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Cytotoxicity of Alkyl-lysophospholipid Derivatives and Low-Alkyl-Cleavage Enzyme Activities in Rat Brain Tumor Cells

Division of Hematology and Oncology, Department of Medicine I, Technical University [W. E. B., E. G., U. F., A. R., J. R.], and Department of Functional Pathology, Ludwig-Maximilians-University [D. S.], 8000 Munich, Federal Republic of Germany, and the Medical and Health Sciences Division, Oak Ridge Associated Universities, Oak Ridge, Tennessee 37830 [D. R. H., F. S.]

Alkyl-lysophospholipids (ALP) and related derivatives inhibited the in vitro incorporation of [³H]thymidine into seven different permanent cell lines derived from rat brain tumors. The cytostatic effect of ALP was dependent on dosage and incubation time. Naturally occurring 2-lysophosphatidylcholine did not exhibit cytostatic effects; under these conditions, the incorporation rates of [³H]thymidine were generally more than 100% of the controls. The trypan blue dye exclusion test, which was used to assess severe cell damage, correlated with the extent that [³H]thymidine incorporation was inhibited by ALP.

Preincubation of ALP (rac-1-octadecyl-lyso-glycero-3-phosphocholine) for more than 8 min with a tetrahydropteridine-dependent O-alkyl cleavage enzyme preparation from rat liver microsomes destroyed almost all of the cytotoxic properties of ALP when tested at a concentration that previously inhibited tumor growth by more than 50%. [³H]Thymidine incorporation rates were greater than 100% for astrocytoma cells incubated with ALP after exposure to the alkyl cleavage enzyme.

Comparison of the microsomal activities of the tetrahydropteridine-dependent alkyl-cleavage enzyme present in astrocytoma 78-FR-G-299 cells and the pleomorphic glioma 78-FR-G-219/S4 cells to that found in normal skin fibroblasts and rat livers revealed a markedly reduced activity in the neoplastic cell lines. Moreover, those tumor cells that were more resistant to ALP cytotoxicity (pleomorphic glioma, 78-FR-G-219/S4) had a 3-fold higher tetrahydropteridine-dependent cleavage activity than a more cytotoxic sensitive line (astrocytoma cells, 78-FR-G-299). Our results indicate that the low-alkyl-cleavage enzyme activities in these neoplastic cells in comparison to normal cells might be a factor in explaining the relatively high cytotoxicity of ALP in tumor cells.

¹ Supported by Deutsche Forschungsgemeinschaft Grants Be 822/2-2 and Sta 134/2. To whom requests for reprints should be addressed: Division of Hematology and Oncology, Department of Medicine I, Technical University, Ismaninger Str. 22, 8000 Munich 80, Federal Republic of Germany.

² In partial fulfillment of the M.D. degree of the Technical University of Munich.

³ Fellowship supported by Grant CA 09336 awarded by the National Cancer Institute to the University of Tennessee and the Oak Ridge National Laboratory.

⁴ Supported by the Office of Energy Research, United States Department of Energy (Contract DE-AC05-760R00033), and the American Cancer Society (Grant BC-70M).

Received 11/19/81. Accepted 11/ 4/82.