Fludarabine Inhibits DNA synthesis and repair; inhibits ribonucleotide reductase; incorporation of fludarabine triphosphate into DNA; induction of apoptosis AML, ALL, CML in blast crisis
Pancreatic cancer, bladder cancer, breast cancer, non-small cell lung cancer, ovarian cancer, non-Hodgkin’s lymphoma, soft tissue sarcoma
Non-Hodgkin’s lymphoma, CLL Nausea and vomiting, myelosuppression with neutropenia and thrombocytopenia, cerebellar ataxia
Nausea, vomiting, diarrhea, myelosuppression
Myelosuppression, immunosuppression, nausea and vomiting, fever, myalgias, arthralgias
Cladribine Inhibits DNA synthesis and repair; inhibits Hairy cell leukemia, CLL, Myelosuppression, nauribonucleotide reductase; incorporation of non-Hodgkin’s lymphoma sea and vomiting, and cladribine triphosphate into DNA; induction immunosuppression of apoptosis 6-Mercaptopurine Inhibits de novo purine nucleotide synthe-AML Myelosuppression, immunosup(6-MP) sis; incorporation of triphosphate into RNA; pression, and hepatotoxicity incorporation of triphosphate into DNA 6-Thioguanine Same as 6-MP ALL, AML Same as 6-MP
ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; DHFR, dihydrofolate reductase; dNTP, deoxyribonucleotide triphosphate; FdUTP, 5-fluorodeoxyuridine-5′-triphosphate; FUTP, 5-fluorouridine-5′-triphosphate; TS, thymidylate synthase.
transported into the cell via the reduced folate carrier and requires activation by FPGS to yield higher polyglutamate forms. While this agent targets DHFR and enzymes involved in de novo purine nucleotide biosynthesis, its main mechanism of action is inhibition of thymidylate synthase (TS). Pemetrexed is currently approved for use in combination with cisplatin in the treatment of mesothelioma, as a single agent in the second-line therapy of NSCLC, in combination with cisplatin for the first-line treatment of NSCLC, and most recently, as maintenance therapy in patients with NSCLC whose disease has not progressed after four cycles of platinum-based chemotherapy. As with MTX, pemetrexed is mainly excreted in urine, and dose modification is required in patients with renal dysfunction. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, fatigue, and hand-foot syndrome. Of note, vitamin supplementation with folic acid and vitamin B12 has been shown to significantly reduce the toxicities associated with pemetrexed, while not interfering with clinical efficacy. The hand-foot syndrome is manifested by painful erythema and swelling of the hands and feet, and treatment with the steroid dexamethasone is effective in reducing the incidence and severity of this skin toxicity.