Several resistance mechanisms to MTX have been identified, and they include (1) decreased drug transport via the reduced folate carrier or folate receptor protein, (2) decreased formation of cytotoxic MTX polyglutamates, (3) increased levels of the target enzyme DHFR through gene amplification and other genetic mechanisms, and (4) altered DHFR protein with reduced affinity for MTX. Recent studies have suggested that decreased accumulation of drug through activation of the multidrug resistance transporter P170 glycoprotein also may result in drug resistance.
MTX is administered by the intravenous, intrathecal, or oral route. However, oral bioavailability is saturable and erratic at doses greater than 25 mg/m2. Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion. As a result, dose modification is required in the setting of renal dysfunction. Care must also be taken when MTX is used in the presence of drugs such as aspirin, nonsteroidal anti-inflammatory agents, penicillin, and cephalosporins, as these agents inhibit the renal excretion of MTX. The biologic effects of MTX can be reversed by administration of the reduced folate leucovorin (5-formyltetrahydrofolate) or by L-leucovorin, which is the active enantiomer. Leucovorin rescue is used in conjunction with high-dose MTX therapy to rescue normal cells from undue toxicity, and it has also been used in cases of accidental drug overdose. The main adverse effects are listed in Table 54–3.
Pemetrexed is a pyrrolopyrimidine antifolate analog with activity in the S phase of the cell cycle. As in the case of MTX, it is
TABLE 54–3 Antimetabolites: Clinical activity and toxicities.
Drug Mechanism of Action Clinical Applications Toxicity
Capecitabine Inhibits TS; incorporation of FUTP into RNA Breast cancer, colorectal can-Diarrhea, hand-foot syndrome, resulting in alteration in RNA processing; cer, gastroesophageal cancer, myelosuppression, nausea and incorporation of FdUTP into DNA resulting hepatocellular cancer, pancreatic vomiting in inhibition of DNA synthesis and function cancer 5-Fluorouracil Inhibits TS; incorporation of FUTP into RNA Colorectal cancer, anal cancer, breast Nausea, mucositis, diarrhea, bone resulting in alteration in RNA processing; cancer, gastroesophageal cancer, marrow depression, neurotoxicity incorporation of FdUTP into DNA resulting head and neck cancer, hepatocellular in inhibition of DNA synthesis and function cancer
Methotrexate Inhibits DHFR; inhibits TS; inhibits de novo Breast cancer, head and neck cancer, Mucositis, diarrhea, myelosup purine nucleotide synthesis osteogenic sarcoma, primary central pression with neutropenia and nervous system lymphoma, non-thrombocytopenia Hodgkin’s lymphoma, bladder cancer, choriocarcinoma
Pemetrexed Inhibits TS, DHFR, and purine nucleotide Mesothelioma, non-small cell lung Myelosuppression, skin rash, synthesis cancer mucositis, diarrhea, fatigue, hand-foot syndrome
Cytarabine Inhibits DNA chain elongation, DNA synthesis and repair; inhibits ribonucleotide reductase with reduced formation of dNTPs; incorporation of cytarabine triphosphate into DNA
Gemcitabine Inhibits DNA synthesis and repair; inhibits ribonucleotide reductase with reduced formation of dNTPs; incorporation of gemcitabine triphosphate into DNA resulting in inhibition of DNA synthesis and function