WBR247

Author	[[PageAuthor::Gerald Chi (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology
Sub Category	SubCategory::Oncology
Prompt	[[Prompt::A novel chemotherapeutic pharmacologic agent of unclear mechanism is under investigation. Following intravenous administration of the investigational agent, hamster ovary cells are found to be arrested at metaphase. Further studies demonstrate that both the investigational agent and paclitaxel bind to beta-tubulins and promote stabilization of microtubules. Which of the following pharmacologic agents has the same mechanism of action?]]
Answer A	AnswerA::Colchicine
Answer A Explanation	[[AnswerAExp::Colchicine is a mitotic poison that inhibits microtubule polymerization by binding to tubulin. The mitosis-inhibiting function of colchicine has been utilized in karyotype studies. Arresting cells in metaphase by adding colchicine facilitates visualization of chromosomes under a light microscope. Apart from inhibiting mitosis, colchicine also inhibits neutrophil motility and produces an anti-inflammatory effect.]]
Answer B	AnswerB::Estramustine
Answer B Explanation	[[AnswerBExp::Estramustine is synthesized by coupling estradiol and mustard through a carbamate link. However, estramustine has a weak DNA-alkylating action. In fact, it binds to beta-tubulin and microtubule-associated proteins and leads to microtubule disassembly. Estramustine is used primarily for the treatment of metastatic or locally advanced, hormone-refractory prostate cancer.]]
Answer C	AnswerC::Irinotecan
Answer C Explanation	[[AnswerCExp::Irinotecan and topotecan are camptothecin analogs approved for clinical use in colorectal, ovarian, and small cell lung cancer. Camptothecins stabilize the normally transient DNA-topoisomerase I cleavable complex and cause an irreversible double-strand DNA break during replication. DNA topoisomerases are nuclear enzymes that reduce torsional stress in supercoiled DNA, allowing selected regions of DNA to become sufficiently untangled for replication, repair, and transcription. Camptothecin analogs inhibit topoisomerase I, while anthracyclines, epipodophyllotoxins, and acridines inhibit topoisomerase II. DNA topoisomerases are nuclear enzymes that reduce torsional stress in supercoiled DNA, allowing selected regions of DNA to become sufficiently untangled for replication, repair, and transcription. Camptothecin analogs inhibit the function of topoisomerase I, while anthracyclines, epipodophyllotoxins and acridines inhibit topoisomerase II.]]
Answer D	AnswerD::Ixabepilone
Answer D Explanation	[[AnswerDExp::The epothilones resemble taxanes in that they bind to beta-tubulin and trigger microtubule nucleation and cell-cycle arrest at the G2-M interface. Epothilones bind to a site distinct from that of taxanes. Ixabepilone is approved for metastatic breast cancer treatment.]]
Answer E	AnswerE::Vincristine
Answer E Explanation	[[AnswerEExp::Vinca alkaloids block cells in mitosis. Vincristine binds specifically to beta-tubulin, thereby blocking the polymerization of beta-tubulin with alpha-tubulin into microtubules. Vincristine does not stabilize the microtubule but rather inhibits its assembly.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::When hamster ovary cells are incubated with the investigational agent, cell division arrests at metaphase. In the absence of an intact mitotic spindle, duplicated chromosomes cannot correctly align along the division plate and may result in apoptosis. Paclitaxel is a microtubule-stabilizing agent that differs from the vinca alkaloids and colchicine derivatives in that it binds to a different tubulin site and promotes, rather than inhibits, microtubule formation. Paclitaxel blocks cell in the G2-M phase of the cell cycle by binding to the beta-subsunit of tubulin. Remarkably also, it has the ability to polymerize tubulin with the absence of any cofactor. The taxanes have a central role in the treatment of ovarian, breast, lung, gastrointestinal, genitourinary, and head and neck cancers. Educational Objective: Paclitaxel is a microtubule-stabilizing agent that differs from the vinca alkaloids and colchicine derivatives in that it binds to a different tubulin site and promotes, rather than inhibits, microtubule formation. Paclitaxel blocks cell in the G2-M phase of the cell cycle by binding to the beta-subsunit of tubulin. The epothilones resemble taxanes in that they bind to beta-tubulin and trigger microtubule nucleation and cell-cycle arrest at the G2-M interface. References: Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Microtubules. Available from: http://www.ncbi.nlm.nih.gov/books/NBK9932/ First Aid 2015 page 411.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Ixabepilone, WBRKeyword::Paclitaxel, WBRKeyword::Chemotherapy, WBRKeyword::Tubulin, WBRKeyword::Microtubules
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::