View source for WBR0157

 {{WBRQuestion
|QuestionAuthor=William J Gibson (Reviewed by  {{YD}})
|ExamType=USMLE Step 1
|MainCategory=Pharmacology
|SubCategory=Gastrointestinal, Oncology
|MainCategory=Pharmacology
|SubCategory=Gastrointestinal, Oncology
|MainCategory=Pharmacology
|SubCategory=Gastrointestinal, Oncology
|MainCategory=Pharmacology
|MainCategory=Pharmacology
|MainCategory=Pharmacology
|SubCategory=Gastrointestinal, Oncology
|MainCategory=Pharmacology
|SubCategory=Gastrointestinal, Oncology
|MainCategory=Pharmacology
|SubCategory=Gastrointestinal, Oncology
|MainCategory=Pharmacology
|SubCategory=Gastrointestinal, Oncology
|MainCategory=Pharmacology
|MainCategory=Pharmacology
|SubCategory=Gastrointestinal, Oncology
|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?
|Explanation=Patients with pancreatic cancer often present with a painless jaundice that results from compression of the bile duct by the mass in pancreatic head. Pancreatic adenocarcinomas account for 95% of pancreatic tumors; they arise from the exocrine cells of the pancreas.  75% of these cancers arise in the head of the pancreas. Mutations of the ''KRAS'' gene are present in 96% of patients with pancreatic adenocarcinomas. A curative pylorus-preserving Whipple procedure (pancreatoduodenectomy) may be performed for patients with localized disease at the time of diagnosis. Otherwise, patients who are not surgical candidates may benefit from palliative chemotherapy that improves quality of life and may gain modest benefit in survival. Pancreatic cancer has an extremely poor prognosis.

The patient in this vignette is being treated with 5-Fluorouracil (5-FU). 5-FU is a pyrimidine analogue indicated for a variety of solid adenocarcinomas, such as pancreatic adenocarcinoma and colorectal cancer. It is also indicated in topical form for actinic keratosis and basal cell carcinoma. Once introduced into a cell, 5-FU is converted to 5-FdUMP which then inhibits thymidylate synthase. Thymidylate synthase is the enzyme responsible for the synthesis of thymine nucleotides, which are essential for 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). Adverse reactions associated with 5-FU administration include bone marrow toxicity, oral ulcerations, photosensitivity, and anorexia.
|AnswerA=Inhibits dihydrofolate reductase
|AnswerAExp=Methotrexate inhibits dihydrofolate reductase, but it is not a uracil analogue.
|AnswerB=Inhibits DNA polymerase
|AnswerBExp=Cytarabine is a competitive inhibitor of DNA polymerase. Upon entering the cell, cyatabine is converted to araCTP which can then be incorporated into a growing strand of replicated DNA, resulting in elongation termination.
|AnswerC=Inhibits RNA polymerase
|AnswerCExp=Dactinomycin inhbits RNA polymerase by intercalating between cytosine and guanine nucleotides in DNA.
|AnswerD=Inhibits thymidylate synthase
|AnswerDExp=5-Fluorouracil (5-FU) is a pyrimidine analogue indicated for the treatment of solid adenocarcinomas. Once introduced into a cell, 5-FU is converted to 5-FdUMP, which then inhibits thymidylate synthase. Thymidylate synthase is the enzyme responsible for the synthesis of thymine nucleotides. Rapidly replicating cancer cells require more DNA synthesis than most normal tissues, thereby enabling a [[therapeutic window]].
|AnswerE=Inhibits hypoxanthine-guanine phosphoribosyltransferase
|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 agent for hematopoetic malignancies. HGPRT is deficient in patients with Lesch-Nyhan syndrome.
|EducationalObjectives=5-FU is a fluorinated uracil anaologue indicated in several solid cancers. 5-FU inhibits thymidylate synthase, an enzyme essential for the synthesis of thymine nucleotides needed for DNA synthesis.
|References=Beck A, Etienne MC, Chéradame S, et al. A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil. Eur J Cancer. 1994;30A(10):1517-22.<br> Kaye SB. New antimetabolites in cancer chemotherapy and their clinical impact. Br J Cancer. 1998;78 Suppl 3:1-7.<br>
First Aid 2014 page 403<br>
|RightAnswer=D
|WBRKeyword=Cancer, Pancreatic, Pancreatic Cancer, Pancreas, Chemotherapy, Antimetabolite, Nucleotide, DNA synthesis, Fluorouracil, 5-FU, 5FU, 5-Fluorouracil, Uracil, Thymidylate synthase, Chemotherapeutic agent, Pyrimidine analogue, 5-FdUMP, Thymine
|Approved=Yes
}}