Comparison of cell-cycle phase perturbations induced by the DNA-minor-groove alkylator tallimustine and by melphalan in the SW626 cell line.
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.
Erba
E
E
Mario Negri Institute, Milan, Italy.
Mascellani
E
E
Pifferi
A
A
D'Incalci
M
M
D000477:Alkylating Agents / Q000494:pharmacology*; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000187:drug effects*; D004247:DNA / Q000737:chemistry* / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000032:analysis; D004214:Distamycins / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008558:Melphalan / Q000494:pharmacology*; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D010051:Ovarian Neoplasms; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D004273:DNA, Neoplasm; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C066900:tallimustine; D004247:DNA; D001973:Bromodeoxyuridine; D008558:Melphalan