This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator.
The aim of this proposal is 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 project involves an approach that will: (1) Define a pharmacokinetics and pharmacodynamics relationship of the antifolate, MTX and the new drug (MTA) Alimta in breast cancer and bone marrow cells, and 2) define the condition whereby MTX and MTA are very likely to have their maximum benefit. During the current year, studies were aimed at developing procedures that would capitalize on the growth inhibitory effects of tamoxifen (Tam) and methotrexate (MTX), trimetrexate (TMQ), and pemetrexed (MTA) in breast cancer, while protecting bone marrow with a priming dose of 5-fluorouracil (5-FU). Results obtained demonstrated that a priming dose of 5-FU protected bone marrow with early Tam yielding a percent inhibition of 67.20 5.81 and late Tam 66.33 5.57% of the control. The new multi-targeted antifolate MTA in the same combinations in breast cancer cells yielded similar results with early Tam 64.50 10.25% of the control, while late Tam yielded 43.20 5.53% of the control. These studies suggest that a) a priming dose of 5-FU protects bone marrow from MTX, TMQ, and MTA cytotoxicity, b) the interactions between Tam and MTX, TMQ, and MTA are sequence-dependent c) Tam decreases the effect of MTX, TMQ, and MTA when Tam administration precedes MTX, TMQ, and MTA.
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