The influence of three newly synthesized pyrimidine-containing compounds on micronucleus induction and tumor growth.
OBJECTIVE
To study the micronucleus (MN)-inducing (both in vivo and in vitro) and antitumor activity in vivo of 3 newly synthesized compounds (DGS-658, DGB-664A and DGS-666), and the influence of these compounds on MN-inducing and antitumor activity of cyclophosphamide (CP).


METHODS
The compounds were tested for their toxicity and MN-inducing activities in HeLa tumor cell line and Swiss mice. Antitumor activity was studied on mouse Ehrlich ascites carcinoma (EAC) by means of evaluation of tumor (ascites) volume and mean lifespan (MLS). To study the influence of the compounds on MN-inducing effect of CP (30 mg/kg), one hour after i.p. injection, mice were treated with the compounds at doses equal to (1/2) of LD(50) (lethal dose). To study the effect of possible enhancement of antitumor activity, the compounds were injected one hour after CP (at doses equal to maximum tolerated dose / MTD), for 6 consecutive days. One day after the last injection half of the mice with EAC were sacrificed and antitumor activity was assessed by means of ascites volume inhibition. Also the frequency of MN and the number of viable cells (by means of trypan blue exclusion) was evaluated in ascites. The rest of the mice were kept until death and then the MLS was calculated.


RESULTS
Only DGS-666 induced significant increase in the number of MN and prolonged the MLS of mice with EAC. Combined action of DGS-658, DGS-664A, DGS-666 and CP showed a significant increase in the number of EAC cells with MN by 17.5%, 23.1% and 50.2%, respectively, compared with CP action (p <0.001). Antitumor effect of combined action of the compounds with CP (based on the ascites volume) was increased compared with CP effect by 17.7% (p >0.05; DGS-658 and DGS-664A) and 28.2% (p <0.001; DGS- 666). Combined action of CP and the DGS-658, DGS-664A, DGS-666 prolonged significantly the MLS of mice compared with CP action by 51.2%, 56.0% and 110.4%, respectively (p <0.001).


CONCLUSIONS
These newly synthesized compounds, practically inactive in MN induction and possessing no or slight antitumor activity, increased significantly the mutagenic and antitumor activity of CP, one of the most frequently used chemotherapeutic agents in clinical oncology. The compounds are practically non-toxic making them very attractive for further studies.
Nersesyan
A
A
National Center of Oncology, Yerevan, Armenia. armen.nersesyan@meduniwien.ac.at
Muradyan
R
R
Arsenyan
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002286:Carcinoma, Ehrlich Tumor / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D006367:HeLa Cells; D006574:Heterocyclic Compounds, 2-Ring; D006801:Humans; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D015162:Micronucleus Tests; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; C527137:DGS-658; C527139:DGS-664A; C527138:DGS-666; D006574:Heterocyclic Compounds, 2-Ring; D011720:Pyrazoles; D011743:Pyrimidines; C030986:pyrimidine