Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow.

Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow. Research Abstract Details 

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Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow. Abstract Text:

Jharna R Das,Elizabeth B Fryar-Tita,Sidney Green,William M Southerland,Donnell Bowen,

BACKGROUND: Pemetrexed (Alimta) is a new-generation multitargeted antifolate that inhibits several key enzymes in the de novo pathways of pyrimidine and purine biosynthesis, including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). Alimta has demonstrated antitumor activity in a broad array of human malignancies, e.g. breast, non-small cell lung cancer, malignant pleural mesothelioma and pancreatic, colorectal, gastric, bladder, head and neck cancer, and is currently in phase III clinical trials. It has been reported that a dose of 600 mg/m2 of pemetrexed showed toxicity to bone marrow and the gastrointestinal system. The aim of this investigation was to evaluate raloxifene (RAL) in combination with 5-fluorouracil (5-FU)/pemetrered multitargeted antifolate (MTA) to determine the most effective regimens and cellular mechanism of action to mitigate pemetrexed cytotoxicity in human bone marrow cells. MATERIALS AND METHODS: In order to determine the sequence-dependent interaction between MTA, 5-FU and RAL on proliferation, cell viability was carried out using the Quick Cell Proliferation Assay by exposing the HS-5 and MCF-7 cells to (i) MTA, 5-FU and RAL alone, or (ii) RAL 24 h prior to 5-FU followed 2 h later by MTA, or (iii) 5-FU 2 h prior to MTA followed 24 h later by RAL. RESULTS: The growth rate in MCF-7 in early RAL was 69 +/- 8.65% and late RAL was 36 +/- 4.6% of the control whereas in bone marrow early RAL was 78 +/- 8.65% and late RAL was 52 +/- 5.49% of the control. The late RAL exhibits significant protection against MTA cytotoxicity in bone marrow. The findings were further supported by cell flow cytometry, apoptosis and Western blot analysis data. CONCLUSION: This study suggests that sequence-dependent administration of RAL (5FU/MTA/RAL), in combination with 5-FU/MTA, protects against MTA toxicity in human bone marrow while maintaining the maximum inhibitory effect of pemetrexed in breast cancer.

Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow. Publishing Authors By Initials

JR Das,EB Fryar-Tita,S Green,WM Southerland,D Bowen,

For similar organic chemicals: hydrocarbons: hydrocarbons, cyclic: hydrocarbons, aromatic: benzene derivatives: benzylidene compounds: stilbenes: tamoxifen: raloxifene research abstracts see: organic chemicals: hydrocarbons: hydrocarbons, cyclic: hydrocarbons, aromatic: benzene derivatives: benzylidene compounds: stilbenes: tamoxifen: raloxifene research

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Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Anticancer research

VOLUME: 27

Page Numbers: 825-33

Journal Abbreviation:

ISSN: 0250-7005

DAY: 3

MONTH: 12

YEAR: 2007

Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8102988

Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow. Keywords Mesh Terms:

KEYWORDS: Raloxifene

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow. Information

Substance Name: Raloxifene

Registry Number: 84449-90-1

Grant and Affiliation Information for Sequence-dependent administration of raloxifene and 5-fluorouracil/pemetrexed protects against pemetrexed cytotoxicity in human bone marrow.

AFFILIATION: Department of Pharmacology, College of Medicine, Howard University, Washington, DC 20059, USA.

Country: Greece

AGENCY: United States NCRR

GRANT: G12RR003048-18

ACRONYM: RR

MEDLINETA: Anticancer Res

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