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  • Life and Medical Sciences  (2)
  • Key words Protein farnesylation inhibitor  (1)
  • folate transport  (1)
  • 1
    Electronic Resource
    Electronic Resource
    A peptidomimetic inhibitor of ras functionality markedly suppresses growth of human prostate tumor xenografts in mice. Prospects for long-term clinical utility (2000)
    Springer
    Cancer chemotherapy and pharmacology 46 (2000), S. 79-83 
    Details
    ISSN: 1432-0843
    Keywords: Key words Protein farnesylation inhibitor ; Human prostate tumors ; Efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: These studies sought to evaluate the antitumor properties of an inhibitor of ras functionality, L-744,832, which acts at the level of its associated protein farnesyltransferase. Methods: Studies were carried out to measure the effects of L-744,832 alone and in combination with paclitaxel (PTXL) against TSU-PR1, DU-145 and PC-3 human prostate tumors xenografted to NCR-nu1 (AT) mice. Tumor-bearing mice were treated on a schedule of daily for 5 days ×2 or 3 with the MTD of L-744,832 and every 3–4 days ×4 with the MTD of PTXL starting 3–5 days after tumor implantation. Tumor volume in millimeters (4/3πr3) was measured 3–5 days after cessation of treatment and the increase in tumor volume in treated and control groups compared. Statistical analysis was carried out by the Chi-squared test. Results: L-744,832 at its MTD markedly inhibited the growth of all three tumors (T/C for increase in tumor mass varied from 11% to 15% and inhibition of growth had a rapid onset (within 1–2 days) and was independent of ras gene status. Estimated tumor doubling times were 8–12-fold greater in treated animals than in control animals. Treatment with L-744,832 for as long as 3 weeks had no untoward effects on the mice as determined by gross examination or necropsy. Administration of L-744,832 with this same dose and schedule potentiated the growth-inhibitory effect of PTXL at its MTD and induced some regression of TSU-PR1 with no obvious deleterious effects on the mice. Conclusions: L-744,832 could be safely administered over a protracted period of time to mice at doses which were markedly inhibitory to the growth of three human prostate tumor xenografts and in combination with PTXL was also well tolerated and brought about some regression of the TSU-PR1 tumor. Overall, these results suggest that L-744,832 could be clinically useful for long-term treatment of early-stage prostate cancer in patients and as an adjunct to cytotoxic therapy for late stages of this disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800000126
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Two-compartment behavior during transport of folate compounds in L1210 cell plasma membrane vesicles (1982)
    Springer
    The journal of membrane biology 68 (1982), S. 19-28 
    Details
    ISSN: 1432-1424
    Keywords: folate transport ; plasma membrane vesicles ; L1210 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary The transport of [3H] 1,l 5-formyltetrahydrofolate, [3H] folic acid, and [3H]methotrexate by L1210 cell plasma membrane vesicles exhibited multicompartmental behavior. Two separate vesicular compartments (parallel relationship) of approximately equal volume were revealed during measurements of influx and efflux. Flux in one compartment was rapid, saturable, highly temperature-sensitive, and inhibited by pCMBS. Flux in the other compartment exhibited all of the characteristics of passive diffusion. These results imply that our plasma membrane vesicle preparations consist of a mixture of two functional species. Transport of folate into one of these species occurs by passive diffusion alone, whereas transport into the other kind of vesicle occurs by both passive diffusion and carrier-facilitated transport.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01872250
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  • 3
    Electronic Resource
    Electronic Resource
    Altered molecular properties of tubulin in a multidrug-resistant variant of Chinese hamster cells selected for resistance to vinca alkaloids (1988)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 136 (1988), S. 341-347 
    Details
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: The basis for the markedly altered intracellular binding of [3H]vincristine in a multidrug-resistant variant (DC-3F/VCRd-5L) of Chinese hamster lung cells (DC-3F) was investigated. Binding of [3H]vincristine by protein in cytosol derived from each cell type exhibited a differing requirement for GTP in MgCl2 containing buffer of low-ionic strength. Binding of [3H]vincristine occurred to cytosolic protein derived from both variant and parental DC-3F cells, but after removal of GTP, binding only occurred to cytosolic protein from parental cells regardless of the presence of added GTP. Although binding by cytosolic protein from parental DC-3F cells did not require GTP, the addition of 0.1 mM GTP increased by two-fold the rate and extent of binding. When cytosol from variant and parental DC-3F cells was incubated with low concentrations of [3H]vincristine in high-ionic strength buffer and analyzed by molecular-sieve HPLC, most of the protein binding [3H]vincristine in parentally derived cytosol eluted as Mr 110,000-115,000 daltons, corresponding to that for dimeric tubulin. The same binding species was not detected in cytosol derived from variant cells. However, these same fractions derived with both parental and variant cytosols contained tubulin as shown by SDS-PAGE and immunoblotting. A smaller peak of [3H]vincristine binding and an amount of tubulin equal to that found in later fractions were found in the void volume during the same HPLC elution runs with cytosol from both variant and parental DC-3F cells. Evidence was also obtained for differences between parental and variant DC-3F cells in β-tubulin isoforms following isoelectric focusing and immunoblotting. Parental-cell cytosol contains a single isoform of β-tubulin. However, in variant cell cytosol the same isoform and, in addition, three more basic isoforms were found. These alterations in [3H]vincristine binding and in isoform compositions of β-tubulin in variant versus parental DC-3F cells may have importance in regard to vincristine resistance in DC-3F cells.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcp.1041360218
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  • 4
    Electronic Resource
    Electronic Resource
    Markedly altered membrane transport and intracellular binding of vincristine in multidrug-resistant Chinese hamster cells selected for resistance to vinca alkaloids (1986)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 126 (1986), S. 266-274 
    Details
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Studies of a multidrug-resistant variant (DC-3F/VCRd-5L) of Chinese hamster lung cells selected for resistance to vinca alkaloids revealed marked alterations in transport and intracellular binding of [3H]vincristine compared to parental DC-3F cells. Influx of [3H]vincristine in DC-3F cells appears to be an equilibrating, but mediated, process. Although saturation kinetics for [3H]vincristine influx were not demonstrated, an extremely high temperature-dependence (Q1027-37°C = 5-6) and trans-inhibition of influx following preloading of cells with nonradioactive vincristine argue in favor of a carrier-mediated process. Efflux of [3H]vincristine from parental cells conformed to first-order kinetics (t1/2 37° = 3.6 ± 0.4) and exhibited a lower temperature-dependence (Q10 27-37°C = 3-3.5) than influx. In variant vs. parental cells, influx of [3H]vincristine was reduced 24-fold and efflux was increased twofold, accounting for the large (approximately 48-fold) reduction in steady-state level of exchangeable drug accumulating in variant cells. Otherwise, transport of [3H] vincristine in these cells showed characteristics similar to parental DC 3F cells. Also, the rate and amount of intracellular binding of [3H]vincristine in variant cells was almost 40-fold lower than in parental cells. These alterations in influx and efflux of [3H]vincristine and its intracellular binding appear to account, at least to a major extent, for the high level of resistance (2,750-fold) of this variant to vinca alkaloids. In contrast, cross-resistance of this variant to daunomycin (178-fold) could be explained only minimally by a transport alteration. Only a two-fold increase in efflux of [3H]daunomycin was demonstrated in variant vs. parental cells along with some decrease in intra-cellular binding. Influx of [3 H]daunomycin was unaltered. In view of these results, we conclude that these two agents most likely do not share the same route for entry in these cells but might share the same efflux route.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcp.1041260217
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