WBR0157

Author	PageAuthor::William J Gibson
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology
Sub Category	SubCategory::Gastrointestinal, SubCategory::Oncology
Prompt	[[Prompt::A 45-year-old man presents to his primary care physician with painless jaundice. Abdominal CT shows a mass at the head of the pancreas. Biopsy confirms the diagnosis of pancreatic adenocarcinoma. The patient is treated with an analogue of uracil. Which of the following describes the mechanism of action of this drug?]]
Answer A	AnswerA::Inhibits Dihydrofolate reductase
Answer A Explanation	AnswerAExp::Methotrexate inhibits dihydrofolate reductase, but it is not a uracil analogue.
Answer B	AnswerB::Inhibits DNA Polymerase
Answer B Explanation	AnswerBExp::Cytarabine is a competitive inhibitor of DNA polymerase. Upon entrance to the cell, cyatabine is converted to araCTP which can then be incorporated into a growing strand of replicated DNA, resulting in elongation termination.
Answer C	AnswerC::Inhibits RNA Polymerase
Answer C Explanation	AnswerCExp::Dactinomycin inhbits RNA polymerase by intercalating between Cytosine and Guanine nucleotides in DNA.
Answer D	AnswerD::Inhibits Thymidylate Synthase
Answer D Explanation	[[AnswerDExp::5-Fluorouracil (5-FU) is a pyrimidine analogue indicated for the treatment of a variety of adenocarcinomas. Once introduced into a cell, 5-FU is converted to 5-FdUMP which then inhibits thymidylate synthase. Thymidylate synthesis is the enzyme responsible for the synthesis of thymine nucleotides. A lack of thymine leads to disruption of DNA synthesis.]]
Answer E	AnswerE::Inhibits Hypoxanthine-guanine phosphoribosyltransferase
Answer E Explanation	[[AnswerEExp::Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) plays a central role in the generation of purine nucleotides through the purine salvage pathway. HGPRT itself is not inhibited by any clinically used chemotherapeutics. However, HGPRT is responsible for the activation of 6-Mercaptopurine, a purine analog used as a chemotherapeutic for hematopoetic malignancies. HGPRT is deficient in Lesch-Nyhan Syndrome.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::Pancreatic cancer often presents with “painless jaundice” resulting from compression of the bile duct by an adenocarcinoma of the pancreatic head. Adenocarcinomas account for 95% of pancreatic tumors and they arise from the exocrine cells of the pancreas. 75% of these cancers arise in the head of the pancreas. Pancreatic cancer has an extremely poor prognosis: for all stages combined, the 1- and 5-year relative survival rates are 25% and 6%, respectively. Mutations of the KRAS gene are present in 96% of pancreatic adenocarcinomas. If the tumor has remained localized at presentation(20%), a curative Whipple procedure can be attempted to remove the mass. In patients not suitable for resection with curative intent, palliative chemotherapy may be used to improve quality of life and gain a modest survival benefit. The patient in this vignette is being treated with 5-Fluorouracil (5-FU). 5-FU is a pyrimidine analogue indicated for the treatment of a variety of adenocarcinomas, most notably colorectal cancers. It may also be used topically to treat actinic keratosis and basal cell carcinoma. Once introduced into a cell, 5-FU is converted to 5-FdUMP which then inhibits thymidylate synthase. Thymidylate synthesis is the enzyme responsible for the synthesis of thymine nucleotides. A lack of thymine leads to disruption of DNA synthesis. 5-FU can also be incorporated into newly synthesized RNA and thereby disrupt RNA synthesis. 5-FU acts only in S-phase of the cell cycle (when the genome is being replicated prior to cell division). Side effects of 5-FU administration include bone marrow toxicity, oral ulcerations, photosensitivity and anorexia. Educational Objective: 5-FU inhibits thymidylate synthase. References: First Aid 2014 page 403]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cancer, WBRKeyword::Pancreatic, WBRKeyword::Pancreatic Cancer, WBRKeyword::Pancreas, WBRKeyword::Chemotherapy, WBRKeyword::Antimetabolite, WBRKeyword::Nucleotide
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