lecture 15 - Intercalation and new targets

Question 1

How can DNA topoisomerase II be targeted in cancer chemotherapy?

Answer 1

Most drugs that target TOP2 kill cells by trapping an enzyme intermediate termed the covalent complex
TOP2-mediated DNA damage can be repaired by several pathways - double strand break repair pathways and other pathways that are specific for the removal of protein-DNA adducts
Catalytic inhibition of TOP2 could be a useful anticancer strategy - new compounds are being delivered to test this

Question 2

What is an important side effect of targeting TOP2 with TOP2 poisons?

Answer 2

Secondary malignancies can arise from drug-induced translocations

Question 3

What is the definition of intercalation?

Answer 3

The reversible insertion of a molecule into a layered structure (DNA)

Question 4

How can doxorubicin target transcription?

Answer 4

It interacts with and stabilises the topo-II-DNA complex to produce a cleavable complex - this results in DNA strand breakage that is associated with the protein-DNA complex

Question 5

How can guanine tetraplexes be used as a treatment for telomerases in cancer therapy?

Answer 5

Telomerase adds DNA sequence repeats to the 3’ end of DNA strands in the telomere regions
Telomeres contain non-coding DNA and prevents loss of important DNA from chromosome ends
Telomeres can form G-quadruplexes
G-quadraplex-interactive drugs can either inhibit helicases or facilitate formation of new quadruplexes, or can sequester newly formed G-quadruplexes