DNA Drug
Design for Cancer Therapy
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.
Comments
Post a Comment