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Pilot Project #3 —
Application of Cellular Kinetics and Molecular Dynamics in Distinguishing
Selectivity among a Non-Toxic 5-Fluorouracil Dose, Reduced Folates, Methotrexate, and Alimta in Breast Cancer and Normal Cells


Donnell Bowen, Ph.D.

Department of Pharmacology

The aim of this project is to acquire the means to conduct research designed to:
  1. Improve the quality of life of breast cancer patients by exploiting the differences in the biochemical pharmacology of methotrexate (MTX) and the multitargeted antifolate (MTA or Alimta) in MCF-7, MDA-MB-436, MDA-MB-175-VII human breast cancer cells and normal cells such as human bone marrow (Hs 824.T); and
       
  2. provide one clear basis for intracellular rescue of only susceptible host cells from MTX and MTA toxicity, respectively, when high-doses of MTX and MTA are used in combination with a priming and non-toxic 5-fluorouracil (5-FU) dose.

The approach is to: (a) Define a pharmacokinetics and pharmacodynamics relationship of MTX and the new MTA Alimta in breast cancer and bone marrow cells, and (b) define the condition whereby MTX and MTA are very likely to have their maximum benefit. Further, utilizing molecular modeling and dynamics, these studies are designed to determine the basis for antagonistic or selective interactions when MTX and MTA are co-administered with reduced-folates and 5-FU. An assessment of the importance or benefit of MTX and MTA with 5-FU involves an evaluation of the growth of breast cancer and bone marrow cells. A comparison of 5-FU and the reduced-folates (leucovorin [LV] and 5-methyl tetrahydrofolate [mTHF] ) in combination with MTX and MTA is also done in breast cancer and bone marrow cells to aid in determining the mechanism and the outcomes of survival and toxicity. This comparison utilizes molecular modeling and dynamics to determine the stability of the complexes of MTX, MTA, 5-FU, LV, and mTHF with thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide transformylase (GART).

A signficant aspect of MTX and MTA selectivity should be the preferential build-up and retention of polyglutamyl forms of these agents in breast cancer cells compared to cells of the bone marrow (less polyglutamates). By conserving reduced-folates with 5-FU, there is protection in bone marrow, but not in breast cancer cells, as a result of the greater formation of MTX -and MTA polyglutamates. This project utilizes resources of the LMCB.

 

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