Platinum-acridine hybrid agents induce apoptosis in several solid tumors models at concentrations up to three orders of magnitude lower than the clinical drug cisplatin. Unlike cisplatin, the hybrid molecules are strong dual inhibitors of replication and transcription. The mechanism of action of these compounds involves formation of unique monofunctional–intercalative DNA adducts in chromatin, which trigger cell-cycle arrest in late G1/early S phase. This presentation discusses key features of the molecular mechanism, structure-activity relationships, and cellular pharmacology that have guided the design and preclinical development of these agents. Immunocytochemical and post-labeling techniques, in conjunction with confocal microscopy, were used to study the hybrids in live and fixed cancer cells. The results of these studies and screening using a yeast-based chemical genomics platform suggest that the hybrid adducts are a more severe form of DNA damage than the classical cisplatin-type cross-links. Novel strategies of reducing the systemic toxicity of the agents based on unique prodrug designs and by directing them to more cancer-specific targets are discussed. These include guanine-rich sequences of the human telomeric repeat and ribosomal DNA transcribed by RNA polymerase I in the cell’s nucleolus.

Tuning the pharmacological properties of platinum-acridine anticancer agents using novel prodrug and subcellular targeting strategies

249th National Meeting (2015)

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