Neoplasia

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Chapter 20 Neoplasia

Alkylators

Description

Alkylators are chemotherapy agents used primarily in the treatment of cancer.

Prototypes and Common Drugs

Nitrosoureas

image Prototype: carmustine
image Others: lomustine, semustine, bendamustine

Bis(chlorethyl)amines

image Prototype: cyclophosphamide
image Others: mechlorethamine, chlorambucil, melphalan, ifosfamide

Aziridines

image Prototype: thiotepa
image Others: triethylenemelamine

Alkyl Sulfonate

image Prototype: busulfan
image Others: treosulfan

MOA (Mechanism of Action)

image The alkylating agents transfer alkyl (chemical) groups to DNA. DNA alkylation in the nucleus leads to the death of the cell.
image Once in the cell, the alkylating agents undergo a structural rearrangement that results in the formation of an unstable intermediate, an ethylene immonium ion.
image This ion either directly, or via another intermediate, a carbonium ion, transfers alkyl groups to nucleic acids such as guanine or to other cellular constituents.
image Alkylation of guanine or other bases results in abnormal base pairing as well as the excision of these bases, which in turn leads to strand breakage.
image Alkylating agents are considered to be cell cycle phase nonspecific, with cells in G1 and S phases being most susceptible (Figure 20-1).
image The connection between DNA alkylation and death of the cancer cell has not been established; however, one of the likely mechanisms is damage to DNA that is sufficient to activate proapoptotic proteins such as p53, leading to cell death.
image Nitrosoureas have an additional mechanism of action. Nitrosoureas undergo another reaction, referred to as carbamoylation, with lysine residues of proteins. Carbamoylation is the transfer of carbamoyl (NH2CO) groups to an amino group, such as that found in amino acids.
image The product of this reaction is referred to as a carbamoylated protein, and this process appears to limit the ability of the cancer cell to repair DNA. This unique mechanism of action limits cross-resistance between nitrosoureas and other members of this class.
image

Figure 20-1

Mechanisms of Resistance

image Mechanisms of resistance include the following:

image DNA repair
image Decreased entry of drug into the cell
image Inactivation of the alkylating agent by glutathione

image Cross-resistance is common among the various subclasses of alkylating agents, with the exception of the nitrosoureas.

Pharmacokinetics

image Oral dosage forms are available for cyclophosphamide, melphalan, chlorambucil, and busulfan. Lomustine is available only in oral dosage forms. The rest are all intravenous.
image Nitrosoureas are highly lipid soluble and readily cross the blood-brain barrier; therefore they are useful in the treatment of brain tumors.
image With the exception of cyclophosphamide and ifosfamide, the alkylating drugs have short half-lives, the most extreme example being mechlorethamine, which has a half-life of 10 minutes.

Indications

Cyclophosphamide

image Lymphomas
image Leukemias
image Multiple myeloma
image Mycosis fungoides
image Neuroblastoma (disseminated)
image Retinoblastoma
image Cancers of the lung, breast, ovary
image Immunosuppression

Melphalan

image Multiple myeloma
image Ovarian (epithelial) carcinoma

Chlorambucil

image Chronic lymphocytic leukemia
image Non-Hodgkin’s lymphomas

Carmustine

image Malignant lymphomas
image Multiple myelomas
image Cancers of the brain, gastrointestinal (GI) tract, skin (melanoma)

Lomustine

image Hodgkin’s disease
image Cancers of the breast, brain, lung, skin (melanoma)

Bendamustine

image Chronic lymphocytic leukemia

Contraindications

Cyclophosphamide

image Severe leukopenia, thrombocytopenia will be exacerbated (see side effects).
image Pregnancy: Like other cytotoxic agents, cyclophosphamide can cause fetal harm.
image Lactation: Cyclophosphamide is excreted in breast milk, so breastfeeding should be avoided.

Melphalan, Chlorambucil

image Radiation: should not be administered with radiation therapy or within 4 weeks of radiation therapy (chlorambucil). Radiation also damages DNA and may impair DNA repair mechanisms in healthy cells, leaving them more susceptible to the DNA-damaging effects of alkylating agents.

Lomustine

image Severe leukopenia and/or thrombocytopenia is a contraindication.
image Lactation: It is not known whether lomustine is excreted in breast milk, but breastfeeding is not advised during treatment.

Side Effects

image Nausea, vomiting: These are common side effects with cytotoxic agents, which tend to target rapidly dividing cells, including those of the GI tract.
image Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in hair follicles. This effect is seen most often with cyclophosphamide.

Serious

image Myelosuppression: Typical of cytotoxic agents, alkylators tend to target cells that are actively dividing, such as those found in the bone marrow.
image Pulmonary toxicity (nitrosoureas and busulfan): Interstitial lung disease may occur.
image Nephrotoxicity is seen most often with cyclophosphamide and ifosfamide.
image Bladder toxicity is seen most often with cyclophosphamide and ifosfamide.
image Hemorrhagic cystitis (cyclophosphamide and ifosfamide) is caused by acrolein, a metabolite of cyclophosphamide and ifosfamide. This effect can be managed by increasing fluid intake and by administering sulfhydryl donors such as N-acetylcysteine or mesna (an antioxidant). These agents bind with acrolein and form a nontoxic compound.
image Leukemia (rare): The alkylating agents work by damaging DNA. If they damage DNA in healthy cells, this may lead to mutations in the genome that rarely result in development of malignancies, particularly leukemia.

Important Notes

image A number of the alkylating agents (cyclophosphamide, ifosfamide, estramustine, melphalan, and chlorambucil) are also known as nitrogen mustards. These agents are related to mustard gas, a biologic warfare agent used during World War I.
image Cyclophosphamide has a significant effect on lymphocytes; therefore it is also used as an immunosuppressant to prevent rejection of transplanted organs, as well as in conditions such as rheumatoid arthritis and nephrotic syndrome. Cyclophosphamide has a steroid-sparing effect, meaning that it can reduce the need for use of corticosteroids.
image Estramustine is a combination of estrogen and a mustine called chlormethine. Accordingly, it has both cytotoxic and hormonal actions and is used primarily in prostate cancer.
image Patients with defective DNA repair mechanisms (ataxia-telangiectasia, Fanconi’s anemia, Bloom’s syndrome, and xeroderma pigmentosa) are more sensitive to DNA-damaging agents.
image The nitrosoureas (lomustine, carmustine) tend to be more lipid soluble and therefore readily cross the blood-brain barrier and are useful for tumors of the brain and meninges.

FYI

image The first rationally designed anticancer agent was a nitrosourea (methyl nitrosourea), developed in 1898.
image The U.S. Army played a role in the development of nitrogen mustards, deriving the prototype to this class (mechlorethamine) from the mustard gases used in the first World War. After an accidental exposure, it was discovered that nitrogen mustard produced lymphopenia, inspiring its use in malignant proliferative disorders.

Anthracyclines

Description

Anthracyclines are cytotoxic anticancer agents that work by damaging DNA and by generation of free radicals. This class is also grouped under a larger class of antitumor antibiotics (but are never used as antibiotics).

Prototype and Common Drugs

image Prototype: doxorubicin
image Others: daunorubicin, idarubicin, epirubicin, aclarubicin, mitoxantrone

MOA (Mechanism of Action)

image The anthracyclines are believed to exert their cytotoxic effects through a variety of mechanisms.
image Topoisomerase II (Top II) plays a key role during DNA synthesis, nicking and resealing the DNA helix so that it does not become tangled during replication.
image The anthracyclines prevent the resealing step from occurring by intercalating into and inhibiting the DNA–topoisomerase II complex after the nicking phase. This results in a large number of DNA fragments, eventually prompting the cancer cell to undergo apoptosis (Figure 20-2).
image As a secondary mechanism, anthracyclines produce free radicals, and these free radicals in turn damage cell membranes, proteins, and lipids. The generation of free radicals is also believed to mediate an important toxicity associated with this class (see Side Effects).
image In addition anthracyclines are DNA intercalators, meaning that they insert themselves into DNA structure, inhibiting transcription and replication.
image

Figure 20-2

Mechanisms of Resistance

image Drug efflux through P-glycoprotein (Pgp-170) or multidrug-resistant (MDR) gene
image Altered topoisomerase II levels
image Mutations in topoisomerase II
image Increased glutathione (a free radical scavenger)
image Increased glutathione peroxidase activity
image Decreased concentration of glucose-6-phosphate (G6P) dehydrogenase

Pharmacokinetics

image Doxorubicin is a prodrug, and idarubicin is the active metabolite.
image Doxorubicin was the first anthracycline to be encapsulated in liposomes to facilitate targeted delivery of the drug and therefore avoid cardiotoxicity (see Side Effects). One of the key mechanisms for this targeted delivery relies on the fact that the liposomes readily extravasate in tissues that have a disrupted vasculature, such as that found in tumors. Blood vessels in tumors tend to be “leaky” owing to the constant angiogenesis that is taking place. Conversely, the liposomes have difficulty exiting vessels in tissues such as the myocardium.
image The anthracyclines are eliminated through hepatic metabolism, through a variety of routes. Because of the toxicities associated with these agents, dose adjustments should be considered in patients with significant hepatic impairment.
image Idarubicin is the only anthracycline that can be given orally; the rest are available only in intravenous formulations.

Indications

Doxorubicin

image Acute leukemias
image Hodgkin’s disease
image Non-Hodgkin’s lymphoma
image Sarcomas
image Cancers of the breast, lung, stomach, thyroid

Daunorubicin

image Acute leukemia

Idarubicin

image Acute leukemia
image Breast cancer

Epirubicin

image Lymphoma
image Cancers of the lung, breast, ovary, stomach

Mitoxantrone

image Prostate cancer
image Non-Hodgkin’s lymphoma

Contraindications

image Severe cardiac disease: Anthracyclines should be used only with extreme caution and after a careful risk-benefit assessment in these patients. See Side Effects.
image Lactation: Patients should not breastfeed while using these agents.

Side Effects

image Nausea and vomiting are common side effect with cytotoxic agents, which tend to target rapidly dividing cells, including those of the GI tract.
image Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in hair follicles. The hair loss is reversible.
image Mucositis or stomatitis is an inflammatory condition of the mouth. Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in the oral mucosa.
image Soft tissue necrosis: If the anthracyclines become extravascular, they can damage surrounding tissue. Infusions should be carried out slowly to reduce the risk of extravasation.

Serious

image Cardiotoxicity: The free radicals generated by the anthracyclines cause peroxidation of the cardiac sarcoplasmic reticulum, leading to a Ca2+-dependent cardiac necrosis. The reason this toxicity is selective for cardiac tissue is that catalase, able to neutralize these free radicals, is not found in cardiac tissue.
image Myelosuppression: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those of the bone marrow. The bone marrow suppression is reversible but does predispose the patient to major complications such as infection while receiving treatment.

Important Notes

image Cardiotoxicity associated with anthracyclines can occur both acutely and chronically. Acute toxicity is characterized by abnormal electrocardiograms (ECGs) and reductions in systolic function. Chronic toxicity is cumulative and dose related. It manifests as congestive heart failure, and once it has reached this point it has a very high mortality rate. This chronic cardiotoxicity is of greater concern, and it is addressed using a number of strategies, including limitations on doses used, as well as use of liposomal formulations and adjuvant agents, as described later.
image Mitoxantrone has a chemical structure that is distinct from that of the anthracyclines, and it is believed to be less cardiotoxic than the anthracyclines. It does not generate free radicals.

Advanced

image Strategies to minimize cardiotoxicity include the use of a cardioprotective drug such as dexrazoxane. The generation of free radicals by anthracyclines is iron dependent. Dexrazoxane chelates iron that is bound in anthracycline complexes, and this prevents the formation of the free radicals that damage the myocardium. Dexrazoxane does not appear to impair the antitumor activity of the anthracyclines.

Drug Interactions

image It appears that the cardiotoxic effects of anthracyclines may be worsened by concurrent administration of trastuzumab. Trastuzumab is a monoclonal antibody that is used in the treatment of breast cancers expressing the HER2/neu receptor. A number of anthracyclines are used in treating breast cancer.

FYI

image The anthracyclines were originally derived from the bacterium Streptomyces peucetius var caesius, and that is why they fall under a larger class of antitumor antibiotics. Other antitumor antibiotics include mitomycin and bleomycin.

Antimetabolites

Description

Also known as DNA synthesis inhibitors, antimetabolites work by inhibiting the actions of enzymes that are involved in the synthesis of DNA precursors and bases.

Prototypes and Common Drugs

Folate Analogues

image Prototype: methotrexate

Pyrimidine Analogues

image Prototype: fluorouracil
image Others: raltitrexed, pemetrexed, cytarabine, gemcitabine

Purine Analogues

image Prototype: mercaptopurine
image Others: fludarabine, pentostatin, cladribine, thioguanine

MOA (Mechanism of Action)

Folate Analogues

image Tetrahydrofolate (THF) is an essential cofactor in the transformation of 2’-deoxyuridylate (dUMP) to 2’-deoxythymidylate (dTMP). This is a required step in the synthesis of purines and thus DNA.
image THF is synthesized by the actions of dihydrofolate reductase (DHFR). Methotrexate has a high affinity for DHFR and competitively inhibits DHFR (Figure 20-3).
image

Figure 20-3

Mechanisms of Resistance

image Reduced transport across cell membranes
image Changes in the conformation of the DHFR enzyme
image Increased concentrations of DHFR
image Increased drug efflux

Pyrimidine Analogues

image Fluorouracil is a uracil analogue. It is converted to FdUMP (fluorodeoxyuridine monophosphate) and although it interacts with thymidylate synthetase, it cannot be converted to dTMP because of the fluoro component and therefore results in a deficiency of dTMP. Without dTMP, DNA synthesis cannot occur. It is considered to be a fraudulent nucleotide.
image Inhibitors of other enzymes important in dTMP synthesis include raltitrexed (thymidylate synthetase inhibitor) and pemetrexed (thymidylate transferase inhibitor).
image Cytarabine, also known as cytosine arabinoside, is an analogue of 2’-deoxycytidine (essentially, cytosine). On entering the cell, it is converted to cytosine arabinoside triphosphate by the same phosphorylation reaction that 2’-deoxycytidine undergoes. The cytosine arabinoside triphosphate competitively inhibits DNA polymerase, inhibiting both DNA synthesis and repair.

Mechanisms of Resistance

image Reduced enzymatic activation or increased enzymatic deactivation

Purine Analogues

image Fludarabine inhibits DNA polymerases, leading to inhibition of DNA synthesis and repair. It also incorporates into DNA and may also promote apoptosis by an undetermined mechanism.
image Pentostatin inhibits adenosine deaminase, an enzyme that transforms adenosine to inosine. This leads to accumulation of intracellular adenosine and deoxyadenosine, which can block DNA synthesis by inhibiting ribonucleotide reductase. Ribonucleotide reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides. Deoxyribonucleotides are used in the synthesis of DNA.
image Mercaptopurine is incorporated into RNA and DNA, halting further DNA and RNA synthesis.

Mechanisms of Resistance

image Mechanisms of resistance include reduced apoptosis secondary to deficiency of p53, a proapoptotic protein, or up-regulation of bcl-2, an antiapoptotic protein. Drugs that have activity against bcl-2 may be synergistic in combination with purine analogues.

Pharmacokinetics

image Methotrexate can be administered orally, intravenously, intramuscularly, or intrathecally. It is not able to cross the blood-brain barrier, so entry into the central nervous system (CNS) can be achieved only by intrathecal administration.
image Only a small fraction of methotrexate is metabolized; most of it is eliminated unchanged in the urine. Because of its potential for nephrotoxicity, dose adjustments must be considered in patients with renal impairment.
image The purine analogues mercaptopurine and thioguanine are available in oral dosage forms. They are metabolized by the liver. One of the enzymes responsible for mercaptopurine metabolism is xanthine oxidase; therefore inhibitors of this enzyme, such as allopurinol, can lead to toxicity. The elimination half-life of mercaptopurine is relatively short (<1 hour).
image Fludarabine and cladribine can be administered intravenously or orally, and pentostatin is administered intravenously. All are primarily eliminated by renal excretion. Dose adjustments should be considered in patients with renal impairment.
image Cytarabine is administered intravenously or subcutaneously, and 5-fluorouracil is administered intravenously or topically. Cytarabine (cytarabine triphosphate) and 5-fluorouracil (5-fluorodeoxyuridine monophosphate and triphosphate) are converted to active metabolites in the body. Both are largely metabolized by the liver, and dose adjustments should be considered in patients with hepatic impairment.

Indications

Methotrexate

image Rheumatoid arthritis
image Acute lymphoblastic leukemia
image Severe psoriasis
image Non-Hodgkin’s lymphoma
image Osteosarcoma
image Cancers of the breast, head and neck, ovary, bladder

Pemetrexed

image Mesothelioma
image Non–small cell lung cancer

Thioguanine, Mercaptopurine

image Leukemia

Fludarabine, Cladribine, Pentostatin, Cytarabine

image Leukemia
image Lymphoma

5-Fluorouracil

image Cancers of the breast, colon and rectum, stomach, head and neck, skin (noninvasive)
image Actinic keratoses

Gemcitabine

image Cancers of the pancreas, lung (non–small cell cancer), ovary, bladder, esophagus, head and neck

Contraindication

image Pregnancy: Most of the antimetabolites are teratogenic in animals.

Side Effects

Folate Analogues

image Myelosuppression: Conventional chemotherapy agents work by targeting rapidly dividing cells. This nonspecific effect can also target rapidly dividing cells in other areas of the body, including bone marrow and the GI tract.
image Damage to GI epithelium: See previous entry.
image Stomatitis: Severe oral ulcers can develop.
image Pneumonitis may occur.
image Nephrotoxicity is caused by precipitation of drug in the renal tubules.
image Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in hair follicles.
image Dermatitis can develop.
image Defective oogenesis or spermatogenesis results from targeting of rapidly dividing cells.
image Hepatic:

image Acute: reversible elevations in liver enzymes
image Chronic: cirrhosis

Purine Analogues

image Myelosuppression develops more gradually than with the folate analogues. It tends to be worse with thioguanine.
image Nausea and vomiting are caused by GI epithelial damage.
image Hepatotoxicity occurs with long term use of mercaptopurine.
image CNS (fludarabine): Altered mental status and seizures may occur.

Pyrimidine Analogues

image Myelosuppression: Cytarabine is a particularly potent bone marrow suppressant.
image GI effects are caused by irritation of GI epithelium.
image Stomatitis may occur.
image Hepatotoxicity: Reversible elevations in liver enzymes may develop.
image CNS: CNS effects are usually seen only with intrathecal administration or high plasma levels. They manifest as cerebellar (ataxia) or cerebral (seizures, dementia, coma) effects.

Pemetrexed-Specific Effects

image Rash: A red, itchy rash is very common with this agent.

Important Notes

image High-dose regimens of methotrexate may require rescue with folinic acid, also known as leucovorin. Folinic acid is a reduced form of folic acid. Methotrexate is an “antifolate” drug, and patients who are taking high doses or receiving chronic therapy are likely to experience severe symptoms of folate deficiency unless they are treated adjunctively with leucovorin.
image The drug interaction between mercaptopurine and allopurinol is particularly relevant because patients taking conventional chemotherapy are predisposed to development of uric acid crystals, also known as gout. Allopurinol is one of the key drugs used for treating gout, thus increasing the likelihood that these agents may be administered simultaneously.
image Gemcitabine is an analogue of cytarabine, with fewer side effects.

Advanced

Pharmacogenetics

image Thiopurine methyltransferase (TPMT) plays a role in the metabolic inactivation of mercaptopurine. Approximately 15% of Caucasians have reduced activity of this enzyme, and these individuals are at greater risk for toxicity. TPMT genotyping is now readily available, and genotype-based dosage recommendations are available.
image Dihydropyrimidine dehydrogenase (DPD) is one of the enzymes involved in the metabolic inactivation of 5-fluorouracil. Korean patients tend to have higher DPD activity, whereas African Americans tend to have lower activity, predisposing them to toxicity.

Drug Interactions

image Tubular secretion plays a role in the excretion of methotrexate, so agents that compete for secretion at the proximal tubule, such as aspirin, may reduce methotrexate clearance.

FYI

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