A study of the influence of newly synthesized acyclonucleosides and 1,2,3,4-tetrahydroisoquinoline derivatives on deoxythymidine and deoxycytidine kinase activities in human neurofibrosarcoma and ovarian cancer.
The influence of nine newly synthesized uracil acyclonucleosides, and 36 derivatives of 1,2,3,4-tetrahydroisoquinoline on the activity of enzymes catalysing dTMP and dGMP synthesis, on the content of dTTP and dGTP in acid soluble fraction and on the incorporation of [14C]dThd and [14C ]dGuo into DNA in tumour homogenates was studied. The influence of the compounds was studied in the cytosol from intraoperatively excised human tumours - neurofibrosarcoma and ovarian cancer. It was shown that dTMP and dGMP synthesis is inhibited competitively by 34.1+/-4.0% in both types of tumours by 0.2 mM 1-N-(3'-hydroxypropyl)-6-methyluracil (1) and 0.2 mM 1-N-(3'-hydroxypropyl)- 5,6- tetramethyleneuracil (2). The mentioned acyclonucleosides reduced the content of dTTP and dGTP in the acid soluble fraction of tumours (59.7+/-3.1% of control). 1-(4-chlorophenyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline (3), 1-(2,3-dichlorophenyl)-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline (4) and 1-(3-methoxyphenyl)-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline (5) at 0.2 mM concentration caused a mixed type inhibition of the synthesis of dTMP and dGMP by, on average, 33.2+/-4.4%, and reduced the content of dTTP and dGTP in the acid soluble fraction (52.6+/-3.7% of control) but were active only in the cytosol of neurofibrosarcoma. While acyclonucleosides undergo phosphorylation in the cytosol by cellular kinases, with their triphosphates being active acyclonucleoside metabolites, active 1,3,4,5-tetrahydroisoquinoline derivatives (compounds not containing a deoxyribose moiety), cannot be phosphorylated. ACN and THI derivatives which inhibit dThd and dCyd kinase activities, inhibit also the incorporation of [14C]dThd and [14C]dGuo (ACN - 50.2+/-2.7%, THI - 53.4+/-3.9% of incorporation inhibition) into tumour DNA. The obtained results point to the mechanism of uracil acyclonucleosides and 1,2,3,4-tetrahydroisoquinoline biological activity consisting in inhibiting the synthesis of DNA components.
Modrzejewska
Hanna
H
Department of Medical Biochemistry, Institute of Physiology and Biochemistry, Medical University of Łódz, Łódz, Poland.
Brzezińska
Elzbieta
E
Dramiński
Marcin
M
Zgit-Wróblewska
Anna
A
Krzykowska
Katarzyna
K
Rozpończyk
Elzbieta
E
Greger
Janusz
J
D002250:Carbon Radioisotopes; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D005260:Female; D019791:Guanidine / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D018319:Neurofibrosarcoma / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011741:Pyrimidine Nucleosides / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000378:metabolism*; D013937:Thymidine Kinase / Q000378:metabolism*; D013938:Thymidine Monophosphate / Q000096:biosynthesis
D002250:Carbon Radioisotopes; D011741:Pyrimidine Nucleosides; D044005:Tetrahydroisoquinolines; D013938:Thymidine Monophosphate; D013937:Thymidine Kinase; D003842:Deoxycytidine Kinase; D019791:Guanidine