WBR0165

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology
Sub Category	SubCategory::Oncology, SubCategory::Reproductive
Prompt	[[Prompt::A 62-year-old woman presents to her physician for vague abdominal pain, bloating, and unintentional 10-pound weight loss over the past two months. Pelvic examination is remarkable for an adnexal mass. A transvaginal ultrasound shows a pelvic mass. Further work-up reveals markedly elevated serum CA-125 level. When the therapeutic regimen is explained to the patient, the patient recognizes the name of one drug saying, “That drug was on the stent my husband received after his myocardial infarction”. What is the mechanism of action of the most likely chemotherapeutic agent?]]
Answer A	AnswerA::Inhibits microtubule polymerization
Answer A Explanation	AnswerAExp::Vincristine binds to beta-tubulin dimers and inhibits the assembly of microtubulues.
Answer B	AnswerB::Inhibits microtubule depolymerization
Answer B Explanation	AnswerBExp::Paclitaxel hyperstabilizes microtubules and inhibits the disassembly of the mitotic spindle, thereby arresting dividing cells in M-phase. It is primarily used in breast and ovarian carcinomas. It is also used to coat coronary artery stents.
Answer C	AnswerC::Inhibits MTOR
Answer C Explanation	AnswerCExp::Sirolimus inhibits MTOR. It is indicated for immunosuppression (eg. renal transplant recipients). It may also be used in drug-eluting stents used in interventional cardiology.
Answer D	AnswerD::Intercalates between cytosine and guanine
Answer D Explanation	AnswerDExp::Dactinomycin inhibits DNA-dependent RNA polymerase by intercalating between cytosine and guanine nucleotides in DNA.
Answer E	AnswerE::Adds alkyl group to guanine N-7
Answer E Explanation	AnswerEExp::Cyclophosphamide is an alkylating agent that covalently cross-links guanine nucleotides at the N-7 nitrogen. While cyclophosphamide may be indicated for ovarian carcinoma, it is not used to coat drug-eluting stents.
Right Answer	RightAnswer::B
Explanation	[[Explanation::Ovarian cancer results from the malignant transformation of the ovarian epithelium. It is usually suspected in pre-menopausal women with enlarging ovarian sizes and post-menopausal women with a palpable adnexal mass. Risk for ovarian cancer is family history, increases with older age, nulliparity, and familial cancer syndromes caused by mutations of the BRCA1 (chromosome 17q) and BRCA2 (chromosome 13q). BRCA1 and BRCA2 normally encode nuclear proteins involved in DNA repair. On the other hand, oral contraceptive use, tubal ligation, pregnancy, and lactation are associated with a reduced risk for the development of ovarian cancer. Histopathological analysis of ovarian cancer may demonstrate any of 4 subtypes: Papillary serous: Most common. Characterized by presence of psammoma bodies. Usually markedly elevated serum CA-125 level Endometrioid: May be associated with endometriosis Mucinous: May be associated with pseudomyxoma peritonei. May be chemoresistant. Less associated with BRCA mutations or elevations in serum CA-125 level Clear-cell: Chemoresistant. Hobnail-shaped with clear cytoplasm. Patients with ovarian cancer may have non-specific abdominal or pelvic symptoms, such as abdominal fullness and bloating, indigestion, early satiety, or pelvic pain. Physical examination may be unremarkable or may be significant for a palpable abdominal or pelvic mass, ascites, or Sister Mary Joseph's nodule (umbilical mass). In the minority of cases, ovarian cancer is associated with paraneoplastic syndromes, such as hypercalcemia, subacute cerebellar degeneration (presence of anti-Purkinje-cell antibodies), Leser-Trelat sign (sudden development of multiple seborrheic keratoses on trunk), and Trousseau's syndrome (migratory superficial thrombophlebitis). A transvaginal ultrasound is useful to confirm the presence of an ovarian mass and is more sensitive than CT scan. Although CA-125 measurement suffers from low sensitivity and specificity, it may be useful to confirm diagnosis, especially among post-menopausal women with palpable adnexal mass and serum CA-125 levels > 65 U/mL. CA-125 is also useful for follow-up and evaluation of response to therapy. The majority of patients require surgical debulking of the tumor followed by adjuvant chemotherapy to fully eradicate residual cancer cells. Chemotherapy often includes carboplatin and paclitaxel. Paclitaxel hyperstabilizes microtubules and inhibits the disassembly of the mitotic spindle (M-phase arrest). Paciltaxel may also be used in drug-eluting stents (DES) that are used in interventional cardiology for patients with myocardial infarction (MI). The use of antiproliferative agents, such as paclitaxel, prevents re-stenosis of a previously deployed stent via inhibition of intimal hyperplasia caused by vascular smooth muscle cells in the stented coronary artery. Educational Objective: Paclitaxel is a chemotherapeutic agent that inhibits microtubule depolymerization. It is indicated for ovarian cancer and may be used in drug-eluting stents. References: Cannistra SA. Cancer of the ovary. N Engl J Med. 2004;351:2519-29. First Aid 2014 page 405]]
Approved	Approved::Yes
Keyword	WBRKeyword::Chemotherapy, WBRKeyword::Stent, WBRKeyword::Ovarian cancer, WBRKeyword::Cancer, WBRKeyword::Mitosis, WBRKeyword::Microtubule, WBRKeyword::Ovarian cancer, WBRKeyword::Pharmacology, WBRKeyword::Paclitaxel, WBRKeyword::Drug-eluting stent, WBRKeyword::Drug eluting stent
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