WBR0159

Author	PageAuthor::William J Gibson
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 on an acute myeloblastic leukemia cell line. He treats the cells with the chemotherapeutic 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 histogram. Which of the following chemotherapeutics was most likely used by this investigator?]]
Answer A	AnswerA::5-Fluorouracil
Answer A Explanation	[[AnswerAExp::Incorrect: 5-Fluorouracil (5-FU) is a pyrimidine analogue that inhibits thymidylate synthase. It is indicated for the treatment of a variety of adenocarcinomas and acts during S-phase of the cell cycle. Therefore, we would not expect to see accumulation of cells in M-phase with doubled DNA content.]]
Answer B	AnswerB::Bleomycin
Answer B Explanation	AnswerBExp::'''Incorrect:''' Bleomycin is a chemotherapeutic used for the treatment of testicular tumors. Bleomycin acts by inducing oxygen free radical and DNA strand breaks. It is notorious for causing pulmonary fibrosis.
Answer C	AnswerC::Cyclophosphamide
Answer C Explanation	[[AnswerCExp::Incorrect: Cyclopophamide is a prodrug which is converted to its active metabolite by the Cytochrome P450 system. It then acts as an alkylating agent, irreversibly cross-linking DNA to cause cell death. A major side effect of cyclophosphamide is hemorrhagic cystitis, which is preventable with 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::Incorrect: 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. Its most notable side effects are ototoxicity and nephrotoxicity.]]
Answer E	AnswerE::Vincristine
Answer E Explanation	[[AnswerEExp::Correct: Vincristine binds to tubulin dimers, thereby inhibiting the assembly of microtubulues and blocking cell progression through mitosis. Because cancer cells divide more rapidly, there is a therapeutic window which allows vincristine to be used as a chemotherapeutic. 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 binds to tubulin dimers, thereby inhibiting the assembly of microtubulues and blocking cell progression through mitosis. Because cancer cells divide more rapidly, there is a therapeutic window which allows vincristine to be used as a chemotherapeutic. 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. Vincristine is used in a variety of cancers including Wilms’ tumor, choriocarcinoma and ALL. However, its use is particularly important in the treatment of Hodgkin’s Lymphoma where it is part of the MOPP protocol. The most prominent side effect is peripheral neuropathy. Educational Objective: Vincristine binds to tubulin dimers, thereby inhibiting the assembly of microtubulues and blocking cell progression through mitosis. References: First Aid 2012 page 401 Educational Objective: References: ]]
Approved	Approved::Yes
Keyword	WBRKeyword::Vincristine, WBRKeyword::Chemotherapy, WBRKeyword::Cell cycle, WBRKeyword::Cancer, WBRKeyword::Leukemia, WBRKeyword::Mitosis
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