Cytokinetic effects of bifunctional antitumor intercalator ditercalinium on Friend erythroleukemia cells.
Ditercalinium (NSC 335153) is a novel 7H-pyridocarbazole dimer in which the two monomers are joined by a rigid bis(ethylpiperidinyl)-linking chain producing a molecule capable of bisintercalation into DNA with extremely high affinity. The effect of ditercalinium on cell proliferation and its interaction with DNA in situ has been investigated in the Friend leukemia cell system. Ditercalinium caused an inhibition of cell growth at 0.5 microM and cell death at 2.5 microM. However, both the cytokinetic and cytotoxic effects became evident only after 1-2 days of continuous drug exposure. In contrast, monointercalators generally affect cell growth within several hours of administration. Furthermore, whereas most intercalators arrest cells in G2 phase, ditercalinium demonstrated no cell cycle phase specificity. In fact, a stathmokinetic experiment, in which vinblastine was used to prevent cell division in exponentially growing Friend leukemia cell cultures, demonstrated that ditercalinium effectively "froze" cells in position throughout the cell cycle, in a dose-dependent fashion. By determining the sensitivity of DNA in situ in fixed Friend leukemia cells to acid-induced denaturation, it was apparent that ditercalinium, rather than stabilizing DNA as do monointercalators, increased the sensitivity of DNA in situ to denaturation induced by acid. It appears, therefore, that the cytokinetic effects and interaction with chromatin of an agent that has the ability to bisintercalate into DNA are qualitatively different from those induced by classical monointercalating drugs.
D000818:Animals; D000970:Antineoplastic Agents; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D007364:Intercalating Agents / Q000494:pharmacology / Q000627:therapeutic use; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D004273:DNA, Neoplasm; D007364:Intercalating Agents; C042804:ditercalinium