Comparison of cell‐cycle phase perturbations induced by the DNA‐minor‐groove alkylator tallimustine and by melphalan in the SW626 cell line

Abstract

Tallimustine or N-deformyl-N-[4-N-N,N-bis(2-chloroethylamino)benzoyl], a distamycin-A derivative (FCE 24517), is a novel anti-cancer agent which alkylates N3 adenine in the minor groove of DNA. The cell-cycle phase perturbations induced by the drug were investigated and compared with those caused by melphalan (L-PAM) in SW626 human ovarian-cancer cells. By coupling bromodeoxyuridine (BUdR) immunoreaction with biparametric flow-cytometric (FCM) analysis, we investigated the cell-cycle phase perturbation induced by tallimustine or L-PAM, considering separately the cells which, during the 1-hr treatment, were in the S phase or in G1-G2/M phases of the cell cycle. L-PAM delayed the S-phase progression of cells exposed to the drug when they were in S phase, with a consequent accumulation of cells as soon as they reached the G2 phase. In contrast, the S-phase cells treated with tallimustine were not perturbed during the DNA-synthesis phase progression, and were blocked in G2 only after they had passed through the G1/S transition of a new cell cycle. In cells which were in G1 or G2/M phases during drug treatment, tallimustine and L-PAM caused similar accumulation in G2. The differences in the cell-cycle perturbation caused by tallimustine and L-PAM may well be related to the different DNA damage the 2 drugs produced. These findings emphasize the different properties of DNA-minor-groove alkylating agents and conventional ones.

A Two-Hit Mechanism for Pre-Mitotic Arrest of Cancer Cell Proliferation by a Polyamide-Alkylator Conjugate

“…38,39,40 Therefore, it is not surprising that 1R-Chl exerts its anti-cancer effect by damaging DNA and inducing G 2 /M arrest. However, unlike other DNA-damaging agents, including the polyamide-Chl conjugates 2-Chl, 6-Chl and 7-Chl, 1R-Chl is selective for cancer cells, and exhibits no significant acute and low chronic toxicity in vivo (Alvarez et al, in preparation).…”

Mode of action of thiocoraline, a natural marine compound with anti-tumour activity

“…The data are the average of three replications and were analysed with the Cell Quest software. The fluorescence pulses were detected using a band pass filter 530 ± 30 nm and 620 ± 35 nm, for green and red fluorescence respectively, in combination with a dichroic mirror 570 nm (Erba et al, 1995). The percentage of the cell cycle phase distribution were calculated by the method of Krishan and Frei (Krishan and Frei, 1976).…”

Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

“…BUdR uptake was detected after 1-h incubation with 100 jl of anti-BUdR monoclonal antibody (diluted 1:10 in 0.5% Tween 20 in PBS), followed by another 1-h incubation with 100 jil of FITC-conjugated goat anti-mouse IgG (diluted 1:50 in 0.5% Tween 20 in PBS). After washing with PBS, the cells were resuspended in a solution of 5 jig ml-' propidium iodide in PBS and 10 000 U of ribonuclease for at least 2 h in the dark (Erba et al, 1995).…”