The introduction of heteroartoms in the pyrazine portion of the pteridine ring has produced compounds which display antifolate activity. The initial objective of this research program was to develop a convenient synthesis of the 8-oxadihydropteridine ring system and to test the resulting compounds for antifolate activity in suitable biological systems.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Pharmacology and Toxicology. Title from title-page of electronic thesis. Bibliography: leaves 266-287.

Folate derivatives are required for nucleotide/DNA synthesis and DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylenctetrahydrofolate to 5-methyltetrahydrofolate, the folate derivative required for homocysteine remethylation to methionine, the precursor of S-adenosylmethionine. Approximately 45%--50% of the general population is heterozygous for a common substitution (677C &rarr; T, A to V) in MTHFR. Due to loss of heterozygosity (LOH) in cancer cells, individuals who are heterozygous for MTHFR in their constitutional DNA may contain only one of the above alleles in their tumor DNA. / Loss of heterozygosity of MTHFR was observed in 40% of ovarian carcinoma tumor samples and in 16% of colon carcinoma samples suggesting that the chromosomal location to which the MTHFR gene maps (1p36.3) undergoes frequent LOH. Examination of cell viability of human fibroblasts and of human colon carcinoma cell lines in minimum essential media (MEM) lacking methionine found both cell types to be extremely sensitive to the methionine deficiency. Replacing methionine with homocysteine and vitamin B12 restored the growth of normal fibroblast lines to levels that approached those of replete MEM, but the transformed lines increased proliferation only slightly under these conditions. These results support earlier reports regarding the increased methionine dependence of transformed lines. Targeting specific MTHFR variants with the antisense oligonucleotide resulted in &sim;50% decreased survival of two carcinoma cell lines (V/V genotype), possibly due to MTHFR's involvement in methionine synthesis. Allele-specific targeting of MTHFR could therefore provide an effective approach for cancer therapy. Furthermore, cancer patients with the V/V genotype may require less aggressive anti-folate chemotherapy since V/V carcinoma lines were highly sensitive to drug treatment (IC50 < 25 nM) whereas the A/A lines were more variable in response.

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Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 85-105).

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [114]-124).

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 186-200).