Abstract
BACKGROUND: In the light of the recent findings concerning the role of apoptosis and of tumor cell enzymes in cancer chemotherapy, the interest in pyrimidine derivatives has greatly increased. Thio- and hydrazine- pyrimidines were synthesized as potential antimetabolites inhibiting the biosynthesis of nucleic acids. Some of them demonstrated biological activity, including antibacterial and antitumor action. The aim of this study was to analyze the cytotoxic activity and the ability of some derivatives to induce apoptosis in murine leukemia cells. METHODS: Exponentially growing cells were incubated with compounds and after 24, 48, and 72 hours were stained with trypan blue and counted hemocytometrically. For detection of the cell fraction undergoing apoptosis, a morphological analysis was made using fluorescent dye propidium iodide. RESULTS: Eight thio- and hydrazine- pyrimidine derivatives were investigated. 2-Thiouracil and 6- hydrazinouracil did not influence the cell growth. 2,4-dithiouracil, 2-thio-4-hydrazinouracil, 2-hydrazinouracil, and 2-thio-5-fluorouracil decreased cell proliferation, but even at the highest studied concentration (1000 ?M) had no cytostatic action. Only high concentrations of 2,4-dihydrazinouracil and 2- chloro-4-hydrazinouracil showed a strong cytotoxic activity. The treatment with 2,4-dihydrazinouracil as well as with 5-fluorouracil caused the appearance of apoptotic cells with typical fragmented condensed nuclei, ghosts and apoptotic bodies. In contrast, dead cells treated with 2-chloro-4-hydrazinouracil did not show apoptotic morphology. CONCLUSION: Among studied eight thio- and hydrazine- pyrimidine derivatives only 2,4-dihydrazinouracil demonstrated strong apoptogenic activity. Its active concentrations were about 100 times higher than apoptogenic concentrations of 5-fluorouracil which points to different mechanisms of cytotoxic action.
Highlights
I ncreased proliferative activity of tumor cells is closely related to the increased activity of essential enzymes that participate in pyrimidine metabolism
This compound inhibits the growth of various microorganisms; it displays an inhibitory effect on the final stages of pyrimidine nucleotide synthesis, on the conversation of orotate into uridine nucleotides, on cytosine triphosphate synthase reaction, and on the maturation of 45 S preRNA [5,6]
In the light of the recent results showing that 5-fluorouracil causes apoptosis in many kinds of tumor cells [9,10], it was interesting to study if hydrazine- and thio- derivatives of pyrimidines are able to induce apoptosis in tumor cells
Summary
I ncreased proliferative activity of tumor cells is closely related to the increased activity of essential enzymes that participate in pyrimidine metabolism. In the course of investigation of wide spectrum of pyrimidine derivatives it has been found that 2-thio-4-hydrazinouracil show the highest activity. This compound inhibits the growth of various microorganisms; it displays an inhibitory effect on the final stages of pyrimidine nucleotide synthesis, on the conversation of orotate into uridine nucleotides, on cytosine triphosphate synthase reaction, and on the maturation of 45 S preRNA [5,6]. In the light of the recent results showing that 5-fluorouracil causes apoptosis (programmed cell death) in many kinds of tumor cells [9,10], it was interesting to study if hydrazine- and thio- derivatives of pyrimidines are able to induce apoptosis in tumor cells. CONCLUSION: Among studied eight thio- and hydrazine- pyrimidine derivatives only 2,4-dihydrazinouracil demonstrated strong apoptogenic activity.
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