Anti-Cancer Drugs — Part 1

Cyclophosphamide is an inactive prodrug requiring hepatic oxidation by cytochrome P450 enzymes, principally cytochrome P450 2B6, to generate 4-hydroxycyclophosphamide. This intermediate spontaneously decomposes in tissues to yield phosphoramide mustard, the active bifunctional alkylating species, and acrolein, a reactive aldehyde that is the primary cause of cyclophosphamide-induced hemorrhagic cystitis. Acrolein is excreted unchanged in urine and achieves high concentrations in the bladder lumen, causing direct urothelial cytotoxicity.

Two strategies prevent hemorrhagic cystitis: forced hydration dilutes urinary acrolein concentrations and promotes rapid elimination, and mesna (sodium 2-mercaptoethane sulfonate) binds acrolein in the urinary tract through a thiol exchange reaction, forming a non-toxic conjugate excreted renally. Mesna is required whenever ifosfamide is used and is reserved for high-dose cyclophosphamide regimens; forced hydration alone suffices for standard-dose cyclophosphamide.

Cyclophosphamide is well absorbed orally (bioavailability above 75%) and undergoes autoinduction of its activating cytochrome P450 enzymes with repeated dosing. It crosses the blood-brain barrier to a limited extent. Significant drug interactions involve inducers and inhibitors of cytochrome P450 2B6 and cytochrome P450 3A4: rifampin increases activation and may increase toxicity; azole antifungals reduce activation and may reduce efficacy.

Ifosfamide is a structural isomer of cyclophosphamide that has a substantially higher rate of side-chain oxidation, generating chloroacetaldehyde, a neurotoxic metabolite responsible for ifosfamide encephalopathy. This presents with confusion, somnolence, cerebellar ataxia, visual hallucinations, seizures, or coma, typically beginning 12 to 48 hours after the start of infusion. Risk factors include hypoalbuminemia, renal impairment, and prior cisplatin exposure.

Treatment for established ifosfamide encephalopathy is methylene blue given intravenously at 50 mg every 4 to 8 hours. Methylene blue corrects the mitochondrial dysfunction caused by chloroacetaldehyde, restoring normal cellular energy metabolism in affected neurons. It is also used prophylactically at 50 mg three times daily in subsequent cycles when encephalopathy has occurred previously. Ifosfamide also produces a higher acrolein load per gram than cyclophosphamide, making mesna prophylaxis mandatory at all doses. Renal tubular toxicity, manifesting as Fanconi syndrome (proximal tubular dysfunction with phosphate, bicarbonate, glucose, and amino acid wasting), is more prominent with ifosfamide and may be dose-limiting in pediatric patients.

Mechlorethamine is the original nitrogen mustard, chemically unstable in aqueous solution, and the most reactive and vesicant of the class. It appears in the MOPP regimen for Hodgkin lymphoma and has largely been replaced in most other settings. Sodium thiosulfate is the antidote for mechlorethamine extravasation. Melphalan is used in multiple myeloma conditioning regimens before autologous stem cell transplantation; oral bioavailability is highly variable (15 to 90%), mandating intravenous dosing for high-dose conditioning, with dose reduction required in renal impairment. Chlorambucil is an oral nitrogen mustard used in chronic lymphocytic leukemia and low-grade lymphomas, well tolerated with predominantly myelosuppressive dose-limiting toxicity. Bendamustine combines a nitrogen mustard alkylating group with a benzimidazole ring that contributes purine analog-like properties; it is active in chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.

Carmustine and lomustine achieve central nervous system penetration not possible with most other alkylating agents because of their high lipophilicity, allowing passive diffusion across the blood-brain barrier. This makes them clinically useful for glioblastoma multiforme, anaplastic glioma, and primary central nervous system lymphoma. Carmustine is also available as a biodegradable polymer wafer (Gliadel) implanted in the surgical resection cavity after glioblastoma debulking, providing sustained local drug delivery without significant systemic exposure.

The most clinically distinctive feature of nitrosourea toxicity is delayed and prolonged myelosuppression. Unlike other alkylating agents whose nadir occurs at 10 to 14 days, nitrosoureas produce a nadir at 4 to 6 weeks, with recovery requiring 6 to 8 weeks from administration. This delayed kinetic profile means nitrosourea cycles are administered no more frequently than every 6 weeks. Clinicians unfamiliar with nitrosoureas who apply standard 3-week intervals will administer a second cycle before the first cycle's nadir has occurred, producing overlapping suppressions that can cause aplasia. Pulmonary fibrosis is a cumulative long-term toxicity of carmustine, typically appearing after total doses above 1,200 mg per square meter. Streptozocin is a nitrosourea with selective tropism for pancreatic beta cells used in metastatic pancreatic neuroendocrine tumors; its dose-limiting toxicity is nephrotoxicity, not myelosuppression.

Busulfan's clinical importance lies almost entirely in its use as a myeloablative conditioning agent before allogeneic and autologous hematopoietic stem cell transplantation. Oral busulfan has highly variable bioavailability (40 to 100%), and intravenous busulfan is now preferred for conditioning because it achieves more predictable plasma exposure. Therapeutic drug monitoring of busulfan plasma area under the curve is performed during conditioning to ensure target exposure (typically 900 to 1,350 micromolar per minute per day) and reduce the risk of hepatic sinusoidal obstruction syndrome from overexposure or graft failure from underexposure. Hepatic sinusoidal obstruction syndrome, formerly called hepatic veno-occlusive disease, is a life-threatening complication of high-dose busulfan conditioning characterized by tender hepatomegaly, jaundice, ascites, and thrombocytopenia. Defibrotide is approved for established severe hepatic sinusoidal obstruction syndrome.

Temozolomide is an orally bioavailable imidazotetrazine prodrug that spontaneously hydrolyzes at physiological pH to generate a methylating species. It methylates deoxyribonucleic acid predominantly at O6-guanine, producing lesions that cause cell death by generating persistent mismatches that trigger futile cycles of mismatch repair, ultimately causing double-strand breaks and apoptosis. Temozolomide is 100% orally bioavailable, crosses the blood-brain barrier effectively, and is used as the standard of care for newly diagnosed glioblastoma in the Stupp protocol (concurrent daily temozolomide with radiation, followed by adjuvant temozolomide for 6 cycles).

The critical predictive biomarker for temozolomide response is O6-methylguanine-deoxyribonucleic acid methyltransferase promoter methylation status. O6-methylguanine-deoxyribonucleic acid methyltransferase is a deoxyribonucleic acid repair enzyme that directly reverses O6-guanine alkylation. Tumors that silence O6-methylguanine-deoxyribonucleic acid methyltransferase expression through promoter methylation cannot repair these lesions and are more than twice as likely to respond to temozolomide. Patients with O6-methylguanine-deoxyribonucleic acid methyltransferase-methylated glioblastoma have substantially better outcomes with temozolomide than those with unmethylated tumors. O6-methylguanine-deoxyribonucleic acid methyltransferase methylation testing is now standard in the initial workup of any newly diagnosed glioblastoma. Myelosuppression, predominantly lymphopenia and thrombocytopenia, is the dose-limiting toxicity; Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole is mandatory during concurrent chemoradiation and recommended during adjuvant temozolomide due to sustained lymphodepletion.

Procarbazine is a methylhydrazine compound used in the PCV regimen (procarbazine, lomustine, vincristine) for anaplastic oligodendroglioma with 1p/19q co-deletion, and historically in MOPP for Hodgkin lymphoma. It requires metabolic activation by cytochrome P450 enzymes and monoamine oxidase, and is itself a weak monoamine oxidase inhibitor. Concomitant use of sympathomimetics, tricyclic antidepressants, selective serotonin reuptake inhibitors, or tyramine-rich foods risks hypertensive crisis or serotonin syndrome. Alcohol causes a disulfiram-like reaction.

Dacarbazine is a triazene requiring hepatic cytochrome P450-mediated hydroxylation to generate the same active methylating species as temozolomide. Because it requires enzymatic activation rather than spontaneous hydrolysis, it is available only as an intravenous formulation and does not achieve meaningful central nervous system concentrations. It is used in ABVD for Hodgkin lymphoma and in combination regimens for malignant melanoma and soft tissue sarcoma. Severe nausea and vomiting are prominent acute toxicities; it is classified as highly emetogenic at high doses.