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HY points followed by a quiz at the end
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Irinotecan / Topotecan
MOA of irinotecan / topotecan?
- Inhibit topoisomerase I (one, not two)
- Topoisomerase is an enzyme that “nicks” the DNA during replication to prevent supercoiling. Therefore these agents interfere with DNA replication.
How will these be tested?
- Physician is treating a patient for leukemia with an agent called irinotecan. This agent inhibits which of the following enzymes? –> answer = topoisomerase I. One of the wrong answers will be “topoisomerase II,” so the USMLE wants you to be able to distinguish.
Etoposide / Teniposide
MOA of etoposide / teniposide?
- Inhibit eukaryotic topoisomerase II
- Should be noted that fluoroquinolones (i.e., ciprofloxacin, etc.) are an antibiotic class that also inhibit topoisomerase II, however these are antibiotics, not anti-cancer agents, and inhibit specifically prokaryotic topoisomerase II, not eukaryotic. Prokaryotic topoisomerase II is also known as DNA gyrase.
- In other words, fluoroquinolones inhibit DNA gyrase, aka prokaryotic topoisomerase II. In contrast, etoposide / teniposide inhibit simply eukaryotic topoisomerase II (not also known as DNA gyrase).
When are these used?
- Can be used for prostate cancer (flutamide + leuprolide is another combo for prostate cancer).
- USMLE is less concerned that you know the specific applications of these anti-cancer agents. Just make sure you know the MOAs.
Imatinib
- One of the highest yield anti-cancer agents for Step 1.
MOA of imatinib?
- bcr-abl tyrosine kinase inhibitor used for chronic myelogenous leukemia (CML).
What will USMLE ask me about this drug?
- CML is caused by the t(9;22) translocation (Philadelphia chromosome).
- USMLE specifically wants you to know that bcr-abl is an oncogenic product.
- That oncogenic product is specifically a tyrosine kinase.
- Therefore imatinib inhibits a tyrosine kinase that is a bcr-abl oncogenic product in CML.
- Sounds redundant, but I can’t reiterate more that the Step 1 will ask numerous questions around these points.
HY side-effect of imatinib?
- Fluid retention (edema).
- The three highest yield agents causing fluid retention / edema for the Step are:
- Dihydropyridine calcium channel blockers (i.e., amlodipine, nifedipine, etc.)
- NSAIDs (↓ synthesis of vasodilating prostaglandins → ↓ renal blood flow due to narrowing of renal afferent arterioles → kidney thinks there’s low blood volume → PCT attempts to reabsorb more fluid to compensate → accomplishes this by reabsorbing more Na+, where water follows sodium → edema).
- Imatinib
Erlotinib
MOA of ertlotinib?
- EGFR tyrosine kinase inhibitor used for non-small cell carcinoma.
- That’s all you need to know. The USMLE will ask you straight-up the MOA.
- 49F + large cell bronchogenic carcinoma + started on drug called erlotinib; which of the following best represents the molecular target of this agent? –> answer = “EGFR tyrosine kinase.”
Cetuximab
- Monoclonal antibody against EGFR (epidermal growth factor receptor).
- That’s all you need to know for cetuximab. Just its MOA.
- “Okay, noted.”
Rituximab
MOA of rituximab?
- Monoclonal antibody against CD20 on B cells.
- One of the highest yield anti-cancer drugs for Step 1.
When is it used?
- For lymphomas and leukemias.
- Most lymphomas and leukemias are B cell.
- USMLE wants you to know CD20 is a specific B cell marker.
Bortezomib
MOA of bortezomib?
- Proteasome inhibitor.
- Used rarely in multiple myeloma and mantle cell lymphoma.
- Just know it’s a proteasome inhibitor.
Trastuzumab (Herceptin)
MOA of trastuzumab?
- Monoclonal antibody against HER2/neu receptor (produced by ErbB2 gene).
When is it used?
- Breast cancer that has positivity for HER2/neu receptor.
- Should be noted that HER2/neu (+) breast cancer carries worse prognosis than HER2/neu (-) breast cancer, despite Trastuzumab being available as a pharmacologic agent for the former.
Toxicity of trastuzumab?
- Cardiotoxic.
- Sounds nitpicky, but is known to show up.
- It’s to my observation some students won’t even know how diabetes works, but they’ll remember trastuzumab is cardiotoxic.
Alemtuzumab
- Monoclonal antibody against CD52 in chronic lymphocytic leukemia (CLL).
- Just memorize the above sentence.
Vemurafenib
MOA of vemurafenib?
- Inhibitor of BRAF serine-threonine kinase.
- Used for metastatic melanoma (+) for BRAF.
- BRAF is an oncogene encoding BRAF protein.
Tamoxifen / Raloxifene
MOA of tamoxifen / raloxifene?
- Selective-estrogen receptor modulators used for ER (+) breast cancer.
- Both antagonists at breast tissue.
- Both agonists at bone.
- Tamoxifen only is a partial agonist at endometrium (↑ risk of endometrial cancer).
Highest yield points for USMLE?
- Tamoxifen increases the risk of endometrial cancer.
- USMLE Q might give you a big paragraph vignette where they casually mention the patient’s surgical history (e.g., appendectomy, hysterectomy), and then ask you what element of the patient’s history best qualifies her for tamoxifen; answer = “history of hysterectomy” or “the patient’s surgical history.” → only give tamoxifen to women who do not have a uterus.
- ER (+) breast cancer has better prognosis than ER (-) breast cancer.
Adverse effects of tamoxifen / raloxifene?
- Increase the risk of thrombotic events (DVT, MI)
- Vasomotor symptoms (e.g., hot flashes).
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