Abstract #2146

Background:
 DNA topoisomerase I (Top1) has been identified as the molecular target of a variety of drugs, due to the important roles that they play in biological systems. Studies show that breast cancer cell lines are sensitive to Top1 agents such as camptothecin. Recent clinical trials have suggested that breast cancer patients may respond to drugs which target Top1. This suggests that some breast cancers may have elevated expression of the enzyme.
 Thus, development of Top1 inhibitors may be a good target for anticancer therapy. To better target cancer cells, the drugs can be linked to a pH-sensitive linker such as the N-Ethoxybenzylimidazoles (NEBIs) developed in our lab. The NEBIs are designed to undergo hydrolysis in slightly acidic aqueous solutions at physiological temperature, comparable to the environment found in endosomes, lysosomes, and the extracellular environment of tumors. The hydrolysis of the NEBI causes the dissociation of the drug from a carrier (e.g. Herceptin), and the rates can be tuned by modifying the electron withdrawing and donating groups on the NEBI ring. It was demonstrated that the rates can be tuned to give half-lives ranging from 36 minutes to 9 months.
 Materials and Methods:
 We have developed a new class of imidazole-containing drugs which may inhibit Top1 activity. These compounds have a 4-ring, indenoisoquinoline structure and were synthesized by a simple condensation reaction which gives good yield. Ring substituents were modified to achieve molecules of optimal potency. The resulting drugs were subsequently linked to the NEBI, and hydrolysis studies were performed to determine the rate of active drug release.


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 Cytotoxicity of cleaved drugs was screened using the sulforhodamine B (SRB) assay and topoisomerase inhibition assays will be performed in the near future.
 Results:
 Cytotoxicity studies showed that the hydrolyzed drugs are toxic to the 10μM range in cancer cells. One of the compounds has recently been approved for the National Cancer Institute screen, in which the activity will be evalutated with 60 different cancer cell lines of diverse tumor origins. Ongoing studies will assess the topoisomerase I inhibition activity of these compounds.
 Discussion:
 We have developed a novel prodrug which comprises of a toxic Top1 inhibiting drug attached to a pH-sensitive linker. This may prove to be an effective approach to anticancer therapy. Future studies will be pursued in using folic acid as the drug carrier to target breast cancer cells. Studies show that folate receptor overexpression is associated with poor outcome in women with breast cancer. Furthermore, it has been shown that folate receptors may undergo endocytosis, which will trigger the release of the active drug from the linker.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2146.

Thirty-first San Antonio Breast Cancer Symposium Dec 10-14, 2008; San Antonio, TX

©2009 American Association for Cancer Research.
2009