Holley, Jane Louise; (1993) The design and evaluation of novel polyamine-cytotoxic conjugates as antitumour agents. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

A polyamine uptake system for the transport of polyamines into tumours and rapidly proliferating cells has been described. In this study, the effect of conjugating cytotoxics to polyamine carriers on their delivery and cytotoxicity to tumour cells in vitro and in vivo was investigated. In Ehrlich Ascites tumour cells, a number of nitroimidazole-polyamine conjugates had a high affinity for the uptake system but were not toxic. A chlorambucil-spermidine conjugate was found to have a high affinity for the uptake system and 30-fold greater toxicity than chlorambucil to ADJ/PC6 plasmacytoma cells in vitro. Polyamine depletion further enhanced the toxicity of the conjugate. A 10,000-fold greater reactivity with naked DNA compared to chlorambucil was also seen. In vivo, however, chlorambucil-spermidine was only two fold more active than chlorambucil. A novel HPLC method for measuring chlorambucil and chlorambucil-spermidine in biological samples showed that the poor in vivo activity was not due to cleavage of the conjugate. In ADJ/PC6 cells in vitro and all tissues studied in vivo, there was enhanced uptake of chlorambucil-spermidine compared to chlorambucil. There was no apparent selective uptake of chlorambucil- spermidine into tumour tissue, even when pharmacokinetics and polyamine depletion were utilized in an attempt to increase the delivery to tissues with a polyamine uptake system. The role of the polyamine uptake system in the uptake of the chlorambucil-spermidine conjugate was unclear. In addition, unchanged chlorambucil-spermidine could still be detected in tissues several days after administration, suggesting that it may become bound intracellularly at sites distant from its DNA target. In four human ovarian carcinoma cell lines, the in vitro toxicity of chlorambucil-spermidine was greater than chlorambucil. Toxicity, however, did not appear to be related to the affinity of the conjugate for the polyamine uptake system or the ability of the different cells to accumulate polyamines. In summary, conjugation of chlorambucil to spermidine increased its delivery and toxicity to tumour cells both in vitro and in vivo. Conjugation of a polyamine to a cytotoxic clearly increased its affinity for DNA but the role of the polyamine uptake system in the delivery of the conjugate was unclear. Competition for DNA binding by endogenous polyamines and intracellular binding of chlorambucil-spermidine at sites distant from the DNA may have contributed to the poorer than expected in vivo activity.

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