Antimetabolites

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)


In general, antimetabolites mimic naturally occurring substrates and thus interfere with nucleic acid activity. Available antimetabolites vary in their specific mechanisms of action; however, classic antimetabolites are cell cycle phase-specific and inhibit DNA and/or RNA synthesis.

Some antimetabolites are incorporated into DNA and others may inhibit key enzymes important for DNA synthesis. Some examples are included in figure 9.1. Fluorouracil and floxuridine inhibit thymidylate synthase whereas methotrexate inhibits dihydrofolate reductase. Pemetrexed is an inhibitor of both of these enzymes, in addition to other key enzymes involved in folate metabolism.

Antifolates

  • Understanding antimetabolite action necessitates knowledge of folate biochemistry.
  • The enzyme thymidylate synthase (TS) acts as rate-limiting step in the synthesis of thymidylate, conver ting dUMP into dTTP by transferring a methyl group from CH2 to FH4.
  • The supply of reduced folate is maintained by the enzyme dihydrofolate reductase (DHFR).

Methotrexate (MTX)

Clinical indications

  • Breast cancer, osteogenic sarcoma, GI cancers, choriocarcinoma, leukemias and lymphomas, and prevention of graft-versus-host disease, and for its immunosuppressive effects in various autoimmune disorders

Dosing

  • The total dose per cycle ranges from a low dose (<100 mg/m2) up to 10,000 mg/m2 typically infused over 4 –24 hours.
  • The dose must be reduced for renal insufficiency.
  • Consider dosage reduction for severe hepatic impairment.
  • May be given intrathecally (usual adult dose 10 –12 mg)

Adverse events

  • Bone marrow suppression
  • Mucositis
  • Nausea and vomiting
  • Nephrotoxicity
  • Hepatotoxicity
  • Encephalopathy (with high doses)
  • Myelopathy
  • Interstitial pneumonitis
  • Pulmonary fibrosis
  • Teratogenesis
  • Impaired fertility
  • Alopecia
  • Dermatologic toxicity
  • Ocular toxicity
  • Tumor lysis syndrome
  • Rhythm distrubances
  • Arachnoiditis (more likely with intrathecal administration)

Oxford American Handbook of Oncology-Oxford University Press (2015) F9.1

Figure 9.1. Main sites of action of antimetabolites.

Additional comments

  • Methotrexate (MTX) distributes into third spaces; strong consideration should be given to draining identified effusions before the administration of methotrexate.
  • Leucovorin must be given with “high-dose” methotrexate to effectively rescue normal cells from related toxicity.
  • Toxicity of high-dose methotrexate can also be minimized by aggressively hydrating the patient and by alkalinizing the urine to promote excretion of the drug.
  • Serum concentrations of methotrexate should be monitored until the drug has been cleared from the body.
  • Widely used in many cancers, methotrexate is frequently used in breast cancer, osteogenic sarcoma, GI cancers, and choriocarcinoma.

Pharmacology

  • MTX is well absorbed orally below 25 mg/m2, but it is usually administered IV, except in maintenance regimens and treatment of benign connective tissue diseases.
  • There is some hepatic metabolism to the active drug 7-oh-MTX, and approximately 10% of the drug is cleared by biliary excretion.
  • Dose adjustments are not usually necessary with hepatic dysfunction.
  • Significant third-space effects occur in the presence of fluid collections (e.g., ascites, pleural effusions) and can increase toxicity through reduced clearance.
  • MTX excretion can also be inhibited by probenicid, penicillins (and cephalosporins), and nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Common toxicities include mucositis, myelosuppression, and nephrotoxicity.

Pemetrexed

Clinical indications

  • Lung cancer and mesothelioma, bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck cancer, pancreatic cancer, renal cell cancer

Dosing

  • Mesothelioma: 500 mg/m2 IV on day 1 of a 21-day cycle (in combination with cisplatin)
  • Non-small– cell lung cancer: 500 mg/m2 IV on day 1 of each 21-day cycle (single agent).
  • Other regimens for lung cancer and other malignancies have been studied.
  • Do not administer if CrCl <45 ml/min.

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting
  • Diarrhea
  • Mucositis
  • Elevated hepatic enzymes
  • Nephrotoxicity
  • Rash
  • Neuropathy
  • Dyspnea
  • Anaphylactoid reactions

Additional comments

  • Measures should be used to reduce toxicity associated with pemetrexed.
  • Patients should receive folic acid 400 µg daily for at least 5 days before initiating pemetrexed and continuing for 21 days after completion of the final dose of pemetrexed.
  • Vitamin b12 1000 µg iM should be given before initiating pemetrexed therapy and every three cycles thereafter.
  • Dexamethasone 4 mg twice daily for three days should be considered beginning the day before each dose of pemetrexed to decrease skin reactions.
  • Do not give pemetrexed if CrCl is <45 ml/min.
  • Can give leucovorin rescue for severe or prolonged myelosuppression and/or mucositis.

Thymidylate synthase inhibitors

  • New agents have been developed that directly inhibit thymidylate synthase (TS) (in contrast to indirect inhibitors, e.g., 5-fluorouracil [5-FU] and MTX) and interact with the folate-binding site of TS.
  • Raltitrexed (Tomudex) causes prolonged inhibition of TS by enhanced retention in cells due to polyglutamation of the parent molecule.
  • After IV administration it has triphasic elimination, with a rapid initial fall in concentration but very prolonged final phase.
  • 50% of the drug is renally excreted unchanged. It is active in breast and colorectal cancer with toxicities including myelosuppression, diarrhea, and transaminitis.

Fluoropyrimidines

These prodrugs are intracellularly activated and their products inhibit pyrimidine synthesis.

5-Fluorouracil

  • Clinical indications: Actinic keratosis, basal cell carcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, ovarian cancer, pancreatic cancer

Dosing

  • 300 –500 mg/m2 IV bolus daily for 4 –5 days every 28 days or 600 –1500 mg/m2 IV bolus once weekly or every other week
  • 300 –1000 mg/m2 per day continuous IV infusion for 4 –5 days every 28 days or 300 mg/m2 per day continuous IV infusion indefinitely
  • Numerous dosing schedules are used
  • Consider dosage reduction with significant hepatic impairment

Adverse events

  • Bone marrow suppression (dose-limiting with bolus injection or high-dose continuous infusion)
  • Neurotoxicity or cerebellar toxicity (dose-limiting with high-dose continuous infusion)
  • Diarrhea
  • Mucositis
  • Nausea and vomiting (mild)
  • Palmar – plantar erythrodysesthesia
  • Cardiotoxicity (angina, myocardial infarction)
  • Ocular irritation
  • Injection-site reactions
  • Skin hyperpigmentation
  • Photosensitivity
  • Rash

Additional comments

  • Do not use in patients with dihydropyrimidine dehydrogenase deficiency (severe toxicity will result from the inability to metabolize fluorouracil).
  • Concurrent leucovorin administration may increase efficacy and toxicity.
  • This is a widely prescribed agent with particular activity in breast cancer, GI cancers, and head and neck tumors.
  • 5-FU is metabolized to FdUMP, which, in the presence of CH2-FH4, forms a stable complex inhibiting TS. It also inhibits RNA synthesis and pre-ribosomal RNA processing.

Pharmacology

  • 5-FU is given IV both as a bolus and as a prolonged infusion. It has a short initial half-life, with significant hepatic, renal, and lung clearance. Active metabolites (e.g., 5dUMP and fUTp) have variable pharmacokinetics.
  • Toxicities of 5-FU include myelosuppression and, particularly with longer administration schedules, stomatitis and diarrhea.
  • Prolonged infusion overcomes the initial rapid clearance, resulting in differing toxicities with minimal bone marrow effects. Instead, cutaneous toxicity known as hand-foot syndrome occurs.
  • Neurotoxicity and cardiotoxicity may also occur.

5-Fluorouracil prodrugs

Capecitabine

Capecitabine is an oral prodrug of fluorouracil. When administered twice daily, it somewhat mimics continuous IV infusion of fluorouracil.

  • Clinical indications: Colorectal cancer and breast cancer
  • Dosing: 2500 mg/m2 per day in 2 divided doses with food for 14 days followed by 7 days of rest (repeat every 21 days)

The dose must be reduced for renal impairment (25% dose reduction for CrCl 30 –50 ml/min; do not use if CrCl <30 ml/min).

Adverse events

  • Myelosuppression including lymphopenia
  • Diarrhea
  • Mucositis
  • Nausea and vomiting
  • Palmar-plantar erythrodysesthesia
  • Dermatitis
  • Hyperbilirubinemia
  • Paresthesia
  • Eye irritation
  • Dyspnea
  • Venous thrombosis
  • Headache
  • Edema
  • Fatigue
  • Fever
  • Angina
  • Photosensitivity
  • Radiation recall

Additional comments

  • This is an orally active prodrug of 5-FU.
  • It is preferentially activated in tumor and liver tissue and has the potential to replace prolonged or continuous-infusion 5-FU.
  • It has been shown to be active in a wide range of cancers and is licensed for breast and colorectal cancer.

2-Fluoro-2’-deoxyuridine (floxuridine)

  • Clinical indications: Used almost exclusively for hepatic artery infusion for colon cancer metastatic to the liver.
  • Dosing: 0.1– 0.6 mg/kg per day as a continuous intra-arterial infusion into the hepatic artery. Consider dose reduction with significant renal or hepatic impairment.

Adverse events

  • Hepatotoxicity
  • Cholangitis
  • Bone marrow suppression
  • Peptic ulcer disease
  • Acute cerebellar syndrome
  • Confusion, drowsiness
  • Nystagmus, seizures, ataxia
  • Alopecia
  • Diarrhea
  • Mucositis
  • Rash
  • Photosensitivity
  • Skin hyperpigmentation
  • Nausea and vomiting

Additional comments

  • Given IV, this agent can be metabolized both into 5-FU and directly into FdUMP, theoretically giving increased efficacy.
  • Its clinical use has largely been confined to hepatic artery infusion because it is less toxic than single-agent 5-FU used by this route for treating colon cancer.

Modulation of 5-Fluorouracil

  • A number of agents have been combined with 5-FU to increase either its efficacy or therapeutic index.
  • 5-FU and folinic acid combinations are the mainstay of treatment of colon cancer.
  • Folinic acid is given by infusion, before or concomitant with 5-FU.
  • By increasing the supply of CH2–FH4, folinic acid potentiates interaction between 5-FU and TS.
  • Although more toxic, it has a higher response rate in advanced colorectal cancer with combined treatment than single-agent 5-FU.

Antipurines

Purine analogs

Purine analogs are widely used to treat leukemias and as immunosuppressives (azathioprine) and antivirals (acyclovir, gancyclovir).

6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG) both inhibit de novo purine synthesis, and their nucleotide products are incorporated into DNA. Hypoxanthine guanine phosphoribosyl transferase (HGPRT) produces monophosphates that inhibit early stages of purine synthesis and then conver t into triphosphates that are incorporated into DNA, causing strand breaks.

There are synergistic effects with MTX, due to 5-phosphoribosylpyrophosphate (pRpp) buildup, facilitating phosphorylation by HGPRT. Resistance develops due to HGPRT deficiency and reduced substrate affinity. Variable oral bioavailability may contribute to some treatment failures in childhood ALL.

Both drugs have a short half-life and are primarily metabolized. The important difference is that 6-MP is a substrate for xanthine oxidase, and dose alterations are necessary when coadministered with allopurinol. There is poor cerebrospinal fluid (CSF) penetration, but otherwise these agents are widely distributed.

The main toxicity is myelosuppression, but 6-MP can also cause hepatotoxicity. Nausea, vomiting, and mucositis can also occur, more commonly with 6-MP.

The most common indication is hematological malignancy: 6-MP is used for maintenance therapy of ALL, and 6-TG is used for both remission induction and maintenance in AML.

Cytarabine

Cytarabine is triphosphorylated and subsequently incorporated into DNA, which results in the inhibition of DNA synthesis.

Clinical indications

  • Acute myelogenous leukemia, acute lymphocytic leukemia, carcinomatous meningitis, chronic myelogenous leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma

Dosing

  • AML induction (usually in combination with daunorubicin or idarubicin): 100 –200 mg/m2 per day as a continuous infusion over 7 days
  • AML induction (high-dose): 1000 –3000 mg/m2 IV twice daily for 8 –12 doses
  • Reduce dose for renal insufficiency
  • Liposomal cytarabine (for intrathecal [IT] administration): 50 mg IT every 14 days on weeks 1, 3, 5, 7, 9 and then at week 13, then every 28 days on weeks 17, 21, 25, and 29
    • Administer dexamethasone 4 mg po/IV twice daily for 5 days beginning on the day of each administration.
    • If drug-induced neurotoxicity develops, decrease the dose to 25 mg.

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (dose-related)
  • Mucositis
  • Fever
  • Hepatotoxicity
  • Rash
  • Palmar – plantar erythrodysesthesia
  • Cerebellar toxicity (high doses)
  • Chemical conjunctivitis (high doses)
  • Respiratory distress
  • Anaphylactoid reactions
  • Peripheral neuropathy
  • CNS toxicity (including arachnoiditis) with intrathecal therapy
  • Tumor lysis syndrome

Additional comments

  • Ara-C is actively transported, and its metabolite Ara-CTP is incorporated into DNA, inhibiting DNA polymerases and possibly phospholipid synthesis.
  • Unlike gemcitabine, no further normal nucleotides are added, so that damaged DNA is susceptible to DNA repair.
  • Ara-C is active in NHL and AML, but not in solid tumors.
  • There is renal excretion of deaminated compound; because of rapid clearance, better activity is observed when Ara-C is given by continuous infusion.
  • Side effects are emesis, alopecia, and myelosuppression.
  • It can cause “Ara-C syndrome” with fevers, myalgias, rash, keratoconjunctivitis, and ar thralgias. Rarely, lung and pancreatic damage occur.

Gemcitabine

Gemcitabine (difluorodeoxycytidine) is closely related to cytarabine; however, the spectrum of activity is significantly different. Gemcitabine is triphosphorylated and subsequently incorporated into DNA. An additional base pair is added after insertion of the analog into DNA, which inhibits DNA replication and repair. This is termed “masked termination.” Ultimately, sensitive tumor cells exposed to gemcitabine undergo apoptosis.

Gemcitabine has self-potentiating effects, resulting in increased intracellular concentrations and prolonged intracellular retention.

Clinical indications

  • Breast cancer, lung cancer, ovarian cancer, pancreatic cancer, bladder cancer, mesothelioma

Dosing

  • Lung cancer (in combination with cisplatin): 1000 mg/m2 IV on days 1, 8, 15 of a 28-day cycle, or 1250 mg/m2 IV on days 1 and 8 of a 21-day cycle
  • Lung cancer (in combination with paclitaxel): 1000 mg/m2 IV on days 1 and 8 of a 21-day cycle
  • Pancreatic cancer: 1000 mg/m2 IV once weekly for up to 7 consecutive weeks followed by 1 week of rest then weekly for 3 weeks followed by 1 week of rest for subsequent cycles
  • Additional regimens exist for breast and ovarian cancer

Adverse events

  • Bone marrow suppression
  • Fever
  • Rash
  • Alopecia
  • Anaphylactoid reactions
  • Injection-site reactions (irritant)
  • Nausea and vomiting
  • Diarrhea
  • Mucositis
  • Elevated hepatic enzymes
  • Hyperbilirubinemia
  • Hemolytic uremic syndrome
  • Renal failure
  • Dyspnea
  • Pulmonary toxicity (rare)
  • Radiation recall

Additional comments

  • This fluorinated analog has better membrane permeation and affinity for deoxycytidine kinase than Ara-C.
  • Intracellular retention is prolonged, partly due to a unique self-potentiation in which the biand triphosphates facilitate the phosphorylation of the parent compound, as well as inhibiting its catabolism.
  • Active metabolite dF-CTP is incorporated into DNA, followed only by one more normal nucleotide, resulting in protection of the DNA from repair enzymes (masked termination).
  • It is probably the saturable formation of dF-CTP that contributes to the clinical schedule dependency of gemcitabine, usually given IV, weekly for 3 weeks out of 4.
  • Toxicities include flu-like symptoms, transaminitis, peripheral edema, myelosuppression, and possible nephrotoxicity.
  • There is some evidence for synergy with cisplatin, the extent of which appears to be schedule-dependent. Gemcitabine is active in pancreatic cancer as well as in lung, breast, and bladder cancer.

Nelarabine

Nelarabine is a prodrug of 9-β-D-arabinofuranosyl guanine (Ara-G). Nelarabine undergoes intracellular phosphorylation to the active form Ara-GTP, which is toxic to T lymphocytes. The active form is incorporated into DNA, which results in inhibition of DNA synthesis and cell death. Ara-G also inhibits RNA synthesis and ribonucleotide reductase. Its mechanism of action is similar to that of other purine analogs such as cladribine, fludarabine, and pentostatin.

Clinical indications

  • T-cell leukemia/lymphoma and chronic lymphocytic leukemia

Dosing

  • Adults: 1500 mg/m2 IV over 2 hours on days 1, 3, and 5 repeated every 21 days
  • Children: 650 mg/m2 IV over 1 hour daily for 5 days repeated every 21 days

Adverse events

  • Neurotoxicity (dose-limiting, may be irreversible)
  • Bone marrow suppression
  • Nausea and vomiting
  • Diarrhea
  • Elevated hepatic enzymes
  • Hyperbilirubinemia
  • Tumor lysis syndrome
  • Hypotension, sinus tachycardia, chest pain
  • Cough, dyspnea, pleural effusion, wheezing
  • Fatigue
  • Fever
  • Peripheral edema
  • Mucositis

Additional comments

  • Discontinue therapy in patients that develop grade 2 or higher neurotoxicity.
  • Closely monitor patients with renal or hepatic impairment; dosage adjustments may be warranted with severe impairment, although specific recommendations are not available.

Adenosine analogs

  • Three adenosine analogs have come into clinical practice, active in low-grade NHL, Waldenstrцm’s macroglobulinemia, and CLL.
  • ALL have similar effects and interact with enzyme adenosine deaminase (ADA), a deficiency of which causes severe combined immunodeficiency.
  • Toxicity includes myelosuppression with particular effects on lymphocytes, including depression of CD3 and CD4 levels, and reduced natural killer (NK) activity.

Cladribine

Cladribine (2-chlorodexocyadenosine; 2-CdA) is a synthetic purine analog that is resistant to the effects of ADA. It is phosphorylated intracellulary to its active form, which is toxic primarily against lymphocytes. It also has activity against myeloid malignancies.

Cladribine is incorporated into DNA and interferes with DNA synthesis. It also inhibits DNA polymerase, DNA ligase, and ribonucleotide reductase. Cladribine affects both resting and proliferating lymphocytes.

  • Clinical indications: hairy cell leukemia, other leukemias and lymphomas, hematopoietic stem cell transplantation
  • Dosing: 0.09– 0.1 mg/kg per day as a continuous IV infusion for 7 days; alternative bolus regimens also exist

Adverse events

  • Bone marrow suppression
  • Immunosuppression
  • Fever
  • Opportunistic infections
  • Rash
  • Nausea
  • Neurotoxicity (dose-related)
  • Nephrotoxicity (dose-related)
  • Tumor lysis syndrome

Additional comments

  • Consider prophylaxis against opportunistic infections.

Fludarabine

Fludarabine is a synthetic purine analog with a mechanism of action similar to that of cladribine. Its spectrum of activity is comparable.

Clinical indications

  • Chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, other leukemias and lymphomas, hematopoietic stem cell transplantation

Dosing

  • 25 mg/m2 IV daily for 5 days repeated every 28 days as a single agent; alternative combination regimens exist

Dosage adjustments are recommended in patients with renal impairment:

  • CrCl >70 ml/min: No adjustment required
  • CrCl 30 –70 ml/min: Reduce dose by 20%
  • CrCl <30 ml/min: Do not administer

Adverse events

  • Bone marrow suppression
  • Immunosuppression
  • Opportunistic infections
  • Edema
  • Nausea
  • Neurotoxicity (dose-related)
  • Nephrotoxicity (dose-related)
  • Tumor lysis syndrome
  • Autoimmune hemolytic leukemia
  • Idiopathic thrombocytopenic purpura
  • Interstitial pneumonitis

Additional comments

  • Consider prophylaxis against opportunistic infections.
  • Resistant to ADA, it is particularly useful in treating CLL.
  • It is actively transported into the cells and its mode of action is a consequence of phosphorylation, following which it is incorporated into DNA and probably RNA, and may even cause topoisomerase ii inhibition. It can cause hemolytic anemia.

Pentostatin

Pentostatin (2’-deoxycoformycin) is an inhibitor of adenosine deaminase. This inhibition results in the intracellular accumulation of deoxyadenosine triphosphate, which results in apoptosis of lymphocytes. The mechanism of action is similar to that of cladribine and fludarabine.

Clinical indications

  • Hairy cell leukemia, other leukemias and lymphoma, hematopoietic stem cell transplantation, graft-versus-host disease

Dosing

  • 4 mg/m2 IV once every other week as a single agent; alternative regimens exist

The dose should be reduced for renal impairment:

  • CrCl =60 ml/min: No dosage adjustment
  • CrCl 30 – 60 ml/min: Reduce dose 50%
  • CrCl <30 ml/min: Do not administer

Adverse events

  • Bone marrow suppression
  • Immunosuppression
  • Opportunistic infections
  • Nausea and vomiting
  • Rash
  • Neurotoxicity (dose-related)
  • Nephrotoxicity (dose-related)
  • Pulmonary toxicity
  • Tumor lysis syndrome
  • Anorexia and diarrhea
  • Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome

Additional comments

  • Consider prophylaxis against opportunistic infections.
  • It has a very high affinity for ADA, and the resultant complex is stable for over 24 hours, resulting in enzyme inhibition.
  • Its major indication is treatment of hair y-cell leukemia.
  • Actively transported into cells, it is phosphorylated and incorporated into DNA and also produces inhibitory dATP.
  • It inhibits both DNA synthesis and DNA repair.

Clofarabine

Clofarabine is a purine analog with a mechanism of action similar to that of cladribine, fludarabine, and pentostatin.

Clinical indications

  • Acute lymphocytic leukemia

Dosing

  • Children: 52 mg/m2 (up to 70 mg/m2) IV over 2 hours daily for 5 days
  • Adults: 40 mg/m2 IV over 2 hours daily for 5 days

Adverse events

  • Bone marrow suppression
  • Immunosuppression
  • Opportunistic infections
  • Nausea and vomiting
  • Dehydration
  • Hypotension
  • Diarrhea
  • Elevated hepatic enzymes
  • Hyperbilirubinemia
  • Nephrotoxicity
  • Edema
  • Tachycardia
  • Pericardial effusions
  • Left ventricular systolic dysfunction
  • Impaired fertility
  • Capillary leak syndrome
  • Respiratory distress
  • Fever
  • Mucositis

Additional comments

  • Consider prophylaxis against opportunistic infections
  • Consider prophylactic cor ticosteroids (hydrocor tisone 100 mg/m2 on days 1–3) to prevent signs and symptoms of systemic inflammatory response syndrome (SIRS) or capillary leak

Hydroxyurea

Clinical indications

  • Myeloproliferative disorders, hyperleukocytosis with acute leukemias, use as a radiosensitizing agent, sickle cell anemia

Dosing

  • 10 –20 mg/kg per day initially by mouth; titrate to desired effect; consider dosage reductions in renal impairment

Adverse events

  • Bone marrow suppression
  • Edema
  • CNS toxicity (dose-related)
  • Erythema, rash, hyperpigmentation
  • Tumor lysis syndrome
  • Nausea and vomiting
  • Mucositis
  • Hepatotoxicity
  • Weakness
  • Peripheral neuropathy
  • Pulmonary toxicity (rare)

Additional comments

  • This oral agent inhibits ribonucleotide reductase, which reduces availability of all deoxynucleotides.
  • It crosses the blood-brain barrier and is used in myeloproliferative disorders.
  • Toxicities are myelosuppression, gastrointestinal toxicities, and sometimes hyperpigmentation of the skin.
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