The influence of 14 acyclonucleosides, derivatives of
adenine,
guanine,
uracil and
thymine on the phosphorylation of dAdo, dGuo, dCyd and dThd occurring in the cytosol of growing
amelanotic melanoma transplanted to Syrian hamsters, as well as on inhibition of
tumor growth were studied. From among the studied ACNs eight were tested earlier (Modrzejewska et al., 1996, The influence of alkoxymethyl
purine and
pyrimidine acyclonucleosides on growth inhibition of Kirkman-Robbins
hepatoma and possible mechanism of their
cytostatic activity, Z. Naturforch. 51c, 75-80); from among the newly synthesized ACNs, 1,3-N,N-diallyloxymethylthymine (AMT2), 1-N-allyloxymethyl-5,6-tetramethyleneuracil (AMUTM), and tested previously 1-N-allyloxymethylthymine (AMT1), administered i.p. in a dose of 0.2 mmol/kg
body weight reduce the
tumor mass from 0.98 g to 0.64 g +/- 0.11 g (i.e. 35% +/- 12%). 48 hours after i.p. administration of the mentioned ACNs in the same dose a reduction of
tumor mass is accompanied by the inhibition of dAMP,
dGMP and
dTMP synthesis. AMT1 inhibits dThd phosphorylation from 6.2 to 4.22; AMT2 suppresses dAdo, dGuo and dThd phosphorylation by, correspondingly, from 2.8 to 1.7, from 10.8 to 7.5 and from 6.2 to 4.2; AMUTM depresses dAMP synthesis from 2.8 to 1.6 (all data: mumol of 2'dNMP formed per mg of
protein per min. x 10(-4)). None of the 14 studied acyclonucleosides influences
dCMP synthesis. In vivo, after hydration of allyloxymethyl group to hydroxypropoxymethyl residue (having -CH2OH group), AMT1, AMT2 and AMUTM undergo phosphorylation to corresponding triphosphates. Phosphorylated ACNs are not incorporated into
tumor DNA, however they inhibit dAdo, dGuo and dThd incorporation into
DNA. It is concluded that
ACN triphosphates are not substrates for
DNA polymerase but, competing with dATP
dGTP and
dTTP, inhibit incorporation of these 2'dNTP into
DNA and, in consequence, reduce
tumor growth, which is presumed to be the main mechanism of
cytostatic activity of the studied ACNs.