ANTIMETABOLITES Antimetabolites are structurally related to normal compounds that exist within the cell They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are in S-phase and are, therefore, cell cycle specific.

5-FLUOROURACIL – (5-FU, EFUDEX, ADRUCIL,FLUOROPLEX) – available in a 500-mg or 10-mL vial for IV use and as a 1% and 5% topical cream. – 5-FU is used in the treatment of several carcinoma types including breast cancer, colorectal cancer, stomach cancer, pancreatic cancer, and topical use in basal cell cancer of the skin. – MOA: inhibition of the enzyme TS by the deoxyribose monophosphate metabolite, 5- FdUMP. – RESISTANCE : can occur as a result of increased expression of TS, decreased levels of reduced folate substrate 5,10-methylenetetrahydrofolate, or increased levels of dihydropyrimidine dehydrogenase. – DRUG INTERACTIONS : include enhanced toxicity and antitumor activity of 5-FU following pretreatment with leucovorin. – TOXICITIES: dose-limiting myelosuppression, mucositis, diarrhea, and hand–foot syndrome (numbness, pain, erythema, dryness, rash, swelling, increased pigmentation, nail changes, pruritus of the hands and feet).

CAPECITABINE (XELODA) – 150- and 500-mg tablets for oral use. – is used to treat breast cancer and colorectal cancer.

FLOXURIDINE (FLUORODEOXYURIDINE, FUDR) – 500-mg vial of lyophilized powder. – USES: to treat metastatic GI adenocarcinoma. – MOA:involves metabolic conversion to 5-fluorouracil (5-FU) metabolites resulting in inhibition of TS thus disrupting DNA synthesis, function, and repair. – Resistance: can occur because of increased expression of TS, decreased levels of reduced folate 5,10-methylenetetrahydrofolate, increased activity of DNA repair enzymes, and increased (expression of dihydropyrimidine dehydrogenase the major catabolic enzyme).

CYTARABINE (CYTOSINE ARABINOSIDE, ARA-C, CYTOSAR-U, TARABINE) – 100-, 500-, 1,000-, and 2,000-mg multidose vials for IV use. – Cytarabine is used in the treatment of acute myelogenous leukemia and CML. – MOA: inhibition of DNA synthesis and function. – RESISTANCE: can occur because of decreased activation or transport and increased catabolic breakdown. Metabolic breakdown within the GI tract leads to poor bioavailability. – DRUG INTERACTIONS: antagonism of the effects of gentamicin, decreasing the oral bioavailability of digoxin, as well as enhancing the cytotoxicity of various alkylating agents, cisplatin, and ionizing radiation. – TOXICITIES: include myelosuppression, leukopenia and thrombocytopenia, nausea and vomiting anorexia, diarrhea, and mucositis.

GEMCITABINE (DFDC, GEMZAR) – available as the hydrochloride salt in 200- and 1,000-mg lyophilized single- dose vials for IV use. – USES: to treat bladder cancer, breast cancer, pancreatic cancer, and NSCLC. – MOA: inhibition of DNA synthesis and function via DNA chain termination. – Drug toxicity: includes myelosuppression, fever, malaise, chills, headache, myalgias, nausea, and vomiting.

CLADRIBINE (2-CHLORODEOXYADENOSINE, 2-CDA, LEUSTATIN) – 10-mg or 10-mL single-use vial for IV use. – USES: for chronic lymphocytic leukemia, hairy cell leukemia, and non-Hodgkin’s lymphoma. – MOA: Involves incorporation into DNA resulting in inhibition of DNA chain extension and inhibition of DNA synthesis and function. – RESISTANCE: To the anticancer effects can occur because of decreased expression of the activating enzyme or overexpression of the catabolic enzymes. – TOXICITIES: myelosuppression, neutropenia, immunosuppression, fever, nausea, and vomiting.

FLUDARABINE (2-F-ARA-AMP, FLUDARA) – 50-mg vial for IV use. – USES: Treat chronic lymphocytic leukemia and non-Hodgkin’s lymphoma. MOA: Involves the triphosphate metabolite and its inhibition of DNA chain elongation. – RESISTANCE: Can occur via decreased expression of the activating enzymes and decreased drug transport. – DRUG INTERACTIONS: an increased incidence of fatal pulmonary toxicity when fludarabine is used in combination with pentostatin. – TOXICITIES: myelosuppression, immunosuppression, – fever, nausea, and vomiting.

MERCAPTOPURINE (6-MP, MERCAPTOPURINUM, PURINETHOL) – USES: treatment of lymphoblastic leukemia, acute lymphocytic leukemia, and Crohn disease. – MOA: Inhibits synthesis and function of the resulting modified DNA or RNA. – RESISTANCE: Can occur via decreased expression of the activating enzymes or increased expression of the major catabolic enzymes. – TOXICITIES: myelosuppression, immunosuppression, nausea, vomiting, – diarrhea, dry skin, urticaria, and photosensitivity

THIOGUANINE (6-THIOGUANINE, 6-TG, TABLOID) – 40-mg tablets for oral use. – USES: To treat acute nonlymphocytic leukemia. – MOA: Involves incorporation of the triphosphate into DNA and RNA, resulting in inhibition of processing and function. – RESISTANCE: Decreased expression of the activating enzyme, decreased drug transport, and/or increased expression of catabolic enzymes. – TOXICITIES: myelosuppression, immunosuppression, nausea, vomiting, mucositis, and diarrhea.

PENTOSTATIN (DEOXYCOFORMYCIN,DCF, NIPENT) – 10-mg vials for IV use – USES: Treat leukemia such as hairy cell leukemia, chronic Lymphocytic leukemia, and lymphoblastic leukemia. – MOA: Involves inhibition of the enzyme adenosine deaminase yielding increased cellular levels of deoxyadenosine and deoxyadenosine triphosphate (dATP). – RESISTANCE: Appears to involve decreased cellular transport or increased expression of catabolic enzymes. – TOXICITIES: myelosuppression, immunosuppression, nausea, vomiting, headache, lethargy, and fatigue.

PEMETREXED (MTA, ALIMTA) – 100-mg sterile vial for IV use – The drug appears to be effective against a range of tumors including – mesothelioma, NSCLC, colorectal cancer, bladder cancer, and lung cancer. – MOA: inhibition of TS resulting in inhibition of thymidylate and – DNA synthesis. – RESISTANCE: Can occur by increased expression of TS, decreased binding affinity for TS, or decreased drug transport into cells.

TRIMETREXATE (TMTX, NEUTREXIN) – 5- or 30-mg vials for IV use – USES: To treat colorectal cancer, head and neck cancer as well as NSCLC. – MOA: Involves folate antagonism and inhibition of thymidylate synthesis. – RESISTANCE: can occur by increased expression of the target enzyme, decreased binding affinity for the target enzyme, or decreased intracellular drug transport.

HYDROXYUREA (DROXIA, HYDREA) – 500-mg capsule for oral use. – USES: To treat myelogenous leukemia, ovarian cancer, and essential thrombocytosis. – MOA: involves inhibition of DNA biosynthesis by inhibition of the enzyme ribonucleotide reductase. – RESISTANCE: can occur via increased expression of ribonucleotide reductase. – TOXICITIES: Includes myelosuppression, leucopenia, nausea, vomiting, pruritus hyperpigmentation, headache, drowsiness, and confusion.