Anti-Cancer Drugs — Part 1

The most extensively characterized resistance mechanism is overexpression of P-glycoprotein, an energy-dependent efflux pump embedded in the plasma membrane that uses adenosine triphosphate hydrolysis to actively transport a broad range of structurally diverse hydrophobic compounds out of the cell, reducing intracellular drug concentrations below cytotoxic thresholds. Its substrate range includes anthracyclines, vinca alkaloids, taxanes, epipodophyllotoxins, and many tyrosine kinase inhibitors. Tumor cells acquire P-glycoprotein overexpression through gene amplification, promoter hypomethylation, or selection of pre-existing P-glycoprotein-high clones during chemotherapy exposure.

Additional adenosine triphosphate-binding cassette family transporters contribute to multidrug resistance. The multidrug resistance-associated protein 1 transports organic anions and glutathione conjugates and is particularly relevant to resistance against anthracyclines, vinca alkaloids, and methotrexate. The breast cancer resistance protein is highly expressed in hematopoietic stem cells and confers resistance to mitoxantrone, camptothecin derivatives, and several oral kinase inhibitors.

For prodrugs that require intracellular activation, reduced expression of the activating enzyme confers resistance. Cytarabine resistance in acute myeloid leukemia frequently involves downregulation of deoxycytidine kinase, the enzyme responsible for phosphorylating cytarabine to its active triphosphate form. 6-mercaptopurine resistance involves loss of hypoxanthine-guanine phosphoribosyltransferase, the enzyme that converts 6-mercaptopurine to its active nucleotide form.

Target amplification or mutation directly reduces drug binding. Dihydrofolate reductase gene amplification is the prototypic mechanism of methotrexate resistance: the tumor cell produces so much dihydrofolate reductase enzyme that therapeutic methotrexate concentrations cannot inhibit all of it, and the residual uninhibited fraction is sufficient to maintain folate metabolism and deoxyribonucleic acid synthesis.

Most cytotoxic drugs kill cells by inducing apoptosis. Loss of functional p53 is present in approximately 50% of human cancers and eliminates the primary transcription factor responsible for upregulating pro-apoptotic genes in response to deoxyribonucleic acid damage. Without p53-mediated apoptotic signaling, cells with drug-induced deoxyribonucleic acid damage arrest but do not die, allowing time for deoxyribonucleic acid repair and eventual resumption of proliferation.

Overexpression of BCL-2 (B-cell lymphoma 2 protein) and its relatives tilts the balance at the mitochondrial outer membrane toward cell survival by sequestering pro-apoptotic proteins. BCL-2 overexpression was first identified in follicular lymphoma through the translocation that places the BCL-2 gene under immunoglobulin heavy chain promoter control; it subsequently became a therapeutic target addressed by venetoclax, a selective BCL-2 inhibitor discussed in Chapter 34.

Febrile neutropenia is defined as a temperature above 38.3 degrees Celsius as a single measurement, or above 38.0 degrees Celsius sustained over one hour, in a patient with an absolute neutrophil count below 500 cells per microliter or below 1,000 cells per microliter and expected to fall below 500 within 48 hours. It carries a mortality risk of 5 to 10% in unselected oncology patients. Management requires prompt broad-spectrum antibacterial coverage initiated within one hour of presentation. For low-risk febrile neutropenia (solid tumors, absolute neutrophil count expected to recover within 7 days, no significant comorbidities), oral fluoroquinolone plus amoxicillin-clavulanate outpatient management is appropriate. High-risk febrile neutropenia requires hospital admission and intravenous anti-pseudomonal beta-lactam therapy, most commonly piperacillin-tazobactam as first-line.

Granulocyte colony-stimulating factors stimulate neutrophil precursor proliferation and differentiation in the bone marrow, shortening the duration of chemotherapy-induced neutropenia by three to five days and reducing the incidence of febrile neutropenia by approximately 50% in high-risk regimens. Filgrastim is a non-glycosylated recombinant human granulocyte colony-stimulating factor requiring daily subcutaneous injection beginning 24 to 72 hours after the last dose of chemotherapy. Pegfilgrastim is filgrastim conjugated to polyethylene glycol, which dramatically reduces renal clearance and prolongs half-life, allowing single-injection per-cycle dosing. Granulocyte colony-stimulating factor should not be started within 24 hours of chemotherapy because it mobilizes proliferating neutrophil precursors that become vulnerable to cycle-specific cytotoxic agents if drug levels are still elevated.

Chemotherapy-induced nausea and vomiting is classified by its temporal relationship to chemotherapy administration and the emetogenic potential of the regimen. Acute nausea and vomiting, occurring within 24 hours of chemotherapy, is mediated primarily by serotonin release from enterochromaffin cells stimulating vagal afferent serotonin type 3 receptors. Delayed nausea and vomiting, occurring 24 to 120 hours after chemotherapy, is mediated predominantly by substance P binding to neurokinin-1 receptors in the brainstem. Anticipatory nausea and vomiting is a conditioned response best prevented by achieving optimal control from the first cycle.

Highly emetogenic chemotherapy, including cisplatin, cyclophosphamide at doses above 1,500 mg per square meter, and dacarbazine, requires triple-drug antiemetic prophylaxis with a serotonin type 3 receptor antagonist (ondansetron, granisetron, or palonosetron), a neurokinin-1 receptor antagonist (aprepitant or fosaprepitant), and dexamethasone. Moderately emetogenic chemotherapy such as carboplatin, doxorubicin, and irinotecan requires at minimum a serotonin type 3 antagonist plus dexamethasone.

Tumor lysis syndrome results from the massive release of intracellular contents into the systemic circulation when large numbers of tumor cells die simultaneously after initiation of cytotoxic therapy. The metabolic consequences are hyperuricemia from nucleic acid catabolism, hyperkalemia from intracellular potassium release, hyperphosphatemia from intracellular phosphate release, and secondary hypocalcemia from calcium-phosphate precipitation. Clinical consequences include acute uric acid nephropathy, life-threatening cardiac arrhythmias from hyperkalemia, and hypocalcemic tetany or seizures. The highest-risk tumors are those with large cell mass and high proliferative rate that are highly chemosensitive: Burkitt lymphoma, acute lymphoblastic leukemia with high white blood cell counts, and acute myeloid leukemia with blast counts above 100,000 cells per microliter.

Tumor lysis syndrome prophylaxis begins before chemotherapy with aggressive intravenous hydration, allopurinol (a xanthine oxidase inhibitor that blocks new uric acid production, initiated 24 to 48 hours before chemotherapy), and correction of pre-existing electrolyte abnormalities. For patients at high tumor lysis syndrome risk, rasburicase (recombinant urate oxidase) is preferred over allopurinol because it rapidly degrades existing uric acid to allantoin, a highly soluble product readily excreted. Allopurinol only prevents new uric acid formation and does not lower the pre-existing uric acid burden. Rasburicase is absolutely contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency because the hydrogen peroxide generated by the rasburicase reaction causes severe hemolytic anemia in glucose-6-phosphate dehydrogenase-deficient erythrocytes.