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The Effect of a Phthalanilide Derivative on Lipide Metabolism in L1210 Leukemia Cells^*

Alfred Gellhorn, Mary Wagner, Matthew Rechler, Zeev Koren and William Benjamin

( Department of Medicine and Institute of Cancer Research, College of Physicians and Surgeons, Columbia University, New York, N.Y.)

An active ant-ileukemic phthalanilide, 2-chloro-4'-4''-di-2-imidazolin-2-ylterephthalanilide (NSC-60339) markedly inhibited the in vitro incorporation of acetate into lipides of L1210 cells after in vivo administration. The depression of lipide biosynthesis is considered to be the primary mechanism of anti-leukemic action of this class of compounds because (a) it is not found when an inactive congener is injected into tumor-bearing mice, (b) there is only partial inhibition of lipide metabolism in the phthalanilide-resistant L1210 tumor following treatment, (c) the drug inhibits fatty acid and cholesterol synthesis to a significantly greater extent than protein synthesis, (d) methotrexate, 6-mercaptopurine, 5-fluorouracil, cyclophosphamide, and a nitrosourea derivative, all therapeutically effective against L1210, fail to depress lipide biosynthesis significantly, and (e) the effect of the phthalanilide on fatty acid synthesis in normal adipose tissue is an irregular inhibition in contrast to a regular and profound depression of lipide metabolism in L1210 cells.

From a comparison of the ineffectiveness of NSC-60339 on lipide biosynthesis when added in vitro with the marked inhibition of lipide metabolism in the tumor cells following the subcutaneous administration of the drug it is suggested that the parent molecule is modified to an active form in vivo. Support for this hypothesis has been provided by the demonstration that in vitro lipide biosynthesis in L1210 cells from untreated mice is inhibited when these cells are resuspended in ascitic fluid from treated animals.

The indication that the principal mechanism of action of the phthalanilides is on lipide metabolism provides a unique opportunity to assess the role of lipides in neoplastic growth.

^* This work was supported in part by U.S.P.H.S. Grants Cy-2332 and CRTY-5011, and by the Alma Toorock Memorial Fund.

Magnes Fellow, Medical School of Hebrew University, Israel.

Received 8/23/63.