The nucleus offers a variety of potential targets for anti-cancer drug design. Historically, most nucleus-specific agents have been designed to interact with DNA, causing extensive DNA damage leading to induction of cell death. The new strategy in drug design is to tailor the drug to the specific cancer diagnosed in an attempt to provide the most suitable treatment with the least deleterious side effects to the patient. The outcomes of this approach include drugs targeting specific signalling molecules such as BCR/ABL in the case of Glivec and chronic myelogenous leukemia. In addition to reduced toxicity, using defined targets in combination therapy may help to reduce the development of drug resistance. Targeting specific key molecules in the nuclear environment, such as chromatin-associated proteins, proteins involved in replication, recombination, repair, and transcription is another level at which to disrupt requisite cancer-promoting pathways. The HDAC inhibitors in combination with the DMNTs shows promise of specifically activating genes that are important tumour suppressors silenced by hypermethylation more effectively than when used as single agents. Many topoisomerase targeted compounds have been successfully used in the clinic thus far, and certainly set the stage for the targeting of other proteins involved in DNA replication and recombination including some important helicases and repair proteins. The DNA-associated HMG proteins are another useful target and set a precedent for examining other DNA distortion- recognizing proteins and proteins that bind to specific DNA regions such as MARs.
Alternatively, as we understand more about genomic DNA itself, specific sequences and regions, secondary structures, nucleosome formation and higher-order compaction, and interactions with the nuclear matrix and associated proteins, drugs have been and will continue to be designed to disrupt these processes specifically. It is hoped that this approach will provide the same benefits as outlined above for targeting the associated proteins, but may be broader by interfering with multiple processes that occur at the affected locations.
An exciting area of research being developed is conjugation of compounds capable of recognizing certain sequences with compounds that exert another function. Examples of this are the polyamide-chlorambucil and CBI conjugates[93,94] that connect highly specific DNA sequence recognition with DNA alkylation and mostly work by inhibiting specific gene expression, but this approach could be extended to facilitate targeting of the DNMT and HDAC inhibitors, for instance, to specific tumour suppressor promoters to activate transcription. Lastly, another important area of research is focused on taking these small molecules and developing them into tumour-specific pro-drugs as another means of reducing deleterious side effects to the patient.