Cross-resistance pattern of cell lines selected for resistance towards different cytotoxic drugs to membrane-toxic phospholipids in vitro.
The synthetic ether lipids ET-18-OCH3 and BM41.440 and a derivative, hexadecylphosphocholine, were tested for inhibition of [3H]-thymidine uptake into a Chinese hamster ovarian cell line (AUXBl) and its multidrug-resistant subline selected for colchicine resistance (CHRC5). The activity of all three compounds against the multidrug-resistant subline was equal to or higher than that against the parent line. The same result was found for their activity against a human leukemic lymphoblastic cell line (CEM/O) and its methotrexate-resistant subline (CEM/MTX). In contrast, two multidrug-resistant cell lines selected for resistance to Adriamycin, the mouse leukemia cell line P388/ADR and the murine sarcoma cell line S180/ADR, expressed modest cross-resistance to the lipids as measured by thymidine uptake. Experiments performed using the trypan-blue dye-exclusion assay yielded comparable results, although this system revealed a slightly different sensitivity in showing the cytotoxicity of the drugs. By this assay, modest cross-resistance for ET-18-OCH3 and BM41.440 to Adriamycin was found only after 24 h incubation and decreased after 48 h incubation, with almost equal sensitivity to both drugs being shown by the parental (P388/W) and resistant lines (P388/ADR). Furthermore, findings from a human tumor-cloning assay were in accordance with these data, although they did not indicate cross-resistance for the P388/ADR cell line. These results suggest that certain ether lipids and derivatives might represent valuable anticancer drugs warranting further study in the setting of resistant disease.
Himmelmann
A W
AW
Department of Medicine I, Technische Universität München, Federal Republic of Germany.
Danhauser-Riedl
S
S
Steinhauser
G
G
Busch
R
R
Modest
E J
EJ
Noseda
A
A
Rastetter
J
J
Vogler
W R
WR
Berdel
W E
WE
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D010743:Phospholipids / Q000037:antagonists & inhibitors*; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D003470:Culture Media; D010743:Phospholipids; D014316:Tritium; D013936:Thymidine