Cytokinetic and morphologic differences in ovarian cancer cells treated with ET-18-OCH3 and the DNA-interacting agent, etoposide.
New antineoplastic agents with different cytotoxic mechanisms are of interest for their ability to overcome resistance to conventional DNA-interacting agents. Ether lipids are known to be active against ovarian carcinoma both in vitro and in vivo, and the cell membrane is believed to be the target of their antitumor activity. In this study we have investigated the different cytokinetic and morphologic responses of human ovarian carcinoma cells (BG-1) to one of the ether lipids (ET-18-OCH3) and to etoposide. Etoposide induced a significantly greater G2/M block. However, the proportion of the cycling cell fraction decreased significantly in cells treated by ET-18-OCH3 and induction of the hypodiploid traction was strongly correlated with reduction of the cycling cell fraction. On the other hand, the hyperdiploid fraction was found to correlate with reduction of the cycling cell fraction in etoposide treated cells. Despite the significant appearance of the hypodiploid fraction, apoptosis was not observed by DNA-gel assay. Microscopic study showed that the hyperdiploid fraction represented cells with multiple nuclei. These observations support the unique lethal effect of ET-18-OCH3 on ovarian carcinoma cells, distinguishing it from the action of a typical DNA-interacting agent. The membrane-targeted ether lipids deserve consideration for the future chemotherapy of ovarian carcinoma, perhaps in combination with the appropriate DNA-interacting agent. New antineoplastic agents with different cytotoxic mechanisms are of interest not only for their unique inhibitory properties but also for their potential of overcoming resistance to conventional DNA-interacting agents. Ether lipids are known to be active against ovarian carcinoma both in vitro (1, 2, 3) and in vivo (4, 5), and the cell membrane is believed to be the target of their antitumor activity. Etoposide, a DNA-interacting agent, is also active against human ovarian cancer cells in vitro (6) or in clinical trials either as a single agent (7) or in combination with cisplatin (8). We have reported that a cytotoxic dose of one of the ether lipids, ET-18-OCH3, induces a G2/M block in BG-1 human ovarian cancer cells, and also a hypodiploid fraction as shown on DNA analysis by flow cytometry (FCM) (9). The G2/M block was also observed in BG-1 cells following etoposide treatment (6). In the present study, we have investigated the differences in the cytokinetic and morphologic responses of BG-1 cells to ET-18-OCH3 and to etoposide.
Fujiwara
K
K
Department of Obstetrics and Gynecology, Kawasaki Medical School, Kurashiki-City, Japan.
Koike
H
H
Ohishi
Y
Y
Shirafuji
H
H
Kohno
I
I
Modest
E J
EJ
Kataoka
S
S
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology*; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D004171:Diploidy; D005047:Etoposide / Q000633:toxicity*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007364:Intercalating Agents; D007700:Kinetics; D010051:Ovarian Neoplasms / Q000473:pathology*; D010742:Phospholipid Ethers / Q000633:toxicity*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D010742:Phospholipid Ethers; C026659:edelfosine; D005047:Etoposide