Methotrexate (MTX) is a widely used and important agent in the treatment of breast cancer. MTX is often used in combination with other agents in the treatment of breast cancer. MTX is often used in combination with other agents in the treatment of breast cancer. These MTX regimens used in breast cancer treatment include cyclophosphamide, MTX, and 5-fluorouracil (CMF) and cyclophosphamide, MTX, 5-fluorouracil and prednisone (CMFP). Intracellularly, MTX bindings to dihydrofolate reductase (DHFR) at the folate binding site and inhibits the enzyme. DHFR is ultimately required for the production of thymidylate nucleotides which are essential for the synthesis of DNA. Chronic and high dose of MTX is often hampered by the development of MTX resistance in the host cells. MTX resistance is often manifested as a relapse of cancerous growth during treatment or during post-treatment evaluations. MTX resistance may occur via several different molecular mechanisms. These include 1) amplification of the DHFR gene, 2) synthesis of mutant DHFRs, 3) diminished transport of MTX inside cells, 4) decreased ability to synthesize polyglutamates, 5) decreased thymidylate synthase activity. The objective of the proposed research is to use computer-assisted molecular modeling and design methods in conjunction with the available detailed three-dimensional structural knowledge of the folate binding site of human wild type and MTX resistant mutant dihydrofolate reductase (DHFRs) to design new anti-folate analogs which do not required intracellular polyglutamation nor a membrane carrier for transport into host cells. These new agents will also be capable of effectively inhibiting both the wild type and MTX resistant mutant DHFR molecules. This group of new agents will not be susceptible to three of the five known mechanisms of MTX resistance and are expected to represent a significant advancement in the treatment of breast cancer.

Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
28
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Howard University
Department
Type
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
Faruque, Mezbah U; Chen, Guanjie; Doumatey, Ayo P et al. (2017) Transferability of genome-wide associated loci for asthma in African Americans. J Asthma 54:1-8
Johnston, Henry Richard; Hu, Yi-Juan; Gao, Jingjing et al. (2017) Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome. Sci Rep 7:46398
Kessler, Michael D; Yerges-Armstrong, Laura; Taub, Margaret A et al. (2016) Challenges and disparities in the application of personalized genomic medicine to populations with African ancestry. Nat Commun 7:12521
Liu, Ching-Ti; Raghavan, Sridharan; Maruthur, Nisa et al. (2016) Trans-ethnic Meta-analysis and Functional Annotation Illuminates theĀ Genetic Architecture of Fasting Glucose and Insulin. Am J Hum Genet 99:56-75
Rand, Kristin A; Rohland, Nadin; Tandon, Arti et al. (2016) Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk. Hum Mol Genet 25:371-81
Mathias, Rasika Ann; Taub, Margaret A; Gignoux, Christopher R et al. (2016) A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun 7:12522
Ehret, Georg B (see original citation for additional authors) (2016) The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 48:1171-1184
Kurian, P; Dunston, G; Lindesay, J (2016) How quantum entanglement in DNA synchronizes double-strand breakage by type II restriction endonucleases. J Theor Biol 391:102-12
Ogunjirin, Adebowale E; Fortunak, Joseph M; Brown, LaVerne L et al. (2015) Competition, Selectivity and Efficacy of Analogs of A-84543 for Nicotinic Acetylcholine Receptors with Repositioning of Pyridine Nitrogen. Neurochem Res 40:2131-42
Winchester, Danyelle; Ricks-Santi, Luisel; Mason, Tshela et al. (2015) SPINK1 Promoter Variants Are Associated with Prostate Cancer Predisposing Alterations in Benign Prostatic Hyperplasia Patients. Anticancer Res 35:3811-9

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