Tetrahydrohomofolate, a Specific Inhibitor of Thymidylate Synthetase

Further Evaluation of the Antitumor Activity of Homofolate and its Reduced Derivatives against Methotrexate-Insensitive Tumors

“…The moderate antitumor effect of homofolate is understandable on the basis that like folate, homofolate might be reduced in vivo to tetrahydro derivatives, although to a lesser degree than the dihydrohomofolate. These results clearly substantiate the rationale of an enzyme-dependent regeneration of a pseudo-cofactor for obtaining a highly selective antitumor activity against tumors with increased levels of dihydrofolate-reductase [4], The rationale was further supported by the experiments in which the antitu mor activity of the reduced homofolates was decreased by blocking the dihydrofolate reductase activity with methotrexate pretreatment. Al though in vitro assays have shown pronounced inhibition for 24 h of the reductase activity in mouse liver after administration of 1.5 mg/kg of methotrexate [5], in vivo methods based on column chromatography and UV absorption spectrophotometry have shown that the inhibition of the enzyme which is nearly 90% at 2-hour time interval does not last more than 4 h [10].…”

“…On the basis of this new evidence it ap peared likely that H2HF might have antitumor activity comparable to that of H4HF. The demonstration of antitumor activity of H2HF would support the original rationale, namely, an enzyme-dependent lethal syn thesis of a pseudo-cofactor [4]. In the present study, an attempt was made to determine the contribution of dihydrofolate reductase and/or other factors to the antitumor activity of reduced homofolates.…”

Biotransformation of Homofolate from a Growth Inhibitor to a Growth-Promoting Derivative

“…1), and its de rivatives have been studied for their anti bacterial [1], antimalarial [2] and antitu mor [3] properties. Tetrahydrohomofolate (THHF) is a potent inhibitor of Escheri chia coli thymidylate synthetase [1,4]; 50% inhibition being obtained at 2 x 10'6Af in the presence of 80 times higher concentra tions of tetrahydrofolate (THF). Dihy drofolate reductase reduces HF as well as folic and dihydrofolic acid to the tetrahydro-derivative.…”

“…THHF also inhibits markedly the growth of Streptococcus faecium (ATCC 8043) [5] and Lactobacillus casei ATCC 7469, while HF is a poor inhibitor of the bacteria [6], This inhibition is completely reversed by either thymidine [1] or thy mine [5]. In contrast, Pediococcus cerevisiae is not affected by TH H F (1).…”

The emergence of drug resistance in tumours: a characteristic which may be exploited therapeutically

“…Goodman's group first suggested that tumour resistance to the anti-metabolite methotrexate might be exploited therapeutically (Goodman et al, 1964). They had observed that tumour cells which developed resistance to this agent frequently had increased levels of the enzyme dihydrofolate reductase (Friedkin et al, 1962 (Mishra and Mead, 1972).…”