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Targeting of Tumor Cells and DNA by a Chlorambucil-Spermidine Conjugate¹

Medical Research Council Toxicology Unit, Woodmansterne Road Carshalton, Surrey, SM4 5EF [J. L. H., G. M. C.]; Department of Chemistry, University of Leicester, Leicester, LE1 7RH [A. M., R. T. W., P. M. C.]; and Department of Oncology, University College and Middlesex School of Medicine, 91 Ridinghouse Street, London, WIP 8BT [J. A. H., J. P. B.], United Kingdom

Many tumor cells, including murine ADJ/PC6 plasmacytoma cells, possess an active energy dependent polyamine uptake system which selectively accumulates endogenous polyamines and structurally related compounds. We have attempted to target the cytotoxic drug chlorambucil to a tumor possessing this uptake system by conjugating it to the polyamine spermidine. Furthermore, since polyamines have a high affinity for DNA, the attachment of spermidine to chlorambucil should also facilitate its targeting to DNA. This was supported by the observation that the chlorambucil-spermidine conjugate was approximately 10,000-fold more active than chlorambucil at forming interstrand cross-links with naked DNA. In vitro cytotoxicity and in vivo antitumor studies were carried out using the ADJ/PC6 plasmacytoma. In vitro, using [³H]thymidine incorporation to assess cell viability following a 1-h exposure to control and polyamine depleted ADJ/PC6 cells, chlorambucil-spermidine was 35- and 225-fold, respectively, more toxic than chlorambucil. The increased toxicity of the conjugate compared to chlorambucil was possibly due to enhanced DNA binding and/or facilitated uptake via the polyamine uptake system. The enhanced toxicity of the conjugate but not chlorambucil by prior polyamine depletion with difluoromethylornithine, together with the observation that the conjugate but not chlorambucil competitively inhibited spermidine uptake into tumor cells, supported the suggestion that the conjugate utilized the polyamine uptake system. In vivo following a single i.p. dose, the conjugate was 4-fold more potent than chlorambucil in its ability to inhibit ADJ/PC6 tumor growth in BALB/c mice. However, the therapeutic index was not increased.

Our results support the hypothesis that polyamines linked to cytotoxics facilitate their entry into tumor cells possessing a polyamine uptake system and increase their selectivity to DNA. This may have therapeutic application in the delivery of cytotoxic agents linked to polyamines to certain tumors.

¹ We thank the Cancer Research Campaign of Great Britain for generous support of this work.

² To whom requests for reprints should be addressed.

Received 1/31/92. Accepted 5/27/92.

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