Genotoxic Activity of a Newly Synthesized Derivative of Pyrrolin-2-one and its Oxygen Analogue in Mouse Lymphoma and Bone Marrow Cells

Armen K. Nersesyan1, Gagik S. Melikyan2, and Helga Stopper3

1 Laboratory of Carcinogenesis, Cancer Research Centre, Yerevan Armenia
2 Department of Organic Chemistry, State University, Yerevan, Armenia
3 Department of Toxicology, Institute of Pharmacology and Toxicology, Julius-Maximilians University, Würzburg, Germany

Corresponding author: Armen K. Nersesyan, PhD, DSc
    Laboratory of Carcinogenesis
    Cancer Research Centre
    Yerevan 52, Armenia
    Telephone: (+3741) 52 34 23
    Fax number: (+3741) 28 69 22
    E-mail: armenn@freenet.am

CEJOEM 2003, Vol.9. No.1.: 45–53

Key words:
pyrrolin-2-one derivatives, micronuclei, comet assay, L5178Y mouse lymphoma cells, mouse bone marrow cells

Abstract:
Possible genotoxic activity of two newly synthesized compounds with in vitro antitumor activity [a derivative of pyrrolin-2-one (lactame, IPATP), and its oxygen structural analogue (lactone, IPATB)] was studied both in in vitro and in vivo murine test systems. In L5178Y mouse lymphoma cells, IPATB did not induce micronuclei (MN) at the highest available concentration, while IPATP induced them only at high doses (3-fold and 4-fold more than in negative control at doses of 500 and 1000 µg/ml, respectively). IPATB was not toxic for cells at maximum used (soluble) dose (10 µg/ml), but IPATP significantly decreased the number of cells (57% and 39% at doses 500 µg/ml and 1000 µg/ml, respectively, compared to negative (solvent) control. In experiments on possible DNA damaging activity (i.e., comet assay) of both substances using the same doses as in in vitro mutagenesis assay, we did not reveal any evidence of DNA damage. The acute toxicity of compounds was studied on male Swiss albino mice. IPATP was dissolved in DMSO and injected intraperitoneally. Because of its limited solubility in DMSO, IPATB was dispersed in 1% solution of starch, and administered by gavage. LD50 values of IPATP and IPATB were 460 and 80 mg/kg, respectively. Both substances induced MN only at doses equal to ½ of LD50. IPATP was more potent MN inductor and increased the number of MN 5-fold compared to negative control. The increment of MN induced by IPATB was 2-fold. Administration of substances at doses equal to 1/5 of LD50 did not induce any significant increase of MN in bone marrow cells. IPATP possessing weak genotoxic potency and comparatively low toxicity, along with its antitumor activity in vitro, is a good candidate for in vivo antitumor studies on rodents.

Received: 14 August 2003
Accepted: 22 September 2003
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