WBR0160

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
Prompt	[[Prompt::A 7-year-old boy is brought by his mother to the physician's office for pain in his left thigh. Following history-taking and physical examination, X-ray shows a destructive mass at the metadiaphysis of the left femur. Biopsy demonstrates anaplastic, small, blue, CD99 positive cells. Karyotype of the tumor demonstrates a t(11;22) translocation consistent with Ewing’s sarcoma. The patient is placed on a chemotherapy regimen which includes an agent that inhibits RNA polymerase by inserting into the minor groove of the DNA double-helix between adjacent cytosine and guanine base pairs. Which of the following agents is most likely administered in this patient?]]
Answer A	AnswerA::5-Fluorouracil
Answer A Explanation	AnswerAExp::5-Fluorouracil (5-FU) does not intercalate between DNA nucleotides, but rather acts as an antimetabolite. 5-FU is a pyrimidine analogue that inhibits thymidylate synthase.
Answer B	AnswerB::Bleomycin
Answer B Explanation	AnswerBExp::Bleomycin is a chemotherapeutic agent indicated for testicular tumors. Bleomycin acts by inducing free radical oxygen species and breaks in the DNA strand.
Answer C	AnswerC::Carmustine
Answer C Explanation	AnswerCExp::Carmustine is a derivative of mustard gas that acts as a chemotherapeutic agent by forming inter-strand cross-links in DNA, thereby preventing DNA replication and DNA transcription.
Answer D	AnswerD::Dactinomycin
Answer D Explanation	AnswerDExp::Dactinomycin inhibits DNA-dependent RNA polymerase by intercalation between cytosine and guanine nucleotides in DNA and formation of dactinomycin-DNA complexes.
Answer E	AnswerE::Etoposide
Answer E Explanation	[[AnswerEExp::Etoposide is a topoisomerase II inhibitor that causes DNA damage by inducing strand breaks. Etoposide is a cell-cycle-specific chemotherapeutic agent that acts primarily during S and G2 phases. It is indicated for a variety of solid tumors including small cell lung carcinoma and hematopoetic malignancies. Classically, administration of etoposide is associated with bone marrow suppression.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::Ewing’s sarcoma is an aggressive poorly-differentiated bone and soft tissue cancer of childhood. It is usually caused by a translocation between chromosomes 22 and 11 (t11;22), where an oncogenic fusion of EWS gene on chromosome 22 to an Ets factor (usually FLI1 on chromosome 11) results in the expression of a potent transcription factor and initiates oncogenesis. Although Ewing's sarcoma is a rare disease, it is considered the second most common primary bone tumor, accounting for 5% of all childhood tumors. It has a male predominance, and it commonly affects the Caucasian population. The majority of patients with Ewing's sarcoma present with tumor-associated symptoms, including pain, swelling, fracture following minimal trauma, or palpation of firm solid mass. Ewing's sarcoma commonly affects the metaphysis and diaphysis of lower-extremity long bones, such as the femur and tibia, or flat bones, such as the pelvis, ribs, and scapula. On imaging, Ewing's sarcoma appears as a destructive, infiltrative lesion with occasional presence of a laminated onion-skin appearance due to periosteal reaction formation. On biopsy, tumor cells have a characteristic small, round blue appearance, which are almost always CD99 positive. Although Ewing's sarcoma is a rapidly growing tumor associated with high aggressiveness and poor prognosis, it is often chemotherapy-sensitive. Chemotherapy regimens may include dactinomycin (classical drug for Ewing's sarcoma and other tumors of childhood), cyclophosphamide, doxorubicin, vincristine, or carmustine. Dactinomycin inhibits DNA-dependent RNA polymerase by intercalating (inserting or wedging) within the small grooves of the DNA double-helix between adjacent cytosine and guanine nucleotides and formation of dactinomycin-DNA complexes. Cancer cells are transcriptionally very active and are thus susceptible to therapies that target DNA-dependent RNA polymerase. However, dactinomycin can be quite toxic to normal cells as well; adverse events include bone marrow suppression, GI toxicity, alopecia, and mouth ulcers. Educational Objective: Dactinomycin inhibits DNA-dependent RNA polymerase by intercalating (inserting or wedging) between cytosine and guanine nucleotides in DNA and formation of dactinomycin-DNA complexes. References: Balamuth N, Womer RB. Ewing's sarcoma. Lancet Oncol. 2010;11:184-92. Jedlicka P. Ewing sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions. Int J Clin Exp Pathol. 2010;3(4):338-47. First Aid 2014 pages 404]]
Approved	Approved::Yes
Keyword	WBRKeyword::Chemotherapy, WBRKeyword::Sarcoma, WBRKeyword::Cancer, WBRKeyword::Ewing’s sarcoma, WBRKeyword::Childhood cancer, WBRKeyword::Translocation, WBRKeyword::Transcription
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