Review Question - QID 108444

Etoposide is a topoisomerase II inhibitor that is used to treat solid tumors as well as leukemia and lymphoma. Topoisomerase II creates selective nicks in DNA in order to unwind supercoiling ahead of replication forks.

Chemotherapeutic agents can be broadly categorized into groups based on their mechanisms of action. Common groups include antimetabolites (that function by interrupting crucial cell metabolic pathways such as DNA synthesis), DNA damaging agents (that either directly crosslinks DNA or prevents DNA replicative functions), microtubule agents, and specific oncogene inhibitors (that target mutations common in certain tumors). Knowing specific chemotherapeutic regimens is beyond the scope of step I; however, you should be familiar with mechanisms of action if provided with the drug. The drug eTOPOside inhibits TOPOisomerase II, an enzyme that nicks DNA and causes relaxation of DNA supercoiling. Supercoils accumulate ahead of a replication fork because of the helical nature of DNA. Therefore, inhibition of this enzyme leads to defects in DNA replication and increases DNA degradation. Tumor cells are rapidly dividing so this degradation of DNA is most harmful to neoplastic cells.

Incorrect Answers:
Answer 1: Attachment of alkyl groups to DNA is the mechanism of action for alkylating agents such as nitrosureas and cyclophosphamide. These DNA modifications lead to DNA dysfunction and inhibits tumor cells due to their dependence on accurate DNA activity for rapid division.

Answer 2: DNA crosslinking agents such as platinum compounds (carboplatin and cisplatin) lead to diffuse covalent bonding between adjacent DNA sequences. These bonding patterns inhibit proper enzymatic reading of DNA and inhibits tumor cells by disrupting their ability to grow and replicate.

Answer 3: DNA intercalation is the mechanism of action for dactinomycin and anthracyclines (such as doxorubicin). These cause DNA breaks and inhibit replication.

Answer 5: Taxanes stabilize microtubules so that they cannot be degraded or remodeled. The mitotic spindle depends upon remodeling of microtubules to generate the characteristic changes of mitosis so these drugs inhibit mitosis. Rapidly dividing cancer cells are most affected by this inhibition.

Bullet Summary:
Etoposide and teniposide are topoisomerase inhibitors, and the normal function of topoisomerase is to relieve DNA supercoiling through selective generation of DNA nicks.