COMPARISON OF CELL-CYCLE PHASE PERTURBATIONS INDUCED BY THE DNA-MINOR-GROOVE ALKYLATOR TALLIMUSTINE AND BY MELPHALAN IN THE SW626 CELL-LINE

Tallimustine or formyl-N-[4-N-N,N-bis(2-chloroethylamino)benzoyl], a d istamycin-A derivative (FCE 245 17), is a novel anti-cancer agent whic h alkylates N3 adenine in the minor groove of DNA. The cell-cycle phas e perturbations induced by the drug were investigated and compared wit h those caused by melphalan (L-PAM) in SW626 human ovarian-cancer cell s. By coupling bromodeoxyuridine (BUdR) immunoreaction with biparametr ic flow-cytometric (FCM) analysis, we investigated the cell-cycle phas e perturbation induced by tallimustine or L-PAM, considering separatel y the cells which, during the 1-hr treatment, were in the S phase or i n G(1)-G(2)/M phases of the cell cycle. L-PAM delayed the S-phase prog ression of cells exposed to the drug when they were in S phase, with a cansequent accumulation of cells as soon as they reached the G(2) pha se. In contrast, the S-phase cells treated with tallimustine were not perturbed during the DNA-synthesis phase progression, and were blocked in G(2) only after they had passed through the G(1)/S transition of a new cell cycle. In cells which were in G(1) or G(2)/M phases during d rug treatment, tallimustine and L-PAM caused similar accumulation in G (2). The differences in the cell-cycle perturbation caused by tallimus tine and L-PAM may well be related to the different DNA damage the 2 d rugs produced. These findings emphasize the different properties of DN A-minor-groove alkylating agents and conventional ones. (C) 1995 Wiley -Liss, Inc.