Anti-Cancer Drugs — Part 1

Correct Answer

B — Granulocyte colony-stimulating factor

Rationale

Filgrastim is a recombinant human granulocyte colony-stimulating factor that stimulates neutrophil precursor proliferation and differentiation in the bone marrow. It is classified as a granulocyte colony-stimulating factor, distinct from erythropoiesis-stimulating agents (which act on red blood cell precursors), thrombopoietin receptor agonists (which act on platelet precursors), and interleukin-11 analogs (oprelvekin, which also promotes platelet production).

Correct Answer

A — Pegfilgrastim is a long-acting formulation of filgrastim that requires only one injection per chemotherapy cycle

Rationale

Pegfilgrastim is filgrastim conjugated to polyethylene glycol, which dramatically reduces renal clearance and prolongs the half-life, allowing single-injection per-cycle dosing rather than the daily subcutaneous injections required with filgrastim. Both agents are granulocyte colony-stimulating factors that act on neutrophil precursors; pegfilgrastim does not act on erythroid precursors and is not a glucocorticoid.

Correct Answer

C — Serotonin type 3 receptor antagonist

Rationale

Ondansetron is classified as a serotonin type 3 receptor antagonist. It blocks serotonin type 3 receptors on vagal afferent neurons in the gastrointestinal tract and in the chemoreceptor trigger zone, mediating its antiemetic effect. Neurokinin-1 receptor antagonists (such as aprepitant) and dopamine D2 receptor antagonists (such as prochlorperazine) are separate antiemetic classes. Glucocorticoids such as dexamethasone have antiemetic activity through a distinct mechanism.

Correct Answer

D — Neurokinin-1 receptor antagonist

Rationale

Aprepitant is classified as a neurokinin-1 receptor antagonist. It blocks substance P at neurokinin-1 receptors in the brainstem, which mediates the delayed phase of chemotherapy-induced nausea and vomiting occurring 24 to 120 hours after chemotherapy. Serotonin type 3 receptor antagonists such as ondansetron address the acute phase. Dopamine D2 antagonists and glucocorticoids are separate antiemetic classes with different receptor targets.

Correct Answer

A — Xanthine oxidase inhibitor

Rationale

Allopurinol is classified as a xanthine oxidase inhibitor. It blocks the enzyme xanthine oxidase, which catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid, thereby preventing new uric acid synthesis. Rasburicase is the recombinant urate oxidase. Adenosine deaminase inhibitors (such as pentostatin) and dihydrofolate reductase inhibitors (such as methotrexate) are entirely different drug classes with unrelated mechanisms.

Correct Answer

C — Recombinant urate oxidase

Rationale

Rasburicase is a recombinant urate oxidase. It catalyzes the oxidation of uric acid to allantoin, a highly soluble product that is readily excreted by the kidneys, thereby rapidly reducing the existing uric acid burden. Allopurinol is the xanthine oxidase inhibitor. Filgrastim and pegfilgrastim are granulocyte colony-stimulating factors. Ondansetron is the serotonin type 3 receptor antagonist.

Correct Answer

B — Alkylating agents form covalent deoxyribonucleic acid adducts regardless of cell cycle position, while antimetabolites require active deoxyribonucleic acid synthesis to exert their lethal effect

Rationale

Alkylating agents are cycle-nonspecific: they form covalent adducts with deoxyribonucleic acid through direct chemical reaction that does not require the cell to be actively synthesizing deoxyribonucleic acid. This allows them to kill quiescent G0 cells. Antimetabolites such as methotrexate and 5-fluorouracil are S-phase specific — they must be incorporated into active deoxyribonucleic acid synthesis or must inhibit enzymes that are actively supplying nucleotide precursors, processes that occur only in cycling cells. G0 cells that are not synthesizing deoxyribonucleic acid are therefore largely resistant to antimetabolite cytotoxicity.

Correct Answer

D — At any given moment only a fraction of tumor cells are in the drug-sensitive phase, so continuous infusion exposes cells as they enter that phase throughout the infusion period

Rationale

Cycle-specific agents kill only cells that are traversing the drug-sensitive phase at the time of drug exposure. Because only a fraction of tumor cells are in S phase at any given moment, a bolus dose kills that fraction but misses cells that enter S phase after drug concentrations fall. Continuous intravenous infusion maintains cytotoxic drug concentrations throughout the entire duration of the sensitive phase for every dividing cell, exposing a far greater proportion of the tumor cell population. This scheduling principle, rather than toxicity reduction or bioavailability, is the pharmacological rationale for continuous infusion of drugs like cytarabine.

Correct Answer

A — P-glycoprotein is an adenosine triphosphate-dependent efflux pump that transports a broad range of hydrophobic drugs out of the cell, reducing intracellular drug concentrations below cytotoxic thresholds

Rationale

P-glycoprotein is an adenosine triphosphate-binding cassette family efflux transporter that uses adenosine triphosphate hydrolysis to actively pump structurally diverse hydrophobic compounds out of the cell. Its substrate range includes anthracyclines, vinca alkaloids, taxanes, and epipodophyllotoxins — agents with entirely different mechanisms of action — explaining why P-glycoprotein overexpression produces resistance to multiple unrelated drug classes simultaneously (multidrug resistance). It does not methylate deoxyribonucleic acid, does not upregulate dihydrofolate reductase, and does not directly activate BCL-2.

Correct Answer

C — Ten million, because a 3-log kill destroys 99.9% of tumor cells regardless of the starting number

Rationale

The log-kill hypothesis states that a given chemotherapy dose kills a constant fraction of tumor cells, not a constant number. A 3-log kill destroys 99.9% of cells regardless of the starting tumor burden. Starting with 10 billion (10^10) cells, a 3-log kill leaves 10^7 cells — 10 million viable cells. This arithmetic illustrates why even impressive fractional kills do not eradicate large tumors in a single course and why repeated cycles are required to reduce the burden toward zero.

Correct Answer

B — Filgrastim stimulates neutrophil precursor proliferation, and actively dividing precursors are vulnerable to cycle-specific cytotoxic agents if drug levels remain elevated

Rationale

Filgrastim stimulates proliferation and differentiation of neutrophil precursors in the bone marrow. Actively dividing cells are the primary targets of cycle-specific chemotherapy drugs. If filgrastim is given within 24 hours of chemotherapy and drug concentrations are still elevated, the newly mobilized proliferating precursors are exposed to cytotoxic agents at the height of their vulnerability, deepening rather than reducing myelosuppression. For this reason, filgrastim is initiated 24 to 72 hours after the last dose of chemotherapy, after cytotoxic drug concentrations have fallen.

Correct Answer

D — The rasburicase reaction generates hydrogen peroxide, which causes acute hemolytic anemia in patients whose erythrocytes cannot neutralize oxidative stress due to glucose-6-phosphate dehydrogenase deficiency

Rationale

Rasburicase catalyzes the oxidation of uric acid to allantoin, generating hydrogen peroxide as a byproduct. In patients with glucose-6-phosphate dehydrogenase deficiency, erythrocytes cannot neutralize this oxidative stress, causing acute intravascular hemolysis that can be severe and life-threatening. Glucose-6-phosphate dehydrogenase testing is mandatory before rasburicase administration.

Correct Answer

A — Aprepitant blocks substance P at neurokinin-1 receptors in the brainstem, which mediates delayed-phase nausea and vomiting occurring 24 to 120 hours after chemotherapy

Rationale

Delayed-phase chemotherapy-induced nausea and vomiting, occurring 24 to 120 hours after chemotherapy administration, is mediated predominantly by substance P binding to neurokinin-1 receptors in the brainstem rather than by serotonin. Ondansetron blocks serotonin type 3 receptors and is highly effective for acute-phase nausea within the first 24 hours, but provides limited coverage for the delayed phase. Aprepitant, a neurokinin-1 receptor antagonist, specifically blocks substance P at the brainstem neurokinin-1 receptor and therefore addresses the mechanism responsible for delayed nausea.

Correct Answer

C — BCL-2 sequesters pro-apoptotic proteins at the mitochondrial outer membrane, preventing cytochrome c release and caspase activation

Rationale

BCL-2 is an anti-apoptotic protein that resides at the mitochondrial outer membrane. It exerts its survival-promoting effect by sequestering pro-apoptotic proteins such as BAX and BAK, preventing them from oligomerizing and forming pores in the mitochondrial outer membrane. Without pore formation, cytochrome c is not released into the cytoplasm, the apoptosome is not assembled, and caspases are not activated — blocking the intrinsic apoptotic pathway despite the presence of deoxyribonucleic acid damage. BCL-2 does not repair deoxyribonucleic acid, does not activate P-glycoprotein, and does not upregulate p53; p53 loss, not gain, is associated with resistance.

Correct Answer

B — Ondansetron, aprepitant, and dexamethasone, because cisplatin is classified as highly emetogenic and requires triple-drug prophylaxis covering both the acute and delayed phases

Rationale

Cisplatin is classified as a highly emetogenic chemotherapy agent, carrying greater than 90% risk of nausea and vomiting without prophylaxis. Highly emetogenic regimens require triple-drug antiemetic prophylaxis: a serotonin type 3 receptor antagonist such as ondansetron to block acute-phase emesis mediated by serotonin release from enterochromaffin cells; a neurokinin-1 receptor antagonist such as aprepitant to block delayed-phase emesis mediated by substance P; and dexamethasone, which contributes antiemetic activity through mechanisms that complement both other agents. Ondansetron alone is insufficient because it does not cover the delayed phase. Aprepitant alone is insufficient because it does not address the acute serotonergic phase. Dexamethasone is not contraindicated with platinum compounds and is a standard component of triple prophylaxis.

Correct Answer

A — Rasburicase degrades existing uric acid to allantoin, rapidly reducing the pre-existing uric acid burden, whereas allopurinol only prevents new uric acid synthesis and cannot lower uric acid already present

Rationale

When large numbers of tumor cells lyse simultaneously, they release massive quantities of nucleic acids that are catabolized to uric acid. A patient at high risk may already have an elevated uric acid burden before chemotherapy begins, and the lysis event will raise it further within hours. Allopurinol inhibits xanthine oxidase and prevents the synthesis of new uric acid, but it has no effect on uric acid already present in the bloodstream or tissues. Rasburicase, a recombinant urate oxidase, catalyzes the conversion of existing uric acid to allantoin — a highly soluble, rapidly excreted product — and therefore rapidly lowers the pre-existing uric acid burden as well as newly produced uric acid. This is the pharmacological rationale for preferring rasburicase in high-risk patients.

Correct Answer

D — Microscopic residual deposits are growing with a high growth fraction and are therefore in the exponential growth phase, making them more vulnerable to cytotoxic drugs than the original bulky tumor was

Rationale

According to Gompertzian tumor growth kinetics, the growth fraction — the proportion of cells actively cycling — is highest when the tumor is small. As tumor mass increases, the growth fraction falls because blood supply cannot keep pace with the expanding cell population. After surgical resection, any microscopic residual deposits that remain are small and growing in the exponential phase with a high growth fraction. Because cytotoxic drugs preferentially kill actively dividing cells, these microscopic deposits are more chemosensitive than the original bulky primary tumor was. This is the biological rationale for adjuvant chemotherapy: treating when the residual burden is lowest and the growth fraction is highest maximizes the probability of eradication.

Correct Answer

C — The drugs in CHOP have different dose-limiting toxicities affecting different organs, so each can be dosed to its individual organ-specific limit without compounding the critical toxicity of another drug in the regimen

Rationale

The principle of non-overlapping dose-limiting toxicity is the pharmacological basis for rational combination chemotherapy design. Cyclophosphamide and doxorubicin dose-limit on myelosuppression, but vincristine dose-limits primarily on peripheral neurotoxicity with minimal myelosuppression, and prednisone contributes anti-lymphoma activity with negligible myelosuppression. Because the most severe toxicity of each drug affects a different organ or system, none of them forces dose reduction of another. Each drug can therefore be given at or near the dose that would be used in single-agent therapy, preserving the full therapeutic contribution of all four components. This is distinct from mechanisms of action, cell cycle specificity, or metabolic pathways.