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E Friche

Publications and source records attributed to E Friche.

27 records · Page 2Linked to original sources
PubMed1990

Antitumor activity of the two epipodophyllotoxin derivatives VP-16 and VM-26 in preclinical systems: a comparison of in vitro and in vivo drug evaluation.

The epipodophyllotoxines VP-16 and VM-26 are chemically closely related. VM-26 has been found to be considerably more potent than VP-16 in vitro in a number of investigations. Although the drugs have been known for greater than 20 years, they have not been compared at clearly defined equitoxic doses on an optimal schedule in vivo and it has not been clarified as to whether a therapeutic difference exists between them. A prolonged schedule is optimal for both drugs; accordingly we determined the toxicity in mice using a 5-day schedule. The dose killing 10% of the mice (LD10) was 9.4 mg/kg daily (95% confidence limits, 7.4-11.8) for VP-16 and 3.4 (2.5-4.5) mg/kg daily for VM-26. In vitro, we found VM-26 to be 6-10 times more potent than VP-16 in a clonogenic assay on murine tumors P388 and L1210 leukemia and Ehrlich ascites. This pattern was also demonstrated in a multidrug-resistant subline of Ehrlich selected for resistance to daunorubicin (Ehrlich/DNR+), as it was 30 times less sensitive than Ehrlich cells to both VP-16 and VM-26. Using 90%, 45%, and 22% of the LD10 on the same murine tumors in vivo, we found that the effect of the two drugs was equal as evaluated by both the increase in life span and the number of cures. The drugs were also compared in nude mice inoculated with human small-cell lung cancer lines OC-TOL and CPH-SCCL-123; however, they were more toxic to the nude mice and only a limited therapeutic effect was observed. In conclusion, the complete cross-resistance between the two drugs suggests that they have an identical antineoplastic spectrum. VM-26 was more potent than VP-16 in vitro; however, this was not correlated to a therapeutic advantage for VM-26 over VP-16 in vivo.

Animals↗
PubMed1990

Transport of the multidrug resistance modulators verapamil and azidopine in wild type and daunorubicin resistant Ehrlich ascites tumour cells.

Verapamil has been proposed to modulate the multidrug resistance phenotype by competitive inhibition of an energy dependent efflux of cytotoxic drug. However, the accumulation of both 14C-verapamil and 3H-verapamil was similar in wild type EHR2 and multidrug resistant EHR2/DNR+ Ehrlich ascites cells, and was much less in both cell lines in energy deprived medium than in medium containing glucose. Azidopine accumulation was also similar in both EHR2 and EHR2/DNR+ cells but, in contrast to verapamil, did not differ significantly with changes in cellular energy levels. Azidopine photolabelled a 170 kDa protein in EHR2/DHR+ plasma membrane vesicles which was immunoprecipitated by monoclonal antibody towards P-glycoprotein. Azidopine increased daunorubicin accumulation and modulated vincristine resistance in EHR2/DNR+ cells in a similar fashion to verapamil. Azidopine photolabelling was inhibited by vincristine and verapamil, but not by daunorubicin. Vincristine, but not daunorubicin, was able to increase both azidopine and verapamil accumulation in EHR2/DNR+ cells only. Finally, though both verapamil and azidopine are a substrate for P-glycoprotein in EHR2/DNR+ cells, they do not themselves appear to be transported by the multidrug resistance efflux mechanism to any significant extent in these cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

The solvents cremophor EL and Tween 80 modulate daunorubicin resistance in the multidrug resistant Ehrlich ascites tumor.

Cremophor EL (polyoxyethylene castor oil) and Tween 80, used as solvents for cyclosporin A and VP-16, respectively, were found to reverse the multidrug resistant (MDR) phenotype. In daunorubicin (DNR) resistant Ehrlich ascites tumor cells (EHR2/DNR+), both solvents at percentages of 0.01% (v/v) enhanced DNR accumulation to sensitive levels. Cremophor EL and Tween 80 did not influence DNR accumulation in drug-sensitive cells (EHR2). The concentration of cyclosporin A alone that enhanced DNR accumulation in EHR2/DNR+ cells to sensitive levels was 5 micrograms/mL whereas 0.2 micrograms/mL of cyclosporin A dissolved in 0.001% (v/v) Cremophor EL enhanced DNR accumulation to sensitive levels, thus indicating synergy between Cremophor EL and cyclosporin A. Cyclosporin A had a negligible effect on DNR accumulation in the drug-sensitive cells. In clonogenic assays, the LD10 of DNR was 1 microM in EHR2/DNR+ cells. Combining 1 microM DNR with non-toxic amounts of Cremophor EL (0.001% and 0.002%, v/v) potentiated the cytotoxicity of DNR and resulted in a cell kill of 77% and 86%, respectively, in the resistant cells. In non-toxic amounts, CrEL and Tween 80 acted synergistically with reduced concentrations of verapamil, resulting in DNR accumulation approaching close to the sensitive level. Azidopine photoaffinity labeling of P-glycoprotein in plasma membrane vesicles from EHR2/DNR+ cells was inhibited 100% and 80%, by 0.003% (v/v) Cremophor EL or Tween 80, respectively. These data permit the conclusion that non-toxic amounts of CrEL and Tween 80 modulated DNR resistance by raising intracellular DNR levels, due to their abilities to bind to the plasma membrane P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Inhibition of vincristine binding to plasma membrane vesicles from daunorubicin-resistant Ehrlich ascites cells by multidrug resistance modulators.

The multidrug resistance (MDR) phenotype is presumed to be mostly dependent on changes in the resistant cell plasma membrane, notably the emergence of a 170 kDa glycoprotein called P-glycoprotein, which facilitate increased drug efflux. We have previously demonstrated that ATP-enhanced binding of vincristine (VCR) to plasma membrane vesicles is much greater in MDR than in wild type cells. The present study has shown that VCR binding to MDR Ehrlich ascites tumour cell plasma membrane vesicles is inhibited 50% most efficiently by quinidine (0.5 microM) followed by verapamil (4.1 microM) and trifluoperazine (23.2 microM). This is the reverse order of the effect on whole cells where a ranking of efficiency in terms of enhancement of VCR accumulation, inhibition of VCR efflux, DNA perturbation and modulation of resistance in a clonogenic assay, was trifluoperazine greater than or equal to verapamil much greater than quinidine. The detergent Tween 80 inhibited VCR binding to plasma membrane vesicles at 0.001% v/v which agreed with the level which modulated resistance and increased VCR accumulation in whole cells. No effect was observed on daunorubicin binding to MDR plasma membrane vesicles after incubation with either Tween 80 (up to 0.1% v/v) or verapamil (up to 25 microM). We conclude that the effect of a modulating drug in reversing resistance to VCR correlates with its ability to raise intracellular VCR levels but not with its capability to inhibit VCR binding to the plasma membrane. Thus, enhancement of VCR accumulation in MDR cells is hardly solely due to competition for a drug binding site on P-glycoprotein. Furthermore, the lack of a demonstrable effect on daunorubicin binding to the plasma membrane by modulators points to transport mechanisms which do not utilise specific drug binding to the plasma membrane.

Animals↗
PubMed1989

Anthracycline resistance.

The major limitation of the usefulness of anthracyclines is the development of drug resistance. Most of the data related to anthracycline resistance has been obtained in experimental animal tumors or in cultured human cell lines. An important characteristic obtained in these models is the common finding of cross-resistance to a series of drugs structurally unrelated to the anthracyclines and with a mechanism of action which apparently differ from that of the anthracyclines. This phenomenon is defined as pleiotropic drug resistance or multidrug resistance (MDR). The cross-resistance demonstrated includes the vinca alkaloids, actinomycin D, colchicin and the epipodophyllotoxins. The best documented mechanism of resistance and mechanism of cross-resistance is decreased cellular drug accumulation. Several findings indicate that the underlying factor of the altered net uptake is an active drug extrusion in the resistant cells. Another important characteristic is the demonstration of a cell surface protein with a molecular weight of about 170,000 (GP 170). Genetic and biochemical evidence indicate that the MDR phenotype in both animal and human cells result from overexpression of the MDR-1 gene which encodes GP 170. Some findings suggest that GP 170 is a transport protein for cytotoxic hydrophobic drugs like the anthracyclines. Other findings suggest that this gene is also associated with intrinsic (natural) anthracycline resistance.

Animals↗
PubMed1988

Refractoriness to alpha-interferon (Intron A) in previously chemotherapy-treated patients with chronic myelocytic leukaemia.

8 patients with chronic myeloid leukaemia in the chronic phase who had previously received chemotherapy were given alpha-interferon (Intron A). The Intron A was administered subcutaneously at a dose of 2 x 10(6) I.U./m2 three times a week and this was increased to 4-5 million I.U./m2 daily if no response was obtained after 6-8 months. 1 patient was Philadelphia chromosome-negative and was the only one who showed a major response to treatment. The other 7 patients never achieved haematologic remissions, or even a significant reduction in the immature blood leucocyte count or spleen size.

Adult↗
PubMed1987

Effect of verapamil on daunorubicin accumulation in Ehrlich ascites tumor cells.

Previous studies have demonstrated that verapamil may overcome resistance to anthracyclines. In vitro and in vivo experiments were performed on wild-type and resistant Ehrlich ascites tumor cells. Verapamil in concentrations of 25-50 microM enhances the accumulation of daunorubicin (DNR) in resistant cells to the same level as in wild-type cells. No significant effect of verapamil on influx or nuclear binding could be demonstrated, indicating that verapamil enhances DNR uptake by blocking active drug extrusion. Exposure of cells to a high concentration of Ca2+ did not influence the effect of verapamil on DNR accumulation, suggesting a different mode of verapamil action apart from the Ca2+-blocking effect. Attempts to circumvent acquired resistance to DNR in vivo with verapamil showed that the combination of the two drugs was more toxic than DNR given alone. The LD10 of DNR was determined as 3 mg/kg and the LD10 of the combination, as 2.5 mg/kg. The therapeutic effect of verapamil at a dose of 50 mg/kg and DNR of 2.5 mg/kg increased the life span of the mice by 50%. No difference was seen in the wild-type tumor in vivo. These data lead us to conclude that verapamil can reverse DNR resistance completely, but that verapamil at non-toxic dosage only reduces DNR resistance by 50% in vivo.

Animals↗
PubMed1983

Mechanism of resistance to anthracyclines and vinca alkaloids.

Occurrence of cross-resistance between anthracyclines and vinca alkaloids is the rule in experimental tumors with acquired resistance to these drugs. So far, there is no indication that this phenomenon is due to an intracellular mechanism of action common to the two groups of drugs. In nearly all reported studies, acquired experimental resistance and cross-resistance are related to a decreased cellular accumulation of both types of drugs, although other factors also are involved. In Ehrlich ascites tumors, a number of findings at steady-state conditions indicate that the decreased accumulation is dependent on a cellular mechanism for active outward drug transport, which is common to anthracyclines and vinca alkaloids, but changes in inward transport and intracellular binding capacity also contribute. Similar findings have been reported for resistance and cross-resistance in P388 leukemia. Recent results with counteraction of acquired experimental resistance in animal tumors by inhibition of outward drug transport and studies on the effect of different anthracycline derivatives on accumulation of daunomycin in resistant cells are discussed.

Animals↗