WBR0159

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry, MainCategory::Pharmacology
Sub Category	SubCategory::Oncology, SubCategory::General Principles
Prompt	[[Prompt::A scientist is studying the effects of a chemotherapeutic agent on a lymphoma cell line. He treats the cells with the chemotherapeutic agent and then stains them with propidium iodide, a molecule that binds to DNA and fluoresces in proportion to the amount of DNA. He then measures the propidium iodide staining of the cells with flow cytometry and observes the following plot. Which of the following chemotherapeutic agents was most likely used by this investigator?]]
Answer A	AnswerA::5-Fluorouracil
Answer A Explanation	[[AnswerAExp::5-Fluorouracil (5-FU) is a pyrimidine analogue that inhibits thymidylate synthase. It is indicated for a variety of adenocarcinomas. Similar to all antimetabolites, 5-FU acts during S-phase of the cell cycle. Therefore, accumulation of cells in M-phase with doubling of DNA content is not expected with 5-FU therapy.]]
Answer B	AnswerB::Bleomycin
Answer B Explanation	[[AnswerBExp::Bleomycin is a chemotherapeutic agent used for the treatment of testicular tumors. Bleomycin acts by inducing oxygen free radicals and DNA strand breaks. Bleomycin is classically associated with pulmonary fibrosis. It acts at the level of G2-phase.]]
Answer C	AnswerC::Cyclophosphamide
Answer C Explanation	[[AnswerCExp::Cyclophosphamide is an alkylating agent whose active form irreversibly cross-links DNA to cause cell death. Major adverse events associated with prolonged cyclophosphamide administration are bladder cancer and hemorrhagic cystitis, both of which may be preventable with the administration of mesna. Cyclophosphamide acts in a cell-cycle-independent fashion and so would not be expected to cause cells to accumulate with doubled DNA content in M-phase.]]
Answer D	AnswerD::Cisplatin
Answer D Explanation	[[AnswerDExp::Cisplatin is a non-cell cycle specific alkylating agent. It inhibits DNA and RNA synthesis by cross-linking DNA strands, thereby causing strand breaks. It is used for genitourinary tumors and is extremely effective for testicular cancers. Adverse events associated with cisplatin administration include ototoxicity and nephrotoxicity.]]
Answer E	AnswerE::Vincristine
Answer E Explanation	[[AnswerEExp::Vincristine is an alkaloid that binds to β-tubulin dimers, thereby inhibiting the assembly of microtubulues and blocking microtubule formation in the mitotic spindle (M-phase arrest). Because cancer cells divide more rapidly, there is a therapeutic window which allows vincristine to be used as a chemotherapeutic agent. Mitosis occurs after cells have duplicated their genomes in S phase. Thus, cells which are stalled in mitosis will appear to have doubled DNA content, which is pictured in the flow cytometry plot above.]]
Right Answer	RightAnswer::E
Explanation	[[Explanation::Vincristine is an alkaloid that binds to β-tubulin dimers, thereby inhibiting the assembly of microtubules and blocking microtubule formation in the mitotic spindle (M-phase arrest). Because cancer cells divide more rapidly, there is a therapeutic window which allows vincristine to be used as a chemotherapeutic agent. Mitosis occurs after cells have duplicated their genomes in S phase. Thus, cells which are stalled in mitosis will appear to have doubled DNA content, as pictured in the flow cytometry plot below. Vincristine is used in a variety of cancers including Wilms’ tumor, rhabdomyosarcoma, neuroblastoma, and non-Hodgkin's lymphoma. However, its use is particularly important in the treatment of Hodgkin’s lymphoma, where it is part of the MOPP protocol (Mustargen, Oncoverin/Vincristine, Procarbazine, and Prednisone). The most prominent adverse event associated with vincristine is neurotoxicity, such as peripheral neuritis and paralytic ileus. Vincristine is contraindicated in pregnant women and patients with demyelinating forms of Charcot-Marie-Tooth syndrome. Educational Objective: Vincristine is an alkaloid that binds to β-tubulin dimers, thereby inhibiting the assembly of microtubulues and blocking microtubule formation in the mitotic spindle (M-phase arrest). References: First Aid 2014 page 405]]
Approved	Approved::Yes
Keyword	WBRKeyword::Vincristine, WBRKeyword::Chemotherapy, WBRKeyword::Cell cycle, WBRKeyword::Cancer, WBRKeyword::Flow cytometry, WBRKeyword::Leukemia, WBRKeyword::Mitosis, WBRKeyword::Chemotherapeutic agent, WBRKeyword::Chemotherapy, WBRKeyword::Propidium iodide, WBRKeyword::M-phase, WBRKeyword::M-phase arrest, WBRKeyword::Alkaloids, WBRKeyword::Alkaloid, WBRKeyword::Oncoverin
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