Effect of liposomes sensitized with methotrexate-gamma-dimyristoylphosphatidylethanolamine on cells that are resistant to methotrexate.

  title={Effect of liposomes sensitized with methotrexate-gamma-dimyristoylphosphatidylethanolamine on cells that are resistant to methotrexate.},
  author={Stephen C. Kinsky and K Hashimoto and Joan E. Loader and M. Knight and Daniel J. Fernandes},
  journal={Biochimica et biophysica acta},
  volume={885 2},
This study compares the ability of methotrexate and liposomes, in which the drug is anchored to the lipid bilayers via methotrexate-gamma-dimyristoylphosphatidylethanolamine, to inhibit proliferation of human leukemic cells (CEM/O) and cells derived from this line that are resistant to methotrexate because of either a defective transport system (CEM/MTX cells) or elevated levels of dihydrofolate reductase (CEM/R1 cells). Whereas CEM/O and CEM/MTX cells show a 120-fold difference in their… Expand
12 Citations
Inhibition of cell proliferation with antibody-targeted liposomes containing methotrexate-γ-dimyristoylphosphatidylethanolamine
Abstract We have prepared liposomes containing methotrexate-γ-dimyristoylphosphatidylethanolamine (MTX-DMPE liposomes), to which protein A was covalently coupled, permitting specific association ofExpand
Inhibition of cell proliferation by putative metabolites and non-degradable analogs of methotrexate-Y-dimyristoylphosphatidylethanolamine
It is concluded that methotrexate-γ-DMPE must undergo intracellular metabolism to exert optimal inhibition and liposomes prepared with these derivatives are markedly less potent cytotoxic agents than methotxonate-β-D MPE sensitized liposome. Expand
Circumvention of the methotrexate transport system by methotrexate-phosphatidylethanolamine derivatives: effect of fatty acid chain length.
Results suggest that methotrexate-gamma-PE derivatives with appropriate acyl residues might be useful probes to investigate the mechanism by which phospholipids in general are able to traverse cell membranes. Expand
Iodoacetylated and biotinylated liposomes: effect of spacer length on sulfhydryl ligand binding and avidin precipitability.
Biotinyl-(AETA)2-DMPE was incorporated into the same liposomal bilayers that contained the iodoacetylated derivatives, and found that liposomes with bound ligand could be readily precipitated by avidin, and washed free of unreacted IgG by low speed centrifugation. Expand
Liposomes as carriers of antitumor agents: toward a clinical reality.
Although liposomal antitumor agents have no established role in the anticancer armamentarium at this stage, the information available suggests that they may improve the therapeutic index or broaden the applications of available antitumors and possibly act as carriers for newly designed liposome-dependent antitumour agents. Expand
Methotrexate interaction with a lipid membrane model of DPPC
Dipalmitoylphosphatidylcholine (DPPC) liposomes were employed as membrane models for the investigation of the interaction occurring between methotrexate (MTX) and bilayer lipid matrix. Liposomes wereExpand
Liposomes as carriers of different new lipophilic antitumour drugs: a preliminary report.
In vitro cytotoxicity studies of free and liposomal drugs against L1210 cells showed changes in both directions after liposome entrapment, thus suggesting that Liposome Entrapment may alter drug cellular uptake or may result in chemical modifications of the entrapped drug. Expand
Prospects for Liposomes as Drug Carriers
Liposomes are vesicles composed of concentric phospholipid bilayers that are formed spontaneously when an aqueous solution is added to a dried lipid film (Figure 1). Several types ofExpand
Binding of liposomes to human bladder tumor epithelial cell lines: implications for an intravesical drug delivery system for the treatment of bladder cancer.
Data suggest that targeting of drugs to superficial bladder cancer can be achieved by the intravesical administration of PC/PS MLV, which appeared to be specific to tumor cells. Expand
Chemistry and biological activity of antifolates.
  • A. Rosowsky
  • Chemistry, Medicine
  • Progress in medicinal chemistry
  • 1989
Publisher Summary This chapter discusses the structural changes that have been made in each of the above regions of methotrexate (MTX), the synthetic chemical methods used in preparing MTX analogs,Expand


Inhibition of cell proliferation and dihydrofolate reductase by liposomes containing methotrexate-dimyristoylphosphatidylethanolamine derivatives and by the glycerophosphorylethanolamine analogs.
Testing of liposomes with DMPE derivatives indicated that MTX-glyceroPE I was the most effective inhibitor of both cell proliferation and enzymatic activity, and novel use of thiamine pyrophosphate showed that this compound had no influence on inhibition of cell proliferation due to liposome. Expand
Synthesis and characterization of methotrexate-dimyristoylphosphatidylethanolamine derivatives and the glycerophosphorylethanolamine analogs.
Three (I-III) methotrexate derivatives of dimyristoylphosphatidylethanolamine by conjugation of the alpha and/or gamma glutamyl carboxyl groups of the drug with the amino function of the phospholipid are synthesized. Expand
Selective protection against the cytotoxicity of methotrexate and methotrexate-poly(lysine) by thiamine pyrophosphate, heparin and leucovorin.
The results suggest that although MTX and MTX-poly(lys) share the same mode of drug action inside the cell, they possess completely different transport mechanisms at the cell surface. Expand
Liposome encapsulation enhancement of methotrexate sensitivity in a transport resistant human leukemic cell line.
A stable mutant of human leukemia CCRF/CEM cells has recently been isolated which is transport resistant for methotrexate (MTX) and liposome encapsulation may allow such transport resistant tumor cells to become responsive to chemotherapeutic doses of MTX which are currently feasible in human clinical protocols. Expand
Affinity labeling of the 5-methyltetrahydrofolate/methotrexate transport protein of L1210 cells by treatment with an N-hydroxysuccinimide ester of [3H]methotrexate.
An N-hydroxysuccinimide ester of [3H]methotrexate has been employed to covalently label a specific binding protein that resides in the plasma membrane of L1210 cells, supporting a role for this protein in methotrexate transport. Expand
A methotrexate-resistant human breast cancer cell line with multiple defects, including diminished formation of methotrexate polyglutamates.
These studies identify a new mechanism (diminished accumulation of MTX polyglutamates) associated with resistance to MTX and lend additional support to the hypothesis that the formation of these derivatives is an important determinant ofMTX cytotoxicity. Expand
Transport routes utilized by L1210 cells for the influx and efflux of methotrexate.
The demonstration of multiple routes for methotrexate efflux and their differential sensitivities to alterations in energy metabolism thus provides a basis for explaining previously described asymmetries between the influx and efflux of metotrexate in mouse leukemia cells. Expand
Structural requirements for anion substrates of the methotrexate transport system in L1210 cells.
Results support the hypothesis that methotrexate transport proceeds via an anion-exchange mechanism and provide evidence that anion substrates for this system can be identified by their ability to promote metotrexate efflux. Expand
Molecular and karyological analysis of methotrexate-resistant and -sensitive human leukemic CCRF-CEM cells.
The development of resistance to methotrexate (75-fold) was associated with a 20-fold increase of dihydrofolate reductase activity, and an elongated marker chromosome containing a homogeneous staining region not present in the parent line was revealed. Expand