Cancer cells from a 23-year-old male with testicular cancer demonstrate high sensitivity to etoposide. The etoposide-killed cancer cells show a high number of double-stranded DNA fractures. These fractures are due to dysfunction of which of the following?

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Etoposide is a semisynthetic derivative of the plant alkaloid podophyllotoxin, which targets topoisomerase II. The topoisomerases are enzymes that relieve the DNA supercoiling that occurs during DNA replication as a result of separation and unwinding of the double helix. Topoisomerase I makes single-stranded nicks to relieve negative supercoiling, while topoisomerase II induces transient breaks in both DNA strands simultaneously to relieve both positive and negative supercoiling. Etoposide and podophyllin specifically inhibit topoisomerase II's ability to seal the strand breaks it induces, causing chromosomal breaks to accumulate and eventual cell death. Two major uses of etoposide are in testicular cancer and small cell lung cancer. Podophyllin is used topically to treat genital warts. (Choices A and E) Antimetabolites are medications that interfere with nucleotide metabolism, thus inhibiting incorporation of new nucleotides into elongating DNA strands. For example, thymidylate synthase and dihydrofolate reductase are enzymes central to thymidine nucleotide synthesis. 5-Fluorouracil and 5-deoxyuridine are antimetabolites that inhibit thymidylate synthase, and methotrexate is an antimetabolite that inhibits dihydrofolate reductase. (Choice B) Irinotecan and topotecan inhibit topoisomerase I, an enzyme that induces single-strand breaks in DNA to relieve negative supercoiling during replication. (Choice D) Vinca alkaloids like vincristine and vinblastine bind tubulin monomers, disrupting the microtubules necessary for separating chromosome strands during mitosis. Taxanes like paclitaxel also cause microtubular dysfunction. Educational Objective: Etoposide is a chemotherapeutic agent that inhibits the sealing activity of topoisomerase II. Treatment with etoposide causes chromosomal breaks to accumulate in dividing cells, ultimately causing cell death.

Cancer Cells from a 23-Year-Old Male with Testicular Cancer Demonstrate