Onc Pharmacology review Flashcards
The most likely mechanism conferring paclitaxel resistance is:
B) Activation of P-Glycoproteins enhancing paclitaxel efflux
Paclitaxel is a chemotherapy drug that exerts its anti-cancer effects by stabilizing microtubules, leading to cell cycle arrest and apoptosis. Option B, “Activation of P-Glycoproteins enhancing paclitaxel efflux,” refers to the overexpression or activation of a protein called P-glycoprotein (P-gp).
P-glycoprotein is a drug efflux pump that actively transports drugs, including paclitaxel, out of the cancer cells. When P-gp is overexpressed or activated, it can reduce the intracellular concentration of paclitaxel, making it less effective in inhibiting microtubule dynamics and leading to paclitaxel resistance. This mechanism is a common cause of multidrug resistance in cancer treatment.
B) Increased metabolism of cisplatin through upregulation of glutathione
Cisplatin exerts its anticancer effects by forming DNA crosslinks, causing DNA damage in rapidly dividing cells. However, cancer cells can develop resistance through various mechanisms. Option B refers to the upregulation of glutathione, a cellular antioxidant. Glutathione can bind to and inactivate cisplatin, reducing its effectiveness. This increased metabolism and inactivation of cisplatin by glutathione can contribute to resistance in cancer cells.
So, in this context, both option C (enhanced DNA damage repair) and option B (increased metabolism through upregulation of glutathione) could play a role in cisplatin resistance, depending on the specific molecular changes occurring in the cancer cells.
Thioguanine is a medication used in the treatment of chronic myelogenous leukemia (CML). In the context of thioguanine resistance in this case, the most likely mechanism is:
C) Mutation of Hypoxanthine-guanine phosphoribosyltransferase in tumor cells.
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme involved in the salvage pathway of purine synthesis. Mutations in HGPRT can lead to resistance to thioguanine, as the drug is activated via this pathway. A mutation in HGPRT can impair the activation of thioguanine, reducing its efficacy in treating CML.
hioguanine, like other thiopurine drugs, undergoes activation through the salvage pathway of purine synthesis. In this pathway, hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an essential enzyme that converts thioguanine into its active form within the cell.
Option C, “Mutation of Hypoxanthine-guanine phosphoribosyltransferase in tumor cells,” suggests a genetic alteration in the HGPRT gene within the tumor cells. If HGPRT is mutated, it may result in a dysfunctional enzyme, leading to a reduced ability to convert thioguanine into its active metabolites. As a consequence, the therapeutic efficacy of thioguanine would be compromised, and the leukemia cells may become resistant to its effects.
The most likely chemotherapeutic agent responsible for the development of gross hematuria in this patient is:
D) Cyclophosphamide
Cyclophosphamide is known to cause hemorrhagic cystitis as a significant side effect. Cyclophosphamide is metabolized in the liver to its active form, and one of its metabolites, acrolein, is excreted through the urinary system. Acrolein can irritate and damage the bladder lining, causing inflammation and bleeding. This can result in the clinical manifestation of gross hematuria, which is the passage of blood in the urine that is visible to the naked eye.Hemorrhagic cystitis involves inflammation and bleeding in the bladder, leading to symptoms such as gross hematuria. Mesna, a sulfhydryl compound, is often co-administered with cyclophosphamide to reduce the risk of hemorrhagic cystitis by binding to and detoxifying acrolein, a metabolite of cyclophosphamide associated with bladder irritation and injury. Nevertheless, some patients may still experience bladder toxicity despite mesna administration.
The mechanism of anticancer action of cellular metabolites of fluorouracil involves:
D. Irreversible inhibition of thymidylate synthase
Fluorouracil is a pyrimidine analog that gets metabolized within cells to active metabolites, such as fluorodeoxyuridine monophosphate (FdUMP). FdUMP forms a complex with thymidylate synthase, inhibiting the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). This leads to the depletion of intracellular thymidine and the inhibition of DNA synthesis, ultimately interfering with cancer cell proliferation. The inhibition of thymidylate synthase by fluorouracil is irreversible, making it a key aspect of its anticancer mechanism.
The therapy that directly binds and inhibits BCL-2 protein is likely referring to venetoclax, a BCL-2 inhibitor. In the context of the provided scenario, the most likely effect of this therapy on the abnormal cells would be:
C. Increased activation of caspases
BCL-2 is an anti-apoptotic protein that regulates apoptosis (programmed cell death) by preventing the activation of caspases. Inhibition of BCL-2, as seen with venetoclax, allows for the activation of caspases, leading to apoptosis in the abnormal lymphocytes. This mechanism is particularly relevant in certain hematological malignancies, including chronic lymphocytic leukemia (CLL), where overexpression of BCL-2 contributes to the prolonged survival of malignant cells.
Bortezomib exerts its anti-myeloma effects primarily through:
D. Blocking the proteolytic activity of the proteasome
Bortezomib is a proteasome inhibitor that specifically targets the 26S proteasome, a cellular structure responsible for degrading ubiquitinated proteins. By blocking proteasome activity, bortezomib disrupts protein degradation, leading to the accumulation of unfolded or misfolded proteins within the myeloma cells. This accumulation ultimately induces apoptosis (programmed cell death) in the cancer cells. The inhibition of the proteasome is a key mechanism by which bortezomib demonstrates its anti-myeloma effects.
The symptoms described, including “pins and needle” sensations in the extremities, muscle weakness, and difficulty with motor tasks such as executing a deep knee bend, getting up out of a chair, and constipation, are suggestive of peripheral neuropathy. In the context of the chemotherapy drugs mentioned, vincristine is known to be associated with peripheral neuropathy.
Therefore, the most likely causative agent for the neurological symptoms described is:
D. Vincristine
Vincristine is a vinca alkaloid chemotherapy drug that acts by disrupting microtubule function in dividing cells. While it is effective against cancer cells, it can also affect normal cells, particularly peripheral nerves.
Peripheral neuropathy is a common side effect of vincristine, and the symptoms include “pins and needle” sensations (paresthesias), muscle weakness, and difficulty with certain motor tasks. The drug’s impact on microtubules in nerve cells can lead to damage and dysfunction of the peripheral nerves, causing these neurological symptoms.
The patient’s difficulty with motor tasks and constipation could be attributed to the effect of vincristine on motor nerves and the autonomic nervous system, respectively.
B. Cisplatin
Cisplatin is indeed known to be associated with peripheral neuropathy. It’s part of the combination chemotherapy regimen often used for testicular carcinoma, and it can cause neurotoxicity as one of its side effects. Peripheral neuropathy from cisplatin is characterized by sensory symptoms like tingling, numbness, and pain in the extremities.
The symptoms of easy bruising and bleeding gums, along with a low platelet count, suggest thrombocytopenia, a condition characterized by a reduced number of platelets in the blood. In the context of chemotherapy, myelosuppression can occur, leading to a decrease in platelet production.
Among the options provided, the drug that could potentially help with platelet production and allow the patient to continue with her chemotherapy is:
C. Eltrombopag
Eltrombopag is a thrombopoietin receptor agonist that stimulates the production of platelets. It can be used in the management of thrombocytopenia to increase platelet counts, potentially allowing the patient to continue chemotherapy without the increased risk of bleeding. Filgrastim (option A) is a granulocyte colony-stimulating factor and is used to stimulate white blood cell production, not platelets. Epoetin alfa (option B) is used to treat anemia, and Vitamin B12 (option D) and ferrous iron (option E) are not indicated for increasing platelet counts.
The patient in the scenario has chronic myeloid leukemia (CML), as indicated by the presence of the Philadelphia chromosome. The most appropriate drug for the treatment of CML with the Philadelphia chromosome is:
C. Imatinib
Imatinib is a tyrosine kinase inhibitor that specifically targets the BCR-ABL fusion protein, which is produced by the Philadelphia chromosome. This fusion protein is characteristic of CML and plays a key role in the pathogenesis of the disease. Imatinib inhibits the activity of BCR-ABL, leading to suppression of the abnormal proliferation of myeloid cells.
The other options (Methotrexate, Trastuzumab, Bleomycin, Etoposide, Asparaginase) are more commonly associated with the treatment of other types of cancers and are not the first-line therapy for CML with the Philadelphia chromosome.
The drug with the mechanism of action described (depleting the body of an amino acid that can be synthesized by normal cells but not by neoplastic cells) is:
B. Asparaginase
Asparaginase depletes circulating asparagine, an amino acid essential for protein synthesis, by converting it into aspartic acid and ammonia. Normal cells can synthesize asparagine, but some neoplastic cells, including certain types of leukemia cells, lack the enzyme asparagine synthetase and depend on circulating asparagine. By depleting asparagine, asparaginase selectively targets cancer cells that cannot produce their own asparagine, leading to inhibition of protein synthesis and ultimately cell death.
The other options (Vincristine, Daunorubicin, Prednisone, Methotrexate, Cytarabine) have different mechanisms of action and do not involve asparagine depletion.
Methotrexate is an antimetabolite that acts as an inhibitor of dihydrofolate reductase (DHFR), an enzyme involved in the synthesis of tetrahydrofolate, a necessary precursor for the synthesis of nucleic acids. In the context of this patient’s treatment, the substance that will most likely accumulate in embryonic tissues due to methotrexate treatment is:
A. Dihydrofolate polyglutamate
Methotrexate inhibits DHFR, leading to the accumulation of dihydrofolate polyglutamate, which is a polyglutamated form of dihydrofolate. This accumulation disrupts the folate metabolism essential for DNA synthesis, impairs cell division, and contributes to the termination of the ectopic pregnancy.
The drugs described in this scenario are most likely:
D. Methotrexate (Drug X) and Fluorouracil (Drug Y)
Methotrexate inhibits dihydrofolate reductase (DHFR) and interferes with the formation of intracellular thymidylate. Leucovorin (folinic acid) can be used as rescue therapy with methotrexate to provide a source of reduced folate, bypassing the inhibited DHFR and allowing the cell to maintain thymidylate production.
Fluorouracil inhibits thymidylate synthase, another enzyme involved in thymidylate formation. Unlike methotrexate, leucovorin supplementation does not rescue the chemotherapeutic effect of fluorouracil.
