Polyamine-based chemotherapy of cancer

Controlling cancer growth by interfering with its cellular uncontrolled DNA replication is a rational and sound approach for treating this disease. DN A is stabilised by the hydrogen bonding and electrostatic forces provided b y DNA-bound polyamines. Targeting the latter is therefore synonymous with t argeting cancer growth. This was achieved by: a) designing inhibitors of or nithine decarboxylase (ODC), the inducible enzyme that is mainly responsibl e for increasing the intracellular pools of polyamines; b) designing inhibi tors of extracellular polyamine active transport into the cells; c) synthes is of analogues of spermine, the main DNA-bound and tRNA-bound polyamine; t he analogues displace the natural polyamines from the nucleic acids, and al ter cell cycling; d) designing synthetic analogues of spermine with restric ted conformations. The introduction of restriction in the free rotation aro und the single bonds in a flexible molecule, such as spermine, results in a spatial rigidity that introduces bends and kinks at the binding sites. Thu s, the introduction of alicyclic groups enhances the cytotoxicity of the li neal analogues. The cyclopropyl derivatives are more cytotoxic than the cyc lobutyl derivatives, and the latter are more efficacious than the cyclopent ane derivatives. In the unsaturated series the cis-isomers are more cytotox ic than the trans-isomers. By combining the therapies based on a) and b) wi th an appropriate polyamine-free diet, promising results were obtained in c ontrolling cancer growth. An analogue resulting from approach c) is in Phas e 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.