Science, Technology and Engineering

Cutts Laboratory

Department of Biochemistry

Research - Cellular responses to anthracycline-DNA lesions

The anticancer drug Adriamycin is widely used in cancer chemotherapy, and is classified as an inhibitor of topoisomerase II. However, it is now well established that anthracyclines such as Adriamycin can bind covalently to DNA to form DNA adducts via an aminal linkage when activated by formaldehyde. In mammalian cell culture experiments, we can activate Adriamycin to bind covalently to DNA by providing low toxicity formaldehyde-releasing prodrugs such as AN-9 (pivaloyloxymethyl butyrate). It appears that these lesions provide a more lethal death-inducing signal in cells than damage which occurs in the absence of formaldehyde (ie topoisomerase II-mediated damage). The combination of anthracyclines with formaldehyde-releasing agents may prove clinically beneficial. The questions being addressed are:

1. Which members of the anthracycline family of antibiotics cause DNA adducts?
2. How are the DNA adducts recognised in cells and are they efficiently repaired?
3. How do these DNA adducts facilitate the apoptotic process?
4. Is the genomic specificity of adducts important?
5. What is the contribution of other mechanisms of action to these processes?
6. Can anthracycline-resistance mechanisms be overcome by providing formaldehyde-releasing drugs?
7. Do the DNA adducts constitute mutagenic lesions in cells?

Research undertaken in collaboration with Professor Don Phillips (La Trobe University), Dr Ada Rephaeli (Tel Aviv University, Israel), Professor Abraham Nudelman (Bar Ilan University, Israel) and Dr Ken-Ichi Kimura (Iwate University, Japan).