title: Sequential combination chemotherapy in human breast cancer: a basis for increased antineoplastic activity and bone marrow protection.
abstract: These studies were designed to develop procedures that would capitalize on the growth inhibitory effects of tamoxifen (Tam) and methotrexate (MTX) in breast cancer, while protecting bone marrow with a priming dose of 5-fluorouracil (5-FU). High-dose MTX (10 microM) cytotoxicity is maintained in MCF-7 breast cancer cells but reduced in human bone marrow by a priming and nontoxic dose of 5-FU (10 microM). MTX cytotoxicity is decreased in MCF-7 breast cancer cells when the selective estrogen receptor modulator (SERM) Tam (10 microM) is administered 24 hours prior to 5-FU (10 microM) followed two hours later by MTX (early Tam) resulting in a growth rate of 57.42 +/- 4.38% of the control rate. However, when breast cancer cells are exposed to Tam 24 hours after 5-FU + MTX (late Tam), the interaction between MTX and Tam is not antagonistic, the percentage of the control is 29.47 +/- 4.54%. Bone marrow exposure to these drug combinations exhibits a protective effect to the MTX cytotoxicity, with the early Tam combination yielding 59.45 +/- 16.38% of the control for MTX alone. These studies suggest that a) Tam in combination with a priming dose of 5-FU protects bone marrow from MTX cytotoxicity, b) the interactions between Tam and MTX are sequence-dependent, c) Tam decreases the effect of MTX when Tam administration precedes MTX.
authors.affiliation: 1Hampton University, School of Pharmacy, Hampton, VA 23668, USA. jillian.davis@hamptonu.edu
authors.forename: J H
authors.initials: JH
authors.lastname: Davis
authors.forename: J A
authors.initials: JA
authors.lastname: Desoto
authors.forename: E B
authors.initials: EB
authors.lastname: Fryar
authors.forename: W M
authors.initials: WM
authors.lastname: Southerland
authors.forename: D
authors.initials: D
authors.lastname: Bowen
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D005472:Fluorouracil; D008727:Methotrexate