Regulation of ribonucleotide reductase in mammalian cells by chemotherapeutic agents

3,4,5-Trihydroxybenzohydroxamic acid monohydrate, a ribonucleotide reductase inhibitor

“…In an early structure-activity study of hydroxyurea analogues using HeLa cells it was shown that an unsubstituted OH group at the N atom was required for activity (Young, Schochetman, Hodas & Balis, 1967). On the other hand, Elford et al (1979) found that polyhydroxylated benzamides and methyl benzoates were also inhibitors of RNR, indicating that in these compounds the hydroxamic acid moiety is not essential for RNR inhibitory activity. The polyhydroxylated aromatic part of the compounds seems to be the part interfering with the tyrosyl radical of the enzyme.…”

“…3,4-Dihydroxybenzohydroxamic acid (3,4-OHBHA), 2,3,4-trihydroxybenzohydroxamic acid (2,3,4-OHBHA) and 3,4,5-trihydroxybenzohydroxamic acid (3,4,5-OHBHA) were all found to have strong inhibitory activities on partially purified RNR from Novikoff hepatoma cells. These O HO"~ H OH 3,4,5-OHBHA compounds were found to have stronger inhibitory effects than hydroxyurea on the mammalian RNR (Elford, van't Riet, Wampler, Lin & Elford, 1981), whereas the E. coli RNR and the phage T4 RNR were found to be more sensitive towards hydroxyurea than towards the polyhydroxylated benzohydroxamic acids (Kj~ller Larsen, Sj6berg & Thelander, 1982). In an early structure-activity study of hydroxyurea analogues using HeLa cells it was shown that an unsubstituted OH group at the N atom was required for activity (Young, Schochetman, Hodas & Balis, 1967).…”

“…By testing a series of hydroxyurea analogues (Larsen, 1980;Kjoller Larsen et al, 1982) or polyhydroxybenzene derivatives (Elford et al, 1981) it has been found that the ability of a compound to undergo one-electron oxidation is correlated with its inhibitory activity towards RNR. In addition, the most potent inhibitors were approximately planar molecules.…”

“…hydroxylated derivative 2-OHBHA (Kjoller Larsen et al, 1982;Elford et al, 1981). 2-OHBHA is the most planar of the three componds, but has the lowest ability to undergo one-electron oxidation.…”

A phase I and pharmacokinetic study of didox administered by 36 hour infusion

“…The enzyme ribonucleotide reductase provides an excellent target for anti-cancer drugs in view of the importance of the production of deoxyribonucleotides for DNA synthesis (Elford et al, 1981). The enzyme is known to have low activity in resting cells, and increasing with proliferation (Elford et al, 1970), with the level of the enzyme correlated with the rate of replication (Turner et al, 1968).…”