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Cross-resistance pattern of cell lines selected for resistance towards different cytotoxic drugs to membrane-toxic phospholipids in vitro

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Summary

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 (AUXB1) 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.

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Abbreviations

ALP :

alkyl-lysophospholipid derivative(s)

TLP :

thioether-lysophospholipid derivative(s)

EL :

ether lipid(s)

ET-18-OCH 3 :

1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine

BM41.440 :

1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine

MDR :

multiple drug resistance

MTX :

methotrexate

DHFR :

dihydrofolate reductase

ADR :

Adriamycin

FCS :

fetal calf serum

HTCA :

human tumor-cloning assay

IC 50 :

drug concentration inhibiting the 48 h [3H]-thymidine uptake of cells by 50% or resulting in a 50% decrease in trypan-blue dye exclusion or colony formation in the HTCA at the times indicated

RDR :

relative drug resistance

HPC :

hexadecylphosphocholine (D18 506)

PK-C :

protein kinase C

TPA :

12-O-tetradecanoylphorbol-13-acetate

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine I and Department of Medical Statistics and Epidemiology (R.B.), Technische Universität München, D-8000, München 80, Federal Republic of Germany

    Andreas W. Himmelmann, Susanne Danhauser-Riedl, Gabriela Steinhauser, Raymonde Busch, Johann Rastetter & Wolfgang E. Berdel

  2. Department of Biochemistry, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA

    Edward J. Modest & Alessandro Noseda

  3. Division of Hematology and Oncology, Department of Medicine, Emory University, Atlanta, Georgia, USA

    W. Ralph Vogler

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  1. Andreas W. Himmelmann
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Additional information

This work was supported by Deutsche Forschungsgemeinschaft grant DFG BE 822/2-6, by a Heisenberg scholarship sponsored by the Deutsche Forschungsgemeinschaft (W. E. B.), and by grants CA-29 850 (W. R. V.) and CA-41314 (E.J.M.) from the National Cancer Institute

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Himmelmann, A.W., Danhauser-Riedl, S., Steinhauser, G. et al. Cross-resistance pattern of cell lines selected for resistance towards different cytotoxic drugs to membrane-toxic phospholipids in vitro. Cancer Chemother Pharmacol 26, 437–443 (1990). https://doi.org/10.1007/BF02994095

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