Larisa R. answered • 10/23/19
Former Harvard Faculty for PSAT, SAT, and ACT tests
Inhibitors of topoisomerases (TOP) are commonly used in cancer chemotherapy. Topoisomerases are the enzymes that are involved in DNA unwinding during replication, and camptothecin and its derivatives are the commonly used inhibitors of Topoisomerase 1.
Why does inhibition of topoisomerase damage DNA?
TOP inhibitors do not directly cause DNA damage. They create a clamp on the topoisomerase thus, stalling the replication fork. The cells manage to overcome this block by converting the stalled replication fork to a double-strand break
Why do topoisomerase inhibitors damage hair and hematopoietic (blood cells) cells but (hopefully) not other healthy cells.
Most malignant cells lose their cell cycle inhibition control, and therefore, divide uncontrollably. Consequently, at any time, a significant number of malignant cells are undergoing replication. Alternatively, the majority of normal cells (except hair follicles and blood cells) exist in a quiescent state, i.e. they are not dividing. TOP inhibitors do not differentiate between normal and malignant cells but rather target replicating cells. Those tumors that have low proliferation rates may not respond well to the TOP inhibitors.
DNA double-strand breaks usually cause apoptosis in the cell. There are some methods to repair double-strand breaks but they are relatively rare. Why is repairing double-strand DNA breaks difficult? What problem could occur if double-strand DNA repair goes wrong?
As I mentioned, TOP inhibitors indirectly produce double-strand breaks, which is the most dangerous type of DNA damage. If left unrepaired, even one double-strand break triggers apoptotic cell death. At the concentrations that are used,TOP inhibitors produce more breaks than the cell can repair leading to massive cell death..
Double-strand breaks, however, could be repaired by two alternative mechanisms, homologous recombination (HR) and non-homologous end-joining (NHEJ). While the DNA repair by HR is pretty accurate, the second mechanism (NHEJ) intrinsically carries some errors. These errors (or newly acquired DNA mutations) may be responsible for new (and unrelated to the initial one) incidents of cancer.
