Anti-Cancer Drugs — Part 1

5-Fluorouracil exerts cytotoxicity through two distinct mechanisms that determine which toxicities predominate with different administration schedules. The first mechanism is thymidylate synthase inhibition via fluorodeoxyuridine monophosphate, the active metabolite that forms a covalent ternary complex with thymidylate synthase and the folate cofactor 5,10-methylenetetrahydrofolate, permanently inactivating the enzyme and blocking thymidylate synthesis. The second mechanism involves incorporation of fluorouridine triphosphate into ribonucleic acid, disrupting ribonucleic acid processing and ribosome assembly.

With bolus 5-fluorouracil administration, high peak concentrations favor ribonucleic acid disruption, producing predominantly myelosuppression. With continuous infusion, sustained lower concentrations favor thymidylate synthase inhibition, producing predominantly mucositis and hand-foot syndrome (palmar-plantar erythrodysesthesia). Leucovorin administered concurrently with 5-fluorouracil increases intracellular 5,10-methylenetetrahydrofolate, stabilizing the ternary complex and approximately doubling the response rate in metastatic colorectal cancer compared to 5-fluorouracil alone.

The primary catabolic pathway is hepatic oxidation by dihydropyrimidine dehydrogenase, which accounts for more than 85% of 5-fluorouracil elimination and is the dominant pharmacokinetic determinant of plasma half-life (approximately 10 to 20 minutes under normal dihydropyrimidine dehydrogenase activity). Dihydropyrimidine dehydrogenase activity varies approximately fivefold in the normal population, contributing to wide inter-patient variation in both toxicity and efficacy.

Dihydropyrimidine dehydrogenase deficiency is a pharmacogenomic variant affecting approximately 3 to 8% of the general population, caused by loss-of-function variants in the dihydropyrimidine dehydrogenase gene. The most clinically significant variant causes complete loss of dihydropyrimidine dehydrogenase activity in homozygotes. Patients with complete deficiency who receive standard 5-fluorouracil doses experience severe and potentially fatal toxicity: profound myelosuppression, life-threatening mucositis, neurotoxicity, and multi-organ failure occurring within days of the first dose. Patients with partial deficiency (heterozygotes, affecting approximately 3 to 5% of the population) experience severe grade 3 or 4 toxicity at standard doses in approximately 25 to 30% of cases. Dihydropyrimidine dehydrogenase gene testing before 5-fluorouracil or capecitabine administration is now recommended by the European Medicines Agency and is increasingly adopted in North America. Carriers require a starting dose reduction of at least 50%.

Capecitabine is an orally administered prodrug that undergoes three-step enzymatic conversion to 5-fluorouracil, with the final step catalyzed by thymidine phosphorylase, which is expressed at substantially higher levels in many tumor types than in surrounding normal tissue. This tumor-preferential final activation step produces predominantly a continuous infusion-like toxicity profile: hand-foot syndrome is the most frequent and dose-limiting adverse effect, occurring in 50 to 60% of patients, while myelosuppression is generally milder than with intravenous 5-fluorouracil regimens. Capecitabine is subject to the same dihydropyrimidine dehydrogenase deficiency risk as intravenous 5-fluorouracil. Dose reduction is required in renal impairment; capecitabine is contraindicated when creatinine clearance falls below 30 mL per minute.

A major drug interaction involves capecitabine and warfarin. Capecitabine inhibits cytochrome P450 2C9, the primary enzyme responsible for metabolizing the more potent S-warfarin enantiomer, and can increase the international normalized ratio dramatically within days to weeks of starting capecitabine. The international normalized ratio must be monitored weekly or more frequently in patients on warfarin receiving capecitabine. When possible, switching to a direct oral anticoagulant before capecitabine initiation avoids this interaction entirely.

6-Mercaptopurine is a thiopurine prodrug used primarily in acute lymphoblastic leukemia maintenance therapy. It requires intracellular activation by hypoxanthine-guanine phosphoribosyltransferase to thioguanine nucleotides, which are incorporated into deoxyribonucleic acid and trigger mismatch repair-mediated apoptosis. The primary catabolic pathway is methylation by thiopurine methyltransferase, which converts 6-mercaptopurine to an inactive metabolite, and oxidation by xanthine oxidase to 6-thiouric acid.

Thiopurine methyltransferase activity is trimodally distributed: approximately 90% of patients have high (wild-type) activity, approximately 10% have intermediate activity (heterozygous for one low-activity allele), and approximately 0.3% have low or absent activity (homozygous). Patients with low thiopurine methyltransferase activity shunt virtually all 6-mercaptopurine through the activation pathway, accumulating very high thioguanine nucleotide concentrations and experiencing life-threatening myelosuppression at standard doses. Acute lymphoblastic leukemia maintenance protocols routinely include thiopurine methyltransferase genotyping or phenotyping before starting 6-mercaptopurine; patients with intermediate activity receive a 30 to 50% dose reduction and those with low activity receive 10 to 20% of the standard dose.

The interaction between 6-mercaptopurine and allopurinol is among the most dangerous drug interactions in clinical oncology. Allopurinol inhibits xanthine oxidase, a primary catabolic enzyme for 6-mercaptopurine, and co-administration blocks 6-mercaptopurine catabolism, increasing plasma concentrations approximately fourfold and causing potentially fatal aplasia. The standard management is to reduce the 6-mercaptopurine dose to 25% of the usual dose when allopurinol cannot be avoided. For tumor lysis syndrome prevention in patients who will receive 6-mercaptopurine, rasburicase rather than allopurinol should be used as the uric acid-lowering agent whenever possible.

Fludarabine is a fluorinated purine nucleoside analog active in chronic lymphocytic leukemia, typically as part of the fludarabine, cyclophosphamide, and rituximab regimen in fit patients. Its most clinically significant adverse effect is profound and sustained immunosuppression: fludarabine is selectively toxic to CD4-positive T lymphocytes, depleting them to very low levels for months to years after therapy. This creates risks for opportunistic infections including Pneumocystis jirovecii pneumonia, viral reactivations (cytomegalovirus, herpesvirus), and fungal infections. Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole is mandatory during and for at least 6 to 12 months after fludarabine-containing regimens. Fludarabine can also trigger autoimmune hemolytic anemia in chronic lymphocytic leukemia patients; development of autoimmune hemolytic anemia during fludarabine therapy is an indication to discontinue the drug immediately.

Cladribine (2-chlorodeoxyadenosine) is the drug of choice for hairy cell leukemia, producing durable complete remissions in more than 90% of patients with a single 7-day continuous infusion course. Like fludarabine, cladribine causes profound immunosuppression requiring Pneumocystis jirovecii pneumonia and herpesvirus prophylaxis.

Azacitidine and decitabine are cytidine analogs that, after incorporation into deoxyribonucleic acid during S phase, form an irreversible bond with deoxyribonucleic acid methyltransferase 1, the maintenance methyltransferase responsible for replicating the parental methylation pattern on newly synthesized daughter strands. This traps and degrades deoxyribonucleic acid methyltransferase 1, causing progressive loss of methylation marks on CpG islands in promoters of epigenetically silenced tumor suppressor genes across successive cell divisions, a process called passive demethylation. Reactivation of silenced tumor suppressors — including cyclin-dependent kinase inhibitors and E-cadherin — restores differentiation, apoptosis responsiveness, and cell cycle checkpoint function in myelodysplastic syndrome and acute myeloid leukemia cells.

Azacitidine is administered subcutaneously or intravenously for 7 days every 28 days in myelodysplastic syndrome and acute myeloid leukemia unfit for intensive chemotherapy. Decitabine is administered intravenously for 5 days every 28 days in myelodysplastic syndrome and acute myeloid leukemia. The clinical benefit of hypomethylating agents often requires 3 to 6 treatment cycles before a response is apparent, reflecting the time required for passive demethylation to accumulate across multiple cell divisions. A minimum of 4 to 6 cycles should be administered before declaring treatment failure, provided hematological tolerance allows continuation.