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

image The folic acid analogues were one of the first successful classes of chemotherapeutic agents, dating back to their use in the 1950s and 1960s.
image Cytarabine is also known by its full name, cytosine arabinoside, or Ara-C.

Bleomycin

Description

Bleomycin belongs to a family of glycopeptides that exert a cytotoxic effect by damaging DNA.

Prototype

image Prototype: bleomycin

MOA (Mechanism of Action)

image Bleomycin is a DNA intercalator. An intercalator is a molecule that binds DNA and inserts itself into DNA structure.
image Bleomycin binds to Fe2+, and this complex leads to free radical formation when oxygen is added. These free radicals then intercalate between DNA strands, which produces single- and double-stranded breaks in DNA (Figure 20-4).
image When sufficient damage has been done to DNA, the cell dies.
image Once in the cell, bleomycin either translocates to the nucleus or is broken down by bleomycin hydrolase, an enzyme that is found in both normal and malignant cells but is found in decreased concentrations in lung and skin. It is believed that the toxicities seen in lung and skin with these agents are the result of the lack of hydrolase activity in these regions.
image

Figure 20-4

Mechanisms of Resistance

image Increased hydrolase activity, which leads to increased inactivation of bleomycin
image Decreased uptake of bleomycin into cancer cells
image Repair of DNA strand breaks
image Inactivation of bleomycin

Pharmacokinetics

image Bleomycin is a large cation and therefore has difficulty penetrating cell membranes. It enters cells through a special membrane binding protein.
image It is administered parenterally, either intravenously or by the intramuscular or subcutaneous route. Bleomycin can also be instilled directly into the bladder to treat bladder cancer. It can also be given intrapleurally (into the pleural space) to treat pleural effusions.
image Bleomycin is largely eliminated by the kidneys, and dose adjustments should be considered in patients with renal impairment.

Indications

image Lymphoma
image Cancers of the head and neck, cervix, testicles, bladder

Contraindication

image Pregnancy: Like all cytotoxic agents, bleomycin carries the risk of fetotoxicity.

Side Effects

image Cutaneous side effects appear to be more common than with other conventional cytotoxic agents, likely because of the lack of hydrolase activity and relative buildup of bleomycin in skin:

image Hyperpigmentation
image Hyperkeratosis
image Erythema
image Ulceration

image Nausea, vomiting: Cytotoxic agents tend to target rapidly dividing cells, including those of the GI tract, contributing to irritation of the GI tract.

Serious

image Interstitial pneumonitis or fibrosis: This is a very serious complication that results in a fatal outcome in 1% of patients who take bleomycin. Risk increases with higher doses, as well as with advanced age (>70 years) and preexisting pulmonary disease.
image Hypersensitivity reaction: An anaphylaxis-like reaction that is characterized by hypotension and hyperthermia, as well as cardiorespiratory collapse, may occur. Patients should be monitored closely after receiving their dose, especially when therapy is first being initiated.

Important Notes

image Unlike most cytotoxic agents, bleomycin causes minimal bone marrow suppression. The fact that it does not cause myelosuppression makes it a good candidate for combining with other cytotoxic agents that have this toxicity.

FYI

image Bleomycin is actually an antibiotic that was derived from the bacterium Streptomyces verticillus. However, bleomycin is never used to treat infection.

Platinum Compounds

Description

Platinum compounds are cytotoxic agents that work by damaging DNA and are used in the treatment of cancer.

Prototype and Common Drugs

image Prototype: cisplatin
image Others: carboplatin, oxaliplatin

MOA (Mechanism of Action)

image Platinum (Pt) compounds are named for their central Pt ion, surrounded by chloride (Cl−) atoms and ammonia groups.
image The platinum compounds cross-link DNA strands, thereby inhibiting DNA synthesis and function. If the DNA is damaged enough, the cell will undergo apoptosis (Figure 20-5).
image The platinum compounds enter cells through an active transporter.
image On entering the cell, the Cl− ions dissociate, leaving behind a reactive complex that interacts with DNA.
image The dissociation of Cl− ions is favored at low intracellular concentrations of chloride. Higher concentrations of chloride within the cell tend to stabilize the drug.
image

Figure 20-5

Mechanisms of Resistance

image DNA repair mechanisms
image Efflux transporter:

image Platinum compounds enter cells through copper transporters. When copper efflux transporters become overexpressed, more drug is pumped out of the cancer cell, leading to an increased chance of therapeutic failure.

Pharmacokinetics

image The platinum compounds are dependent on the kidneys for their elimination. Given the toxicity associated with anticancer agents, dose adjustments must be considered in patients with renal impairment.

Indications

image Cancers of the testes, ovary, bladder, head and neck, lung

Contraindications

image None of major significance, although as noted, extreme caution must be exercised in patients with renal impairment.

Side Effects

image Nausea and vomiting can be severe. Cytotoxic anticancer drugs target actively dividing cells, such as those found in the GI tract, leading to GI side effects.
image Nephrotoxicity is believed to be primarily mediated by mitochondrial toxicity. Preventive measures such as generous hydration with normal saline to promote diuresis should be undertaken. Nephrotoxicity is more of a problem with cisplatin than with the other agents in this class.
image Myelosuppression is less severe than with other conventional anticancer drugs. Conventional anticancer drugs target actively dividing cells, such as those found in the bone marrow, leading to bone marrow suppression.
image Tinnitus and hearing loss result from promotion of apoptosis in cochlear cells and appear to be less severe with oxaliplatin.
image Peripheral neuropathy: The mechanism has not been established. Neurotoxicity manifests as both acute (shortly after infusion, lasting for a few days) and chronic. The chronic neurotoxicity may be caused by cumulative damage to cells in the dorsal root ganglion.
image Hyperuricemia is likely secondary to the nephrotoxicity noted previously.
image Hypersensitivity may occur.

Important Notes

image The 5-HT3 antagonists (e.g., ondansetron) have proven effective in managing the nausea and vomiting associated with this drug class.
image Compared with cisplatin, carboplatin (a derivative of cisplatin) causes more myelosuppression but less nephrotoxicity, neurotoxicity, ototoxicity, nausea, and vomiting.
image Neurotoxicity seen with platinum compounds tends to be both dose and duration dependent. The longer the patient is on therapy and/or the higher the dose, the more likely he or she is to experience these side effects.
image Infusions of calcium and magnesium before and after oxaliplatin treatment is one strategy used to mitigate neuropathies such as paresthesia and dysesthesia.

FYI

image The discovery of platinum compounds as anticancer agents began with the observation that passing electricity through platinum electrodes caused filamentous growth in bacteria, considered to be a sign of inhibited DNA synthesis.
image Cisplatin was considered to be a major advance in the treatment of testicular cancer, improving cure rates for metastatic disease from 5% to 15% to 70% to 90%.

Taxanes

Description

Taxanes are a group of naturally derived cytotoxic chemotherapy agents that work by inhibiting mitosis.

Prototype and Common Drugs

image Prototype: paclitaxel
image Others: docetaxel

MOA (Mechanism of Action)

image The taxanes are microtubule inhibitors.
image Microtubules perform several important functions in the cell, the key being the segregation of chromosomes during mitosis.
image Microtubules are composed of tubulin, a heterodimer composed of a-tubulin and ß-tubulin. The polymerization of tubulin leads to formation of microtubules.
image Microtubules are in a dynamic equilibrium with the intracellular pool of α-tubulin and β-tubulin. Microtubules are constantly growing and shortening, and this process, known as dynamic instability, leads to the polar movement of chromosomes during anaphase.
image The taxanes bind to β-tubulin, stabilizing the microtubule and preventing its disassembly. This stabilization interferes with the segregation of chromosomes during mitosis, which leads to cell death. This is believed to be the main mechanism for the cytotoxic effects of taxanes (Figure 20-6).
image Vinca alkaloids are also microtubule inhibitors, and they also bind to β-tubulin; the difference is that they prevent polymerization of β-tubulin into microtubules and thus destabilize the microtubule.
image Taxanes, specifically paclitaxel, are also used in drug-eluting vascular stents (often for coronary artery disease) to reduce the incidence of restenosis. Restenosis occurs, in part, because of the growth of new cells in the area of the stent. The taxanes inhibit cell division, thus preventing the growth of these new cells.
image

Figure 20-6

Mechanisms of Resistance

image One mechanism of resistance is increased expression of MDR efflux pumps, which pump drug back out of the cell.
image Tumor cells can overexpress a mutated isoform of β-tubulin, preventing binding of taxanes. These cells may be more sensitive to the effects of vinca alkaloids, if the vinca alkaloids are better able to bind to the mutated β-tubulin.

Pharmacokinetics

image Docetaxel is administered orally, whereas paclitaxel is given intravenously.
image Paclitaxel and docetaxel both rely on the liver for their elimination. Dose adjustments should be considered in patients with severe hepatic impairment.
image The drug-eluting stents release drug from a matrix contained within the stent. This allows for a continual local low dose release of drug over time.

Indications

image Cancers of the breast, ovary, lung, head and neck, prostate (hormone-refractory)
image Prevention of restenosis after angioplasty

Contraindications

image Pregnancy: embryotoxic and fetotoxic in animals
image Lactation
image Severe hepatic impairment: eliminated by the liver, therefore severe toxicity expected with accumulation

Side Effects

image Myelosuppression is a side effect commonly seen with conventional chemotherapy, which targets rapidly dividing cells, including those in the bone marrow.
image Neurotoxicity: Microtubules are believed to play an important role in neuronal function, and this is the likely reason why microtubule inhibitors are associated with neurotoxicity. This manifests itself as a variety of neuropathies:

image Sensory: typically loss of all modalities in feet
image Motor: mild weakness in foot muscles
image Reflexes: reduced ankle reflexes
image Neuropathy occurs more frequently with paclitaxel, which is an older, less potent drug.

image Resistant fluid retention: Pretreatment with oral dexamethasone tends to mitigate the fluid retention. Docetaxel tends to produce more edema than the other agents in this class.
image Hypersensitivity is likely to happen with either agent, and therefore pretreatment with corticosteroids and antihistamines is recommended. This effect results not from the agents themselves but from the solvents (polyoxyethylated castor oil or polysorbate) that each drug has to be dissolved in because of its low solubility.

Important Notes

image Other microtubule binding agents include the cytotoxic vinca alkaloids and colchicine, which is most commonly used for gout.
image Paclitaxel is more likely to elicit a hypersensitivity reaction than docetaxel. This is again believed to occur because of the solvents used for these two agents, which differ slightly.

Advanced

image Paclitaxel is mainly metabolized by CYP2C8 with some contribution from CYP3A4. Docetaxel is metabolized primarily by CYP3A4 and CYP3A5. Inhibitors or inducers of these isozymes may alter the efficacy or toxicity of paclitaxel or docetaxel.

Evidence

For Adjuvant Treatment of Early Breast Cancer

image A 2007 Cochrane review (12 studies, N = 18,304 women) compared taxane-containing with non–taxane-containing regimens as adjuvant treatment for premenopausal or postmenopausal women with early breast cancer. Overall survival (Hazard ratio [HR] 0.81) was improved with taxane-based regimens, as was disease-free survival (HR 0.81).

For Treatment of Metastatic Breast Cancer

image A 2005 Cochrane review (12 studies, N = 3643 women) compared taxane-containing with non–taxane-containing regimens in women with metastatic breast cancer. The authors found that overall survival was improved with taxane-based regimens versus nontaxane regimens (HR 0.93), although this difference was not statistically significant when taxane regimens were used first line. Time to progression was also improved (HR 0.92), as was overall response (odds ratio [OR] 1.34), although with considerable heterogeneity for overall response.

Docetaxel versus Vinca Alkaloids for Treatment of Advanced Non–Small Cell Lung Cancer

image A 2007 systematic review (7 trials, N = 2867 participants) compared docetaxel with vinca alkaloid–based chemotherapy regimens (both are tubulin inhibitors) for treatment of advanced non–small cell lung cancer. Vinorelbine was the comparator in six trials, and vindesine in the remaining trial. The authors found improved overall survival with docetaxel (HR 0.89). The incidence of neutropenia was significantly reduced with docetaxel compared with the vinca alkaloids (OR 0.59), as was the incidence of febrile neutropenia (OR 0.57). There were also fewer serious adverse events with docetaxel compared with the vinca alkaloids.

FYI

image Paclitaxel is derived from the bark of the Pacific yew tree. Originally used in its natural form, it can now be produced semisynthetically, using a precursor found in yew leaves, or can be synthesized completely from scratch.
image New taxanes that are orally available are in clinical development.
image Other microtubule inhibitors include the vinca alkaloids and colchicine, which is used for gout.

Topoisomerase Inhibitors

Description

Topoisomerase inhibitors include two classes of drugs that are derived from natural sources and exert their cytotoxic effects by interfering with DNA. Their mechanism is analogous to that of the fluoroquinolone class of antibiotics.

Prototypes and Common Drugs

Camptothecins

image Prototype: topotecan
image Others: irinotecan

Podophyllotoxins

image Prototype: etoposide
image Others: teniposide

MOA (Mechanism of Action)

image The camptothecins are topoisomerase I inhibitors, whereas the podophyllotoxins are topoisomerase II inhibitors. Topoisomerase is an enzyme that cuts and reseals DNA strands, a process that is essential for DNA synthesis.
image During the process of DNA replication or transcription, a significant amount of torsional strain is placed on the DNA helix. The strain is analogous to twisting a rubber band or a telephone cord.
image The torsional strain is relieved by breaks in DNA strands that are created by the enzymes topoisomerase I (single-stranded DNA) and topoisomerase II (double-stranded DNA). The analogy would be relieving the strain in a twisted rubber band by making small breaks in the band, allowing the band to untwist, then resealing the breaks. The topoisomerase enzymes also reseal the breaks after the tension has been relieved (Figure 20-7).
image Topoisomerase inhibitors block the resealing step, leading to large amounts of fragmented DNA. This destabilizes the cell, leading to cell death.
image

Figure 20-7

Mechanisms of Resistance

image Inadequate accumulation of drug in tumor
image Alterations in the topoisomerase binding
image Altered cellular response to formation of DNA fragments (i.e., enhanced expression of antiapoptotic proteins such as bcl-2)

Pharmacokinetics

image All topoisomerase inhibitors are available in intravenous formulations. Etoposide and topotecan are also available in an oral formulation.
image Topotecan is eliminated renally; therefore dose adjustments may be required in patients with renal impairment. The elimination half-life is 2 to 3 hours.
image Irinotecan is metabolized by the liver; therefore dose adjustments may be required in patients with hepatic impairment. The parent is metabolized by CYP3A4, and it also has an active metabolite, SN-38. SN-38 has much greater antitumor activity than the parent compound, and it is metabolized by glucuronidation via UGT1A1.
image Etoposide is cleared both by renal and nonrenal means.
image Routes of elimination for teniposide have not been well characterized. Renal excretion accounts for about 10% of clearance. Drug interactions have been observed with agents that are known to affect hepatic enzymes; therefore hepatic metabolism is likely.

Indications

Topotecan

image Cancers of the ovary, lung (small cell)

Irinotecan

image Colorectal cancer

Etoposide

image Lymphoma
image Cancers of the lung, testes

Teniposide

image Neuroblastoma
image Non-Hodgkin’s lymphoma
image Acute lymphocytic leukemia

Contraindications

image Pregnancy and lactation: Embryotoxic and teratogenic effects have been observed. Typical of chemotherapy agents, women should be discouraged from becoming pregnant during treatment and advised of the unfavorable risk-benefit profile with respect to breastfeeding.

Topotecan

image Severe bone marrow suppression
image Severe renal impairment

Irinotecan

image Concomitant administration of potent CYP3A4 inhibitors such as ketoconazole should be avoided, as this can lead to significantly increased toxicity.
image Severe leukopenia, thrombocytopenia
image Severe hepatic and/or renal impairment

Side Effects

image Nausea, vomiting: Cytotoxic agents tend to target rapidly dividing cells, including those of the GI tract, contributing to irritation of the GI tract.
image Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in hair follicles.

Serious

image Bone marrow suppression may lead to severe neutropenia, thrombocytopenia, and/or anemia. These have caused fatalities. The mechanism is the same as that seen with other cytotoxic chemotherapy agents, namely destruction of actively dividing cells in the marrow.
image Interstitial lung disease can be fatal. Signs and symptoms include cough, fever, dyspnea, and/or hypoxia. More common with topotecan than irinotecan.

Irinotecan

image Diarrhea can be either early onset or late onset with irinotecan. Late-onset diarrhea can be particularly severe and life-threatening. Early onset diarrhea is caused by cholinergic activation (irinotecan is a cholinesterase inhibitor) and can therefore be managed with atropine. Late-onset diarrhea must be treated promptly with loperamide.

Etoposide, Teniposide

image Hypersensitivity and anaphylaxis are seen with intravenous administration, including acute fatal reactions.
image Hypotension is transient and occurs after intravenous administration. On rare occasions it has lead to sudden death as a result of arrhythmia or hypotension.

Important Notes

image Although topoisomerase inhibitors are used as anticancer treatments, topoisomerase inhibition has been linked to promoting some cancers, particularly leukemia. The reason is that some of the cells with fragmented DNA survive. The fragmented DNA in these surviving cells can recombine, forming mutations that may then lead to development of neoplasms.

Advanced

Pharmacogenetics

image Patients with the UGT1A1*28 polymorphism may have reduced activity of this enzyme, reducing their ability to metabolize SN-38, the active metabolite of irinotecan. This polymorphism is seen in approximately 10% of North Americans, and patients with it may be at greater risk of serious toxicities, including fatal hematologic toxicities such as neutropenia.

FYI

image Podophyllotoxins are derived from Podophyllum peltatum, more commonly known as the mayapple or mandrake plant.
image The camptothecin analogues are inspired by the camptothecin alkaloid found in Camptotheca acuminate. This natural alkaloid actually has relatively weak antitumor activity compared with its synthetic analogues.

Vinca Alkaloids

Description

Vinca alkaloids are cytotoxic anticancer agents that work by inhibiting mitosis.

Prototype and Common Drugs

image Prototype: vincristine
image Others: vinblastine, vindesine, vinorelbine

MOA (Mechanism of Action)

image The vinca alkaloids are microtubule inhibitors.
image Tubulin exists in the cell as a heterodimer consisting of one molecule of α-tubulin and one molecule of β-tubulin. The polymerization of tubulin leads to formation of microtubules, which play an important role in spindle formation. Formation of the mitotic spindle is a key step in the segregation of chromosomes.
image When the vinca alkaloids bind β-tubulin, they inhibit its polymerization into microtubules, preventing spindle formation in dividing cells. This prevents chromosomes from aligning as they normally do, resulting in a disordered dispersion of chromosomes throughout the nucleus. This causes cell cycle arrest at metaphase, and apoptosis (Figure 20-8).
image Other cellular activities that involve microtubules are also inhibited by these agents, including leukocyte phagocytosis and chemotaxis, as well as axonal transport in neurons.
image Taxanes are also microtubule inhibitors, and they also bind to β-tubulin; the difference is that they stabilize the microtubule, preventing it from disassembling. The vinca alkaloids prevent polymerization of β-tubulin into microtubules, and this destabilizes the microtubule.
image

Figure 20-8

Mechanisms of Resistance

image Intracellular levels are reduced secondary to drug efflux through the Pgp transporter. Calcium channel blockers have been used to counteract this mechanism of resistance.
image Mutations in β-tubulin prevent binding of drug.

Pharmacokinetics

image The vinca alkaloids have long elimination half-lives (24 to 48 hours). They are administered intravenously. The main route of elimination for the vinca alkaloids is hepatic, and dose adjustments should be considered in patients with hepatic impairment.
image Vincristine and vinblastine are metabolized by CYP3A4; therefore caution should be used when administering known CYP3A4 inhibitors, as severe toxicity may result. Concomitant administration of CYP3A4 inducers may lead to therapeutic failure.
image A liposomal formulation of vincristine is available; it is eliminated more slowly and has a greater volume of distribution. This formulation may be less neurotoxic.

Indications

image Leukemias
image Lymphomas
image Testicular cancer

Vinorelbine

image Lung cancer
image Breast cancer

Contraindications

image Neurologic diseases that might be worsened by the neurotoxic effects of the vinca alkaloids, particularly vincristine, are contraindications.
image Intrathecal administration: The intrathecal route (into the cerebral spinal fluid via a spinal injection) is fatal.
image Severe bone marrow suppression: The vinca alkaloids cause bone marrow suppression (see Side Effects) and would be expected to worsen preexisting bone marrow suppression. This is particularly the case with vinblastine, which causes the most bone marrow suppression of the group.
image Pregnancy: The vinca alkaloids are fetotoxic and embryotoxic in animals and should not be used in pregnancy.

Side Effects

image Myelosuppression: Conventional chemotherapy agents tend to target rapidly dividing cells, such as those found in the bone marrow.
image Alopecia: Conventional chemotherapy agents also tend to target rapidly dividing cells found in hair follicles, leading to hair loss.
image Peripheral neuropathy may be caused by inhibition of microtubules in long peripheral nerves.
image Nausea, vomiting: Cytotoxic agents tend to target rapidly dividing cells, including those of the GI tract, contributing to irritation of the GI tract.
image Topical: The vinca alkaloids can cause blistering and other skin damage if the infusions extravasate and leak onto the skin, or if injections are mistakenly given by the intramuscular or subcutaneous route.

Important Notes

image Vincristine is less likely to cause bone marrow suppression and is therefore useful in combination regimens in treating leukemia and lymphoma. Vinblastine has less neurotoxicity, whereas vinorelbine is intermediate in terms of both bone marrow suppression and neurotoxicity.

Evidence

Docetaxel versus Vinca Alkaloids in Advanced Non–Small Cell Lung Cancer

image A 2007 systematic review (seven trials, N = 2867 participants) compared docetaxel with vinca alkaloid–based chemotherapy regimens (both are tubulin inhibitors) in advanced non–small cell lung cancer. Vinorelbine was the comparator in six trials, and vindesine in the remaining trial. The authors found improved overall survival with docetaxel (HR 0.89). The incidence of neutropenia was significantly reduced with docetaxel compared with the vinca alkaloids (OR 0.59), as was the incidence of febrile neutropenia (OR 0.57). There were also fewer serious adverse events with docetaxel compared with the vinca alkaloids.

FYI

image The vinca alkaloids are derived from Madagascar periwinkle. They were originally investigated for use in diabetes mellitus, but researchers noted toxicities such as bone marrow suppression in animal studies.

Gonadotropin-Releasing Hormone (GnRH) Analogues

Description

Gonadotropin-releasing hormone (GnRH) analogues are agents that modulate GnRH activity.

Prototype and Common Drugs

Agonists

image Prototype: goserelin
image Others: buserelin, leuprolide, triptorelin, gonadorelin, nafarelin, histrelin, deslorelin

Antagonists

image Prototype: abarelix
image Others: cetrorelix, ganirelix

MOA (Mechanism of Action)

image GnRH is synthesized in the hypothalamus and controls the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. FSH and LH stimulate the gonads (ovaries in females, testes in males), leading to the production of androgens in males.
image Important effects of LH:

image Female: production of estrogen
image Male: production of testosterone

image Important effects of FSH:

image Female: growth of graafian follicles to maturation
image Male: spermatogenesis

image GnRH is released in a pulsatile manner. This intermittent release is crucial for the proper synthesis and release of FSH and LH (Figure 20-9).
image Pulsatile (physiologic) release of GnRH results in increased gonadotropin release. Continuous administration of GnRH results in suppression of gonadotropin release via down-regulation of GnRH receptors, a process called desensitization.

image GnRH agonists can be administered via pulsatile or continuous fashion, depending on the desired effect (stimulation or suppression of gonadotropins respectively).

image GnRH antagonists simply block the GnRH receptor, resulting in reduced release of FSH and LH.
image

Figure 20-9

Pharmacokinetics

image Goserelin as a depot injection provides continuous release of drug over a 29-day period.
image Leuprolide depot is available in formulations that can be administered every month, 3 months, 4 months, or 6 months.
image Buserelin is available as both a nasal spray and an injection formulation.

Indications

image Conditions that benefit from hypoestrogen states (continuous administration):

image Cancers: breast, ovarian, and endometrial
image Endometriosis, dysfunctional uterine bleeding, uterine fibroids
image Precocious puberty

image Conditions that benefit from hypotestosterone states (continuous administration):

image Prostate cancer

image Conditions that benefit from increased GnRH (pulsatile administration):

image Kallmann syndrome (very rare—congenital absence of GnRH)

image As one component of infertility treatment (variable administration)

Contraindications

image Pregnancy: The effects of GnRH analogues on the fetus have not been well studied; however, given the important role GnRH plays in gonadal development, it is assumed that their use in pregnancy should be avoided.
image Undiagnosed vaginal bleeding is a contraindication (cancer could be the diagnosis).

Side Effects

Related to Androgen Deprivation

image Decreased libido
image Flushing
image Gynecomastia
image Weight gain
image Loss of bone mass
image Loss of muscle mass

Related to Estrogen Deprivation

image Hot flashes
image Vaginitis
image Sweating
image Change in breast size

Rare, Serious

image Ovarian hyperstimulation syndrome (OHSS): Through extensive luteinization (transformation of a follicle into a corpus luteum), estrogen, progesterone, and cytokine levels increase, resulting in leaky capillaries and in fluid shifts from the vascular compartment to the extravascular compartments. This can result in edema, ascites, and intravascular hypovolemia.

Antagonists Only

image Allergic reactions: Severe, systemic, rapid onset allergic reactions were observed in trials of abarelix. The mechanism is believed to be a result of the release of histamine from mast cells after binding of active peptides to cell membranes.

Important Notes

image The use of GnRH agonists results in an initial increase in testosterone release, commonly referred to as a flare. This flare can last anywhere from days to weeks. Once the receptors have become desensitized, GnRH is inhibited, and the antiandrogenic effects of the drug are seen. The flare can result in a temporary worsening of the clinical condition before benefits are seen.
image One potential advantage of GnRH antagonists over GnRH agonists is that because they antagonize the GnRH receptor, this flare does not occur.
image Another difference between GnRH agonists and antagonists is that antagonists consistently block both FSH and LH secretion, whereas FSH levels tend to rise after a period of time with agonist therapy. The clinical significance of this difference is not known.
image Prostate cancer tends to be a very hormone-dependent cancer, growing under the stimulation of androgens. The growth stimulating effects of androgens can be reduced in two ways, by either surgical (removal of both testes) or “medical castration.” Medical castration is essentially androgen deprivation therapy.

Advanced

image Elevated prolactin levels decrease GnRH activity.
image The elimination half-life of goserelin varies between genders: 2 hours in females and 4 hours in males.
image Triptorelin is eliminated by both liver and kidneys. Renal and/or hepatic impairment extends the elimination half-life of triptorelin.

Evidence

Preoperative GnRH Analogues in Treatment of Uterine Fibroids

image A 2001 Cochrane review (26 trials) evaluated the role of pretreatment with GnRH analogues before hysterectomy or myomectomy for uterine fibroids. The authors found that the use of GnRH analogues for 3 to 4 months before fibroid surgery reduced uterine volume and fibroid size. The authors also found that midline incisions could be avoided because of a reduction in the size of the uterus.

GnRH Agonists versus Antagonists for Assisted Conception

image A 2006 Cochrane review (27 trials) evaluated the efficacy of GnRH antagonists compared with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception. The pregnancy rate was lower with antagonist therapy (OR 0.84), but there was a reduction in the incidence of severe OHSS (OR 0.61).

FYI

image Leutin is Latin, meaning yellow. The corpus luteum is yellow endocrine tissue released from the graafian follicle in the ovary.
image Myo– refers to muscle. Myome– refers to myometrium, the middle muscular layer of the uterus. Myomectomy is surgical removal of a fibroid (which is composed of myometrium).
image Fibroids can bleed when they get large enough, and this can cause anemia.
image A third human gonadotropin is human chorionic gonadotropin (hCG), present during pregnancy and with some cancers
image The –relin suffix can be a memory tip for releasing hormones.
image The –relix suffix is found in GnRH antagonist names; the “x” can help you remember that these drugs are against the physiology activity.

Angiogenesis Inhibitors

Description

Angiogenesis inhibitors are agents that inhibit the growth of new blood vessels (angiogenesis).

Prototype and Common Drugs

image Prototype: bevacizumab
image Others: ranibizumab

MOA (Mechanism of Action)

image Angiogenesis is essential to the growth of solid tumors. Neoplastic tissue, which is highly metabolically active, must have access to the nutrients in blood in order to continue growing.
image It is believed that complete blockade of angiogenesis will not only prevent the growth of new vessels, but also promote instability and degradation of existing vessels within the tumor.
image Angiogenic growth factors promote angiogenesis. Numerous angiogenic growth factors are found in the body, and each has the potential to play a role in promoting vascularization of neoplastic tissue. Many of these angiogenic growth factors also promote the growth of other tissues.

Vascular Endothelial Growth Factor

image Vascular endothelial growth factor (VEGF) has become the most frequent target of angiogenesis inhibitors. Bevacizumab and ranibizumab bind to VEGF-A, preventing it from binding to its receptor (Figure 20-10).
image

Figure 20-10

Pharmacokinetics

image Bevacizumab is administered by intravenous infusion.
image The metabolism of bevacizumab is unusual in that instead of being cleared by the liver or kidneys, it relies on proteolysis throughout the body, including within endothelial cells.
image Ranibizumab is administered by intravitreal injection (into the vitreus of the eye).

Indications

Bevacizumab

image Colorectal cancer
image Breast (HER2-negative) cancer
image Lung (non–small cell) cancer

Ranibizumab

image Age-related macular degeneration

Contraindications

Ranibizumab

image Suspected ocular infections: Ranibizumab is administered by intravitreal injection and carries a risk of a very serious eye infection called endophthalmitis.

Side Effects

Bevacizumab

image GI perforation: VEGF blockade may lead to ischemia in regions of the GI tract, promoting perforation.
image Hemorrhage, particularly pulmonary hemorrhage, may be fatal in some cases. This is because of the nonspecific destabilization of blood vessels secondary to VEGF blockade.
image Hypertension: VEGF tends to have a vasorelaxant effect, and it is believed that blockade of VEGF leads to elevation in blood pressure, which becomes clinically significant in some patients.
image Thrombosis: VEGF blockade prevents the renewal of endothelial cells and promotes endothelial dysfunction, which in turn promotes the development of thromboses.
image Wound healing: Angiogenesis plays a key role in proper wound healing, so blockade of VEGF prevents efficient healing of wounds.

Ranibizumab

image Ranibizumab is administered locally; therefore the risk of the previously noted systemic side effects should be minimal.

Serious, Rare

image Endophthalmitis may occur because of infection secondary to intraocular injection. Risk is minimal if proper aseptic injection technique is used.

Important Notes

image Bevacizumab is being used off-label in many jurisdictions for the management of age-related macular degeneration. Because it is typically administered in large doses systemically for cancer, small doses of bevacizumab administered locally are much cheaper than ranibizumab.
image Because of its effects on wound healing, bevacizumab should not be initiated within 4 weeks after surgery, and it should be discontinued at least 6 weeks before surgery.
image Ranibizumab was specifically designed to be used in age-related macular degeneration and is not used in cancer. It is administered locally, by intravitreal injection, and therefore lacks many of the side effects of bevacizumab.
image Verteporfin photodynamic therapy (PDT) is another approach used to treat age-related macular degeneration (AMD) and in fact was the favored new therapy before the approval of the angiogenesis inhibitors. This drug was administered intravenously and activated by a laser shone into the eye. The laser stimulated the production of free radicals, which then damaged blood vessels. This was an early antiangiogenic therapy, although it was primitive compared with the newer angiogenesis inhibitors.

Evidence

Age-Related Macular Degeneration

image A 2008 Cochrane review (five trials, N = 2500 participants) investigated anti-VEGF therapies for age-related macular degeneration and included three trials of ranibizumab. Efficacy was measured by the ability to prevent a reduction in visual acuity of 15 letters or more, and ranibizumab prevented vision loss versus verteporfin PDT (number needed to treat [NNT = 3]) and sham (NNT = 3); the combination of ranibizumab and verteporfin PDT prevented vision loss versus verteporfin alone (NNT = 4). Ranibizumab also improved vision by 15 letters or more versus each of these agents.

Metastatic Colorectal Cancer

image A 2009 Cochrane review investigated the efficacy and toxicity of targeted antiangiogenic therapies in addition to chemotherapy in patients with metastatic colorectal cancer. The authors found five trials of bevacizumab (N = 3101 patients). The combination of bevacizumab and first-line chemotherapy significantly improved overall survival (HR 0.81) and progression-free survival (HR 0.61) versus first-line chemotherapy alone. The results for combining bevacizumab with second-line chemotherapy were not conclusive owing to significant heterogeneity.

FYI

image One of the most notorious drugs ever developed, thalidomide, is an angiogenesis inhibitor. When it first came out in the 1950s, it was marketed as an antinauseant for pregnant women. Tragically, thalidomide turned out to be one of the worst teratogens ever developed and caused countless birth defects. Many babies were born with malformed limbs; this was a result of impaired vascular development, an effect of thalidomide that was not known at the time of its development.

Tyrosine Kinase Inhibitors

Description

Tyrosine kinase inhibitors are a heterogeneous group of anticancer agents that work by inhibiting the effects of a variety of growth factors.

Monoclonal Antibodies

Human Epidermal Growth Factor Receptor (HER2)

image Prototype: trastuzumab

Epidermal Growth Factor Receptor (EGFR)

image Prototype: cetuximab
image Others: panitumumab

Prototype and Common Drugs

Small Molecules

EGFR

image Prototype: erlotinib
image Others: gefitinib

BCR-ABL/src

image Prototype: imatinib
image Others: dasatinib, nilotinib

Multikinase Inhibitors

image Prototype: sorafenib
image Others: sunitinib

Dual Kinase Inhibitors: EGFR/HER2

image Prototype: lapatinib

MOA (Mechanism of Action) (Figure 20-11)

image Phosphorylation is a process whereby a protein kinase transfers a phosphate group from adenosine triphosphate (ATP) or guanosine triphosphate (GTP) to free hydroxyl groups of amino acids. In doing so, they modify protein function. Most protein kinases phosphorylate serine and threonine residues, but a subset of protein kinases phosphorylate tyrosine residues.
image The protein tyrosine kinases are subdivided into receptor tyrosine kinases (RTKs) and nonreceptor (cytoplasmic) tyrosine kinases.
image Tyrosine kinase receptors regulate growth and cell differentiation. Therefore ligands for these receptors include several growth factors, and they play an important role in neoplasia. The RTK family includes growth factor receptors such as epidermal growth factor receptor (EGFR).
image Under normal circumstances, frequent binding of growth factors to these tyrosine kinase receptors leads to receptor down-regulation. This blunts the activity of these growth factors, preventing abnormal growth from occurring. In cancer, mutation of these receptors prevents this down-regulation, removing an important check on uncontrolled growth.
image

Figure 20-11 TK, Tyrosine kinase; tyr, tyrosine; thr, threonine, ser, serine.

EGFR/HER

image The epidermal growth factor (EGF) pathway plays an important role in neoplasia. Four receptors belong to the EGF pathway: EGFR and human epidermal growth factors (HER2, HER3, HER4).
image When not bound by ligand, EGFR remains in a closed conformation. When growth factors bind, the receptor “opens” into a conformation that is able to dimerize with other receptors. Once the growth factor binds to this receptor, cell growth is stimulated.
image Trastuzumab antagonizes the HER2 receptor. The HER2 receptor is overexpressed in many breast cancers. Binding of trastuzumab to HER2 appears to inhibit cancers by promoting apoptosis and by reducing cell proliferation.

BCR-ABL/src

image Chronic myelogenous leukemia (CML) is most frequently caused by a chromosomally abnormal hematopoietic stem cell. The BCR (break point cluster) gene of one chromosome and the ABL (Abelson) gene of another chromosome translocate, moving from separate chromosomes onto the same chromosome, fusing to become one gene, known as BCR-ABL. BCR-ABL is referred to as a fusion oncoprotein, because these two genes, when joined together, are associated with the development of cancer.
image Important to drug therapy, ABL codes for tyrosine kinase receptors. BCR-ABL creates a tyrosine kinase receptor that is constitutively active, meaning that it is continually active. Tyrosine kinase receptors are growth factor receptors, meaning that their continual activation leads to dysregulated growth of myeloid cells.

Other Kinases

image Drugs that inhibit multiple kinases were originally thought to be disadvantageous because of an increased likelihood of side effects. Instead, it is now believed that targeting multiple kinases addresses the redundancy that is found among signaling pathways, perhaps leading to enhanced efficacy. Sorafenib and sunitinib are examples of multikinase inhibitors, and their targets include:

image VEGF receptor (VEGFR)
image Platelet-derived growth factor receptor (PDGFR)

• FMS-like tyrosine kinase (FLT3), which is part of the PDGF family of growth factor receptors

image Oncogenes: Kit

Pharmacokinetics

image The small molecule tyrosine kinase inhibitors used in cancer are all orally administered. The monoclonal antibodies are administered by intravenous infusion.
image The bioavailability of sorafenib is reduced with a high-fat meal; therefore it is recommended that it either be taken on an empty stomach or with a low- or moderate-fat meal.
image Sunitinib and its active metabolites have a long elimination half-life (40 to 60 and 80 to 110 hours, respectively).
image Sunitinib, sorafenib, imatinib, dasatinib, and erlotinib are all metabolized by CYP3A4. Interactions with known inhibitors or inducers of these isozymes are to be expected, and concomitant use should be avoided if possible. Because these agents are primarily eliminated by hepatic metabolism, no dose adjustments are required in patients with renal impairment.

Indications

Imatinib, Dasatinib

image Chronic myelogenus leukemia (CML)
image Philadelphia chromosome–positive (Ph+) acute lymphoblastic anemia (ALL)
image GI stromal tumor (GIST)

Gefitinib, Erlotinib

image Non–small cell lung cancer

Sorafenib

image Hepatocellular carcinoma
image Renal cell (clear cell) carcinoma

Sunitinib

image Metastatic renal cell (clear cell) carcinoma
image GIST

Lapatinib

image Breast cancer

Trastuzumab

image Breast cancers overexpressing HER2

Cetuximab

image Cancers of the colon and rectum, head and neck

Panitumumab

image Colorectal cancer

Contraindications

image See Advanced section for information on use in pregnancy.

Side Effects

image Diarrhea
image Rash: common with EGFR inhibitors, likely because of inhibition of epidermal turnover

Serious

Sorafenib, Sunitinib

image Hypertension: VEGF inhibition reduces factors involved in vascular compliance.

Sorafenib, Imatinib

image Left ventricular dysfunction: Cardiotoxicity with imatinib may be caused by mitochondrial dysfunction. Cardiomyocytes are highly energy dependent. The mechanism is not clear with sorafenib, but because the drug is a multikinase inhibitor, it might be inhibiting a kinase involved in myocardial function.

Dasatinib, Imatinib

image Bone marrow suppression (thrombocytopenia, neutropenia, anemia): The mechanism for this effect is not established, but it may be the result of inhibition of progenitor cells. Usually it is of concern only at higher doses
image Hemorrhage from thrombocytopenia may occur.
image Fluid retention: The mechanism for this effect has not been established.

Sorafenib, Sunitinib, Dasatinib

image QT prolongation occurs, possibly because of interactions with a specific potassium ion channel. This channel facilitates the rapid component of myocardial repolarization and is associated with congenital long QT syndrome.

Gefitinib, Erlotinib

image Interstitial lung disease: This side effect appears to be closely associated with the mechanism of action (EGFR blockade), as populations in which tumors respond well to these agents appear to be at higher risk of this side effect.

Erlotinib

image Hepatotoxicity: Rare cases of hepatotoxicity, including liver failure, have been reported with erlotinib.

Trastuzumab

image Cardiotoxicity: Ventricular dysfunction and heart failure have been observed. The mechanism has not been established, although the impact of HER2 blockade on protein synthesis and cell survival pathways is one possibility.
image Hypersensitivity reactions are typically seen with monoclonal antibodies.
image Pulmonary toxicity: Pneumonitis and pleural effusions, among others, have been observed rarely. The mechanism is unknown.

Cetuximab, Panitumumab

image Cardiopulmonary arrest is a rare side effect seen in trials in head and neck cancer.
image Hypomagnesemia is a common side effect. The mechanism is not established, but it may be a result of alterations in renal transporters for magnesium.

Important Notes

image The tyrosine kinase inhibitors are collectively referred to as targeted therapies, a reflection of the fact that they target growth factors that are active only in cancer. The theoretical advantage of targeted therapies is enhanced selective toxicity and avoidance of disabling side effects such as GI effects, myelosuppression, and alopecia. It is important to note, though, that these side effects still occur with many of these targeted therapies but at a lower incidence than with conventional chemotherapy.
image Although the multikinase inhibitors both attack similar targets, sunitinib appears to have stronger binding affinity for many of these targets and therefore enhanced efficacy over sorafenib.

Advanced

Drug Interactions

image Dasatinib absorption may be decreased by antacids, so they should be administered at least 2 hours apart.

Pharmacogenetics

image Dasatinib is one of the first examples of a drug that was specifically designed to target mutations that had developed to the drug of choice for this indication, imatinib.

Pregnancy

image The extent of risk for all the tyrosine kinase inhibitors in pregnancy is approximately the same. Because they inhibit growth factors, in many cases angiogenic growth factors, there is serious concern about their effects on fetal development. These agents are therefore not recommended in pregnancy unless the withdrawal of therapy represents unacceptable risk to the mother.

FYI

image The Abelson (ABL) in BCR-ABL is named for the Abelson virus, which can cause leukemia.
image The translocation that results in the formation of the BCR-ABL fusion oncoprotein is called the Philadelphia chromosome. It was named after the city in which it was discovered.
image The tyrosine kinase inhibitors ending in -nib (e.g., erlotinib, imatinib) are often referred to as small-molecule tyrosine kinase inhibitors to distinguish them from the tyrosine kinase inhibitors that are monoclonal antibodies. Because monoclonal antibodies are proteins, they have a much larger structure.
image The tyrosine kinase receptors are known by several names, making it very confusing. For example, HER2 (human epidermal growth factor receptor 2) and ERBB2 are names for the same receptor. HER2/neu is the gene for HER2, so this receptor is also referred to as HER2/neu.

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