases (26%). There were 12 cases of toxic death (15%), progression was noted in eight patients (10%), and death due to disease in three (4%). No difference existed between the two treatment arms with respect to response. Major adverse events during treatment were haemorrhage (25%), infections (23%), and fever with GM-CSF (21%). GM-CSF did not induce leukaemia nor contribute to haemorrhage induced by AraC, but gave rise to an overall response rate of 46% which is high and relatively durable as compared to other treatments in this disease.

Acute Disease↗
PubMed1992

Teniposide in lymphomas and leukemias.

The epipodophyllotoxins, etoposide and teniposide, have been used in leukemias and malignant lymphomas for the past 15 years. Although etoposide has acquired a place in many first-line protocols for lymphomas and, more recently, for leukemias, the role of teniposide has remained limited. Teniposide is a more potent inhibitor of topoisomerase II than etoposide, and has a less toxic effect on hematopoietic progenitor cells. Both drugs have been regarded as equitoxic and cross-resistant. The role of teniposide in front-line treatment of leukemias has only been established in childhood acute lymphoblastic leukemia (ALL). Some promising results have been obtained in small numbers of patients with refractory adult ALL and acute monoblastic leukemia. However, the remission rates and remission duration were not significantly different from those of other combination regimens. Data on teniposide in untreated acute nonlymphoblastic leukemia are very scarce. In non-Hodgkin's lymphoma, the antineoplastic activity of teniposide has been demonstrated in studies by the European Organization for Research and Treatment of Cancer and in two large studies conducted by the Australian and New Zealand Lymphoma Co-operative Chemotherapy Study Group. In these studies, teniposide had comparable but not significantly better activity than vincristine. The dose-dependent antineoplastic activity of teniposide has led to its use in several conditioning regimens in bone marrow transplantation for leukemias and lymphomas. The limited clinical data currently available on teniposide seem to warrant further clinical trials with this agent in leukemias and lymphomas.

Adult↗
PubMed1979

The effect of whole-body irradiation on skeletal growth in rhesus monkeys.

Late effects of single whole-body doses of 400--500 and 750--900 rads on skeletal growth in 32 rhesus monkeys were studied. Findings indicated growth inhibition strongly related to dose and age at irradiation. Doses of 750--900 rads before the age of 40 months resulted in significantly greater growth inhibition (11%) than doses given during or shortly after adolescence (p less than 0.005). Doses of less than 750 rads were not significant. In view of the close similarity between monkeys and man, irradiation of children at doses greater than 750 rads may carry a strong risk of subsequent growth retardation.

Adolescent↗
PubMed1979

Incidence of cataracts in rhesus monkeys treated with whole-body irradiation.

The incidence of cataract formation was investigated in rhesus monkeys exposed to different doses of whole-body irradiation. Application of 850-900 rad (8.5-9 Gy) caused cataracts in 17% of the monkeys within 3 years after treatment; after 10 to 15 years, incidence increased to 100%. "Young" lenses showed a significantly lower incidence than "adult" lenses, although no differences in the stage of cataractogenesis could be demonstrated. Sex differences did not play a role in incidence and severity of cataracts. Lower doses (400 rad or 4 Gy) did not cause cataracts. In view of the close similarity between monkeys and humans, these results indicate that a single dose of 850-900 rad, sometimes employed in the treatment of acute myeloid leukemia in children, carries a strong risk of cataract development.

Animals↗
PubMed1978

The relevance of cell kinetics for optimal scheduling of 1-beta-D-arabinofuranosyl cytosine and methotrexate in a slow growing acute myeloid leukemia (BNML).

1-beta-D-Arabinosyl cytosine and methotrexate were studied for their antitumor activity in acute myeloid leukemia of the BN rat (BNML), which is characterized by a slow growth rate due to the presence of a high proportion of nonproliferating cells. It was found that the two drugs showed the maximal cytotoxic action when given separately. The effect was highly dependent on the interval between the administration of each drug. The variation of the cell kinetic parameters produced by the recruitment into cycle of the resting population, as determined by labeling indices, correlates well with the antileukemic action of the drug combination.

Animals↗
PubMed1978

Effect of alpha-tocopherol on the cardiotoxicity of adriamycin in the rat.

Adriamycin (ADR)-induced cardiomyopathy was studied in a rat model by means of electrocardiograms (ECGs), light microscopy, and determination of heart weight. Pretreatment with D-alpha-tocopherol (alpha-T) 24 hours prior to a high dose of ADR diminishes cardiotoxic effects, as judged by ECG changes, decreases in heart weight, and histologic changes. The response of an acute myeloid leukemia in a rat model to ADR was not affected by this pretreatment. The results provide evidence that alpha-T might be used to improve the therapeutic index of ADR.

Animals↗