Polyamine-based chemotherapy of cancer

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Abstract
Controlling cancer growth by interfering with its cellular uncontrolled DNA replication is a rational and sound approach for treating this disease. DNA is stabilised by the hydrogen bonding and electrostatic forces provided by DNA-bound polyamines. Targeting the latter is therefore synonymous with targeting cancer growth. This was achieved by: a) designing inhibitors of ornithine decarboxylase (ODC), the inducible enzyme that is mainly responsible for increasing the intracellular pools of polyamines; b) designing inhibitors of extracellular polyamine active transport into the cells; c) synthesis of analogues of spermine, the main DNA-bound and tRNA-bound polyamine; the analogues displace the natural polyamines from the nucleic acids, and alter cell cycling; d) designing synthetic analogues of spermine with restricted conformations. The introduction of restriction in the free rotation around the single bonds in a flexible molecule, such as spermine, results in a spatial rigidity that introduces bends and kinks at the binding sites. Thus, the introduction of alicyclic groups enhances the cytotoxicity of the lineal analogues. The cyclopropyl derivatives are more cytotoxic than the cyclobutyl derivatives, and the latter are more efficacious than the cyclopentane derivatives. In the unsaturated series the cis-isomers are more cytotoxic than the trans-isomers. By combining the therapies based on a) and b) with an appropriate polyamine-free diet, promising results were obtained in controlling cancer growth. An analogue resulting from approach c) is in Phase II clinical trials; and several analogues created by approach d) exhibit powerful cytotoxic effects in vivo. Polyamine derivatives will undoubtedly provide new arrows for the quiver of oncologic drugs.