A direct genetic approach for cancer treatment is represented through DNA (antisense and other oligonucleotides (ODN’s)) drug design. This approach follows the mechanisms that activate genes known to confer a growth advantage to neoplastic cells. They have the ability to block the expression of these genes which allows exploration of normal growth regulation. As the Progress in DNA drug technology has been rapid, the traditional antisense inhibition of gene expression is now viewed on a genomic scale. Several antisense oligonucleotides are in clinical trials. These antisense oligonucleotides are well tolerated, and are potentially, therapeutically active. These drugs are promising molecular medicines for the treatment of human cancer in the near future.
Antisense or decoy DNA drugs can specifically inhibit gene expression and, as indicated in this review, can ultimately affect abnormal cell proliferation. Downregulation of genes that contribute to cancer progression has been the goal of antisense research, with the expectation that such an approach may lead to a selective or preferential inhibition of tumor growth without harming normal cell growth. Such targets include oncogenes, growth factors, cytokines, protein kinases, phosphoprotein phosphatases, and other positive intracellular regulators of cell growth and cell survival. Although a number of studies have demonstrated in vitro the efficacy of these ODNs against tumor growth, an examination of their long-term effects and pharmacological properties is warranted.
Recent advances in high-throughput screening of gene expression by microarray analysis would permit these studies. Results from these studies will not only provide critical information on ODN pharmacokinetics and toxicity, they will also provide insight into the mechanism of action of these molecules on their own targets and on total cellular gene expression. Such studies will thus narrow the number of selected target genes and the discovery of new target genes for antisense therapeutics.
Revisiting antisense-targeted gene expression on a genome-wide scale will facilitate the discovery of clinically appropriate antisense drugs and provide a unique perspective on the development of new chemotherapeutic combinations based on the molecular actions of these drugs.
Unlike conventional chemotherapy regimens, which depend on the maximum tolerated dose of a given drug to achieve optimal tumor-cell kill, treatment regimens involving antisense ODNs may rely more on the concept of an optimal biological dose. The ultimate goal of therapeutic ODNs is their use as long-term biological gene modulators with minimal or no toxicity. In that case, antisense ODNs represent cytostatic rather than cytotoxic drugs. As such, ODNs can induce tumor cells to differentiate or revert, eventually leading to apoptosis, and reduce or eliminate the chance of relapse in cancer patients following initial treatment. For utmost therapeutic effect, these biological target based antisense DNA drugs can be used at nontoxic minimum doses in combination with low doses of conventional cytotoxic drugs or radiation therapy for cancer.