Anti-Cancer Drugs — Part 1

Hydroxyurea inhibits ribonucleotide reductase, the rate-limiting enzyme in de novo deoxyribonucleic acid synthesis that catalyzes the reduction of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. Ribonucleotide reductase contains a stable tyrosyl radical essential for catalytic activity; hydroxyurea scavenges this radical, inactivating the enzyme and blocking deoxyribonucleic acid synthesis. The result is S-phase arrest. Hydroxyurea is administered orally and undergoes renal excretion; dose reduction is required when creatinine clearance falls below 60 mL per minute.

In oncology, hydroxyurea is used as cytoreductive therapy in essential thrombocythemia, polycythemia vera, primary myelofibrosis, and chronic myeloid leukemia when tyrosine kinase inhibitors are not immediately available or are contraindicated. In sickle cell disease, hydroxyurea increases fetal hemoglobin production in erythroid precursors through mechanisms that are not fully characterized. Elevated fetal hemoglobin reduces the proportion of hemoglobin S available for polymerization, decreasing the frequency of vaso-occlusive crises, acute chest syndrome, stroke, and the need for red blood cell transfusions. Hydroxyurea is the most widely used disease-modifying therapy in sickle cell disease. The most common toxicities are myelosuppression requiring periodic complete blood count monitoring, macrocytosis (a consistent finding that does not require dose reduction), and, with long-term use, lower extremity leg ulcers.

Asparaginase catalyzes the hydrolysis of L-asparagine to L-aspartic acid and ammonia, depleting circulating asparagine. Most normal cells synthesize asparagine endogenously and are relatively protected. Certain acute lymphoblastic leukemia blasts, particularly T-cell acute lymphoblastic leukemia, express very low levels of asparagine synthetase and are dependent on exogenous asparagine for protein synthesis; depletion starves these cells of an essential amino acid, inducing endoplasmic reticulum stress and apoptosis. Three formulations exist: native Escherichia coli-derived asparaginase (no longer widely available), pegaspargase (polyethylene glycol-asparaginase, the standard preparation), and Erwinia asparaginase (used as an alternative for patients allergic to Escherichia coli-based preparations).

Pegaspargase is standard in current acute lymphoblastic leukemia protocols. Polyethylene glycol conjugation reduces immunogenicity, extending the plasma half-life from approximately 1.2 days (native asparaginase) to approximately 5.5 to 7 days, allowing less frequent dosing. Hypersensitivity reactions (10 to 20% of patients) remain the most common clinically significant toxicity, ranging from local infusion reactions to systemic anaphylaxis. Silent inactivation of pegaspargase by neutralizing antibodies without clinical hypersensitivity is increasingly recognized and should be suspected when asparagine depletion is inadequate despite apparent clinical tolerance. Beyond hypersensitivity, asparaginase-related toxicities include pancreatitis (1 to 18% incidence), coagulopathy (depletion of fibrinogen and antithrombin III, increasing both thrombotic and hemorrhagic risks), hyperglycemia (from reduced insulin secretion), and hepatotoxicity. Central venous sinus thrombosis occurs in approximately 1 to 4% of patients and requires systemic anticoagulation.

Cytochrome P450 3A4 is the most abundant hepatic cytochrome P450 isoform and metabolizes nearly all taxanes, vinca alkaloids, imatinib, erlotinib, gefitinib, cyclophosphamide, docetaxel, cabazitaxel, and many antiemetics. Major cytochrome P450 3A4 inhibitors encountered in oncology patients include azole antifungals (fluconazole, itraconazole, voriconazole, posaconazole), macrolide antibiotics (clarithromycin, erythromycin — azithromycin does not inhibit cytochrome P450 3A4), human immunodeficiency virus protease inhibitors, cobicistat, and grapefruit juice (which irreversibly inhibits intestinal cytochrome P450 3A4). Major inducers include rifampin, carbamazepine, phenytoin, phenobarbital, and St. John's wort — widely used as an over-the-counter supplement for depression that patients frequently do not disclose.

Cytochrome P450 2C8 is the primary metabolic pathway for paclitaxel; gemfibrozil (a fibrate used for hypertriglyceridemia) is a clinically significant cytochrome P450 2C8 inhibitor that increases paclitaxel exposure approximately twofold and should be discontinued before paclitaxel chemotherapy. Cytochrome P450 2D6 metabolizes tamoxifen to the active metabolite endoxifen; cytochrome P450 2D6 inhibitors (paroxetine, fluoxetine, bupropion) reduce endoxifen plasma concentrations by 65 to 75%, potentially reducing long-term tamoxifen efficacy in hormone receptor-positive breast cancer. Venlafaxine, citalopram, and escitalopram have low cytochrome P450 2D6 inhibitory activity and are preferred antidepressants for patients on tamoxifen. Aprepitant and fosaprepitant, the neurokinin-1 receptor antagonists used for prevention of chemotherapy-induced nausea and vomiting, are both moderate cytochrome P450 3A4 inhibitors and substrates, creating complex interactions with co-administered chemotherapy including docetaxel, vinorelbine, and cyclophosphamide.

Chemotherapy-induced peripheral neuropathy affects up to 40 to 60% of patients receiving neurotoxic chemotherapy, caused predominantly by taxanes, platinum compounds, vinca alkaloids, bortezomib, and thalidomide. Taxane-induced neuropathy results from axonal transport disruption caused by microtubule stabilization, affecting the longest axons first (distal lower extremities). Platinum-induced neuropathy targets dorsal root ganglia neurons directly; oxaliplatin produces both an acute cold-triggered sensory syndrome and a cumulative sensory neuropathy.

For prevention of chemotherapy-induced peripheral neuropathy, the evidence base for pharmacological neuroprotection is limited. Calcium and magnesium infusions before and after oxaliplatin failed to prevent cumulative neuropathy in a randomized trial and are no longer recommended. For treatment of established chemotherapy-induced peripheral neuropathy, duloxetine is the only agent with Level I evidence from a randomized controlled trial (the ACCRU Alliance trial) demonstrating significant reduction in chemotherapy-induced peripheral neuropathy pain and sensory symptoms; a 30 mg daily starting dose titrated to 60 mg daily is the standard approach. Dose reduction or schedule modification remains the most consistently effective neuropathy-sparing strategy where oncologically acceptable.