Chemotherapeutic Drugs

Drug Resistance

Resistance to chemotherapeutic drugs often occurs and has many causes.³ Some chemotherapy agents lead to induction of drug-metabolizing enzymes in the liver, other tissues, or tumor cells, accelerating drug conversion to nontoxic metabolites. Many solid tumors grow so rapidly that portions of the tumor are poorly vascularized, preventing therapeutic concentrations from reaching many target cells. In poorly perfused areas of some tumors, cells remain resistant to chemotherapeutic drugs because of relative hypoxia. Indeed, hypoxia causes resistance to both radiation and most chemotherapeutic drugs (with the exception of malignancies susceptible to treatment with the mitomycins).

As in the treatment of infections, multiple drug resistance describes the clinical circumstance in which a tumor is no longer susceptible to several chemotherapeutic drugs. For a number of agents, P-glycoprotein spans the plasma membrane and acts to pump chemotherapeutic drugs (anthracyclines, vinca alkaloids, and taxanes but not alkylating drugs, platinating drugs, and antimetabolites) to the extracellular space such that an effective toxic intracellular concentration is not reached. In addition to P-glycoprotein, there is an additional family of multidrug resistance proteins (MRPs) that are located on plasma membranes and endoplasmic reticulum of some tumor cell types, which confer drug resistance via an adenosine triphosphate (ATP)–dependent decrease in cellular drug accumulation (with the exception of malignancies susceptible to treatment with the taxanes). Collectively, P-glycoprotein and the MRPs are members of the ATP-binding cassette (ABC) class of transporter proteins that protect normal tissues from a variety of toxicants and are overexpressed in some tumor cells. The breast cancer resistance protein (also known as the ATP-binding cassette subfamily G member 2 or ABCG₂ protein or the mitoxantrone resistance–associated protein) is a specific example of an ABC protein that confers tumor resistance to certain chemotherapeutic agents via active transport of the offending agent out of cells expressing this transporter.

Topoisomerases, enzymes that regulate the overwinding or underwinding of DNA during replication, are the targets for many chemotherapeutic drugs. Resistance to chemotherapeutic drugs can also occur through mutations in the drug-binding domain of the target enzyme. Resistance to the drug methotrexate may reflect mutations in the drug target, the enzyme dihydrofolate reductase; dihydrofolate reductase converts dihydrofolate into tetrahydrofolate and is required for the de novo synthesis of purines and thymidylic acid, which are important for cell growth and proliferation. Resistance to alkylating drugs occurs through overexpression of drug-neutralizing substances and metabolizing proteins.

Classification

Chemotherapeutic drugs are classified according to their mechanism of action (Table 42-1)¹; adverse effects associated with these drugs are generally similar among drugs with similar mechanisms of action (Table 42-2).^4–6 Knowledge of drug-induced adverse effects and evaluation of appropriate laboratory tests (hemoglobin, platelet count, white blood cell count, coagulation profile, arterial blood gases, blood glucose, plasma electrolytes, liver and renal function tests, electrocardiogram [ECG], and radiograph of the chest) are useful in the preoperative evaluation of patients being treated with specific chemotherapeutic drugs. Immunosuppression makes these patients susceptible to iatrogenic infections, thus asepsis and the use of appropriate prophylactic antibiotics is critical. A history of severe vomiting or diarrhea may be associated with electrolyte disturbances and decreased intravascular fluid volume. The existence of mucositis makes placement of pharyngeal airways, laryngeal mask airways, and esophageal catheters questionable. The response to inhaled and injected anesthetic drugs may be altered by drug-induced cardiac, hepatic, or renal dysfunction and induction of hepatic enzymes. The response to older nondepolarizing neuromuscular blocking drugs may be altered by impaired renal function. Theoretically, the effects of succinylcholine may be prolonged if plasma cholinesterase activity is decreased by chemotherapeutic drugs.

Toxicities

Chemotherapeutic drugs typically target proteins or nucleic acids, which are common to malignant and nonmalignant cells and thus possess a narrow therapeutic index. Indeed, using the standard definition of therapeutic index (the dose that causes toxicity divided by the minimum effective dose) is not useful, as these agents all produce significant, even life-threatening toxicities at doses which may not reach levels that are high enough to eradicate cancer (therapeutic index <1). Furthermore, chemotherapeutic drugs are usually administered at maximum tolerated doses. Although toxicities may be unique for specific drugs, many toxicities are shared (nausea and vomiting, myelosuppression, mucositis, alopecia) (see Table 42-2).⁴ Nausea and vomiting result from local gastrointestinal effects as well as activation of the chemoreceptor trigger zone in the central nervous system. Patients who have a history of chemotherapy-induced nausea and vomiting are not necessarily prone to postoperative nausea and vomiting, as there is only weak positive association between the two; however, patients who have a history of tolerating emetogenic chemotherapy regimens are unlikely to develop postoperative nausea and vomiting.⁷ Development of serotonin antagonists as effective antiemetics in addition to combination antiemetic regimens has facilitated the tolerance of emetogenic chemotherapeutic drugs. Mucositis and diarrhea are common gastrointestinal toxicities that reflect the high proliferative rate of gastrointestinal tissues, which makes these tissues more susceptible to the cytotoxic effects of certain chemotherapeutic drugs. Myelosuppression and alopecia reflect similar chemotherapeutic drug effects on highly proliferative tissues. Chemotherapeutic drugs that damage DNA (alkylating drugs, topoisomerases) are associated with secondary malignancies.

Alkylating Agents

Alkylating drugs include nitrogen mustards, alkyl sulfonates, nitrosoureas, and triazenes. These chemotherapeutic drugs form covalent alkyl bonds with nucleic acid bases, resulting in intrastrand or interstrand DNA cross-links which are toxic to cells undergoing division. By altering the structure of DNA, these drugs inhibit DNA replication and transcription. DNA damage produced by alkylating chemotherapeutic drugs is more likely to kill malignant cells than nonmalignant cells because rates of proliferation are greater for the cancer cells. Acquired resistance to alkylating drugs is a common occurrence and may reflect decreased cell membrane permeability to the drugs and increased production of nucleophilic substances that can compete with target DNA for alkylation.

Side Effects

Bone marrow suppression is the most important dose-limiting factor in the clinical use of alkylating drugs, especially busulfan. Cessation of mitosis is evident within 6 to 8 hours. Lymphocytopenia is usually present within 24 hours. Variable degrees of depression of platelet and erythrocyte counts may occur. Hemolytic anemia is predictably present.

Treatment with alkylating drugs is often associated with gonadal dysfunction, including oligospermia and amenorrhea. Hemorrhagic cystitis can result from irritation by the acrolein metabolite of cyclophosphamide or ifosfamide. Gastrointestinal mucosa is sensitive to the effects of alkylating drugs, manifesting as mitotic arrest, cellular hypertrophy, and desquamation of the epithelium. Damage to hair follicles, often leading to alopecia, is a common side effect. Increased skin pigmentation is frequent. All alkylating drugs are powerful central nervous system (CNS) stimulants, manifesting most often as nausea and vomiting. Skeletal muscle weakness and seizures may be present. Pneumonitis and pulmonary fibrosis are potential adverse effects of alkylating drugs. Symptomatic patients may demonstrate a decreased pulmonary diffusing capacity. Inhibition of plasma cholinesterase activity may be present for as long as 2 to 3 weeks after administration of chemotherapy regimens that include an alkylating agent and can lead to prolonged skeletal muscle paralysis after administration of succinylcholine.^8,9

Rapid drug-induced destruction of malignant cells can produce increased purine and pyrimidine breakdown, leading to uric acid–induced nephropathy. To minimize the likelihood of this complication, it is recommended that adequate fluid intake, alkalinization of the urine, and administration of allopurinol be established before drug treatment.

Nitrogen Mustards

The most commonly used nitrogen mustards are mechlorethamine, cyclophosphamide, melphalan, and chlorambucil.

Mechlorethamine

Mechlorethamine is a rapidly acting nitrogen mustard administered intravenously (IV) to minimize local tissue irritation. This drug must be freshly prepared before each administration. Mechlorethamine and other nitrogen mustards are intensely powerful vesicants, requiring that gloves be worn by personnel handling the drug. A course of therapy with mechlorethamine consists of the injection of a total dose of 0.4 mg/kg. The drug undergoes rapid chemical transformation in tissues such that active drug is no longer present after a few minutes. For this reason, it is possible to prevent tissue toxicity from the drug by isolating the blood supply to that tissue. Alternatively, it is theoretically possible to localize the action of mechlorethamine in a specific tissue by injecting the drug into the arterial blood supply to the tissue.

Clinical Uses

Mechlorethamine produces beneficial effects in the treatment of Hodgkin disease and, less predictably, in other lymphomas. The drug is most often used in combination with vincristine, procarbazine, and prednisone (MOPP regimen) for the treatment of Hodgkin disease.

Side Effects

The major side effects of mechlorethamine include nausea, vomiting, and myelosuppression. Leukopenia and thrombocytopenia constitute the principal limitation on the amount of drug that can be given. Herpes zoster is a type of skin lesion frequently associated with nitrogen mustard therapy. Latent viral infections may be unmasked by treatment with mechlorethamine. Thrombophlebitis is a potential complication, and extravasation of the drug results in severe local tissue reactions, with brawny and tender induration that may persist for prolonged periods.

Cyclophosphamide

Cyclophosphamide is well absorbed after oral administration and is subsequently activated in the liver to aldophosphamide for transport to target tissues. Parenteral administration is also effective. Target cells are able to convert aldophosphamide to highly cytotoxic metabolites, phosphoramide, and acrolein that then alkylate DNA. Maximal plasma concentrations of cyclophosphamide are achieved about 1 hour after oral administration, and the elimination half-time is 6 to 7 hours. Urinary elimination accounts for approximately 14% of this drug in an unchanged form.

Clinical Uses

Cyclophosphamide is one of the most frequently used chemotherapeutic drugs, as it is effective in the treatment of a wide range of cancers and inflammatory diseases. Its versatility is improved because of its effectiveness after oral as well as parenteral administration. Given in combination with other drugs, favorable responses have been shown in patients with Hodgkin disease, lymphosarcoma, Burkitt lymphoma, and acute lymphoblastic leukemia of childhood. Cyclophosphamide is frequently used in combination with methotrexate and fluorouracil as adjuvant therapy after surgery for breast cancer when there is involvement of the axillary nodes. Cyclophosphamide has potent immunosuppressive properties, leading to its use in nonneoplastic disorders associated with altered immune reactivity, including Wegener granulomatosis and rheumatoid arthritis.

Side Effects

Hypersensitivity reactions and fibrosing pneumonitis have been noted in patients treated with cyclophosphamide; the incidence is less than 1% and symptoms may develop months to years after initiation of the drug. Large doses of cyclophosphamide are associated with a high incidence of pericarditis and pericardial effusion, which in some cases has progressed to cardiac tamponade.¹⁰ Smaller numbers of treated patients develop hemorrhagic myocarditis with symptoms of congestive heart failure, which may not occur for as long as 2 weeks after the last dose of drug.

Cyclophosphamide differs from other nitrogen mustards in that significant degrees of thrombocytopenia are less common but alopecia is more frequent. Nausea and vomiting occur with equal frequency regardless of the route of administration. Mucosal ulcerations, increased skin pigmentation, and hepatotoxicity are possible side effects. Sterile hemorrhagic cystitis occurs in 5% to 10% of patients, presumably reflecting chemical irritation produced by reactive metabolites of cyclophosphamide. Dysuria and hematuria are indications to discontinue the drug. Inappropriate secretion of arginine vasopressin hormone has been observed in patients receiving cyclophosphamide, usually with doses of greater than 50 mg/kg. It is important to consider the possibility of water intoxication because these patients are usually being hydrated to minimize the likelihood that hemorrhagic cystitis will develop. Extravasation of the drug does not produce local reactions, and thrombophlebitis does not complicate IV administration.

Melphalan

Melphalan is a phenylalanine derivative of nitrogen mustard with a range of activity similar to other alkylating drugs. It is not a vesicant. Oral absorption is excellent, resulting in drug concentrations similar to those achieved by the IV route of administration. The elimination half-time is approximately 1.5 hours, and up to 15% of the drug is eliminated unchanged in urine.

Side Effects

The side effects of melphalan are primarily hematologic and are similar to those of other alkylating drugs. It is usually necessary to maintain a significant degree of bone marrow depression (leukocyte count 3,000 to 5,000 cells/mm³) to achieve optimal therapeutic effects. Pulmonary fibrosis is possible. Nausea and vomiting are not common side effects of melphalan. Alopecia does not occur, and changes in renal or hepatic function have not been reported.

Chlorambucil

Chlorambucil is the aromatic derivative of mechlorethamine. Oral absorption is adequate. The drug has an elimination half-time of approximately 1.5 hours and is almost completely metabolized. Chlorambucil is the slowest acting nitrogen mustard in clinical use. It is the treatment of choice in chronic lymphocytic leukemia and in primary (Waldenström) macroglobulinemia. A marked increase in the incidence of leukemia and other tumors has been noted with the use of this drug for the treatment of polycythemia vera.

Side Effects

Cytotoxic effects of chlorambucil on the bone marrow, lymphoid organs, and epithelial tissues are similar to those observed with other alkylating drugs. Its myelosuppressive action is usually moderate, gradual, and rapidly reversible. Pulmonary fibrosis is possible. Nausea and vomiting are frequent. CNS stimulation can occur but has been observed only with large doses. Hepatotoxicity may rarely occur.

Alkyl Sulfonates

Busulfan is a cell cycle nonspecific alkylating antineoplastic agent in the class of alkyl sulfonates. Busulfan is well absorbed after oral administration. IV administration is also effective. Almost the entire drug is eliminated by the kidneys as methane sulfonic acid. Busulfan produces remissions in up to 90% of patients with chronic myelogenous leukemia. The drug is of no value in the treatment of acute leukemia.

Side Effects

Busulfan can produce progressive pulmonary fibrosis in up to 4% of patients. The prognosis after appearance of clinical symptoms is poor, with a median survival of 5 months.¹¹ Enhanced toxicity with administration of supplemental oxygen has not been noted. Myelosuppression and thrombocytopenia are important side effects of busulfan. Nausea, vomiting, and diarrhea occur. Hyperuricemia resulting from extensive purine catabolism accompanying the rapid cellular destruction and renal damage from precipitation of urates have been noted. Allopurinol is recommended to minimize renal complications.

Nitrosoureas

The nitrosoureas are mustard gas–related compounds used as an alkylating agent in chemotherapy. Nitrosoureas, represented by carmustine, lomustine, semustine, and streptozocin, possess a wide spectrum of activity for human malignancies including intracranial tumors, melanomas, and gastrointestinal and hematologic malignancies. Indeed, the high lipid solubility results in passage across the blood–brain barrier and efficacy in the treatment of meningeal leukemias and brain tumors. These drugs appear to act by carboxylation and alkylation of nucleic acids. With the exception of streptozocin, the clinical use of nitrosoureas is limited by profound drug-induced myelosuppression.

Carmustine

Carmustine is the nitrosourea in widest clinical use. It is capable of inhibiting synthesis of both RNA and DNA. Although oral absorption is rapid, the drug is injected IV because tissue uptake and metabolism occur quickly. Local burning may accompany infusion. Carmustine disappears from plasma in 5 to 15 minutes. Because of its ability to rapidly cross the blood–brain barrier, carmustine is used to treat meningeal leukemia and primary as well as metastatic brain tumors.

Side Effects

Carmustine has been associated with interstitial pneumonitis and fibrosis much like bleomycin.¹² The incidence of pulmonary toxicity is in the range of 20% to 30%, with a mortality in those affected of 24% to 90%. The cumulative dose is the major risk factor, with 50% of patients exhibiting toxicity at doses above the range of 1,200 to 1,500 mg/m². A unique side effect of carmustine is a delayed onset (after approximately 6 weeks of treatment) of leukopenia and thrombocytopenia. Active metabolites may be responsible for this toxicity. CNS toxicity, nausea and vomiting, flushing of the skin and conjunctiva, nephrotoxicity, and hepatotoxicity have been reported.

Lomustine and Semustine

Lomustine and its methylated analogue semustine possess similar clinical toxicity to carmustine, including delayed bone marrow depression manifesting as leukopenia and thrombocytopenia. Lomustine appears to be more effective than carmustine in the treatment of Hodgkin disease.

Streptozocin

Streptozocin has a methylnitrosourea moiety attached to the number 2 carbon atom of glucose. It has a unique affinity for β cells of the islets of Langerhans and has proved useful in the treatment of human pancreatic islet cell carcinoma and malignant carcinoid. In animals, the drug is used to produce experimental diabetes mellitus.

Side Effects

Approximately 70% of patients receiving this drug develop hepatic or renal toxicity. Renal toxicity may manifest as tubular damage and progress to renal failure and death. Hyperglycemia can occur as a result of selective destruction of pancreatic β cells and resultant hypoinsulinism.⁶ Myelosuppression is not produced by this drug.

Mitomycin

Mitomycin is the prototypical alkylating agent and is of value in the palliative treatment of gastric adenocarcinoma in combination with fluorouracil and doxorubicin. The drug is administered IV and is widely distributed in tissues but does not readily enter the CNS. Metabolism is in the liver, with less than 10% of mitomycin excreted unchanged in bile or urine.

Side Effects

Myelosuppression is a prominent side effect of mitomycin and is characterized by severe leukopenia and thrombocytopenia, which may be delayed in appearance. Mitomycin is capable of inducing pulmonary fibrosis, with an incidence ranging between 3% and 12%.¹³ Like bleomycin, mitomycin appears to act synergistically to induce pulmonary fibrosis with thoracic radiation and oxygen therapy, suggesting the need to limit exposure of treated patients to hyperoxia. Nausea, vomiting, gastrointestinal mucositis, and alopecia are recognized toxic effects. Glomerular damage resulting in renal failure is a rare but well-recognized complication.

Platinating Drugs

Cisplatin

Although cisplatin is frequently designated as an alkylating agent, it has no alkyl group and so cannot carry out alkylating reactions. It is correctly classified as alkylating-like. Cisplatin contains a platinum atom, two amines, and two chlorides, which result in chemotherapeutic effects resembling DNA alkylating drugs by cross-linking adjacent or opposing guanine bases to disrupt DNA. The drug must be administered IV because oral ingestion is ineffective. High concentrations of cisplatin are found in the kidneys, liver, intestines, and testes, but there is poor penetration into the CNS. Cisplatin and its analogue carboplatin are components of the treatment of many nonhematologic malignancies, including lung, bladder, testicular, and ovarian cancer.

Side Effects

Renal toxicity is prominent and becomes the dose-limiting toxic effect of cisplatin. Decreased glomerular filtration rate and renal tubular dysfunction produced by cisplatin may begin as early as 3 to 5 days after initiating treatment with this drug. Along with increasing blood urea nitrogen and plasma creatinine concentrations, proteinuria, and hyperuricemia, there is a magnesium-wasting defect in as many as 50% of patients manifesting as some degree of cisplatin-induced renal dysfunction. Acute tubular necrosis may progress to acute renal failure, necessitating hemodialysis. Hydration and diuresis induced with mannitol and furosemide may protect against the development of renal toxicity by dilution of the tubular urinary concentration of cisplatin. The hypomagnesemia that is associated with cisplatin’s renal tubular injury may predispose to cardiac dysrhythmias and decrease the dose requirements for neuromuscular blocking drugs.

Ototoxicity caused by cisplatin is manifested by tinnitus and hearing loss in the high-frequency range. Cisplatin is considered highly emetogenic, with marked nausea and vomiting occurring in almost all patients who do not receive antiemetics, although prophylactic antinausea regimens can be highly effective. Mild to moderate myelosuppression may develop, with transient leukopenia and thrombocytopenia. Peripheral sensory neuropathies, paresthesias, and loss of vibratory and position sense are common findings. Most neuropathies are reversible, although symptoms may persist for months. Hyperuricemia, seizures, and cardiac dysrhythmias have been observed. Allergic reactions characterized by facial edema, bronchoconstriction, tachycardia, and hypotension may occur minutes after injection of the drug.

Antimetabolites

Nucleic acid synthesis inhibitors (antimetabolites) include folate analogues, pyrimidine analogues, and purine analogues. These drugs are particularly effective in destroying cells during the S phase of the cell cycle, which is when DNA is synthesized. Selective effects on cancer cells may relate to greater rates of DNA replication in cancer cells than normal cells. Nevertheless, side effects (myelosuppression and mucositis) reflect effects on proliferating but nonmalignant cells.

Folate Analogues

Methotrexate

Methotrexate is a poorly lipid-soluble folate analogue that is effective in the treatment of different hematologic and nonhematologic cancers and is classified as an antimetabolite (folic acid antagonist). This drug inhibits dihydrofolate reductase, which is the enzyme that uses reduced folate as a methyl donor in the synthesis of pyrimidine and purine nucleosides. Inhibition of dihydrofolate reductase by methotrexate prevents the formation of tetrahydrofolic acid and causes disruption of cellular metabolism by producing an acute intracellular deficiency of folate enzymes. As a result, 1-carbon transfer reactions necessary for the eventual synthesis of DNA and RNA cease.

Methotrexate is readily absorbed after oral administration. Significant metabolism of methotrexate does not seem to occur, with more than 50% of the drug appearing unchanged in urine. Renal excretion reflects glomerular filtration and tubular secretion. Toxic concentrations of methotrexate may occur in patients with renal insufficiency. Methotrexate remains in tissues for weeks, suggesting binding of the drug to dihydrofolate reductase.

Clinical Uses

Methotrexate is widely used in the treatment of malignant and some nonmalignant disorders. It is a useful drug in the treatment of acute lymphoblastic leukemia in children but not adults. Choriocarcinoma is effectively treated with this drug. Improvement in the clinical manifestations of psoriasis in patients reflects the effect of methotrexate on rapidly dividing epidermal cells characteristic of this disease. This drug may also be useful in the treatment of rheumatoid arthritis.

Methotrexate is poorly transported across the blood–brain barrier, and neoplastic cells that have entered the CNS probably are not affected by the usual plasma concentrations of the drug. Intrathecal injection is used to treat cerebral involvement with either leukemia or choriocarcinoma.

Acquired resistance to methotrexate develops as a result of (a) impaired transport of methotrexate into cells, (b) production of altered forms of dihydrofolate reductase that have decreased affinity for the drug, and (c) increased concentrations of intracellular dihydrofolate reductase.

Side Effects

The most important side effects of methotrexate occur in the gastrointestinal tract and bone marrow. Leukopenia and thrombocytopenia reflect bone marrow depression. Ulcerative stomatitis and diarrhea are frequent side effects and require interruption of treatment. Hemorrhagic enteritis and death from intestinal perforation may occur. Pulmonary toxicity may take the form of fulminant noncardiogenic pulmonary edema, or a more progressive inflammation, with interstitial infiltrates and pleural effusions.¹⁴ The incidence of pulmonary toxicity attributed to methotrexate is in the range of 8%, but its frequent use in combination with other chemotherapeutic drugs makes this number uncertain.¹⁵ Methotrexate is associated with renal toxicity, with an incidence approaching 10% in higher doses.¹⁶ Renal insufficiency may be prevented by hydration and urinary alkalinization. Short-term or intermittent therapy with methotrexate results in increases in liver transaminase enzymes. Hepatic dysfunction is usually reversible but may sometimes lead to cirrhosis. It may be useful to measure liver function tests preoperatively in patients who have recently received methotrexate. Encephalopathic syndromes may accompany intrathecal or IV administration of methotrexate and may be transient or permanent.¹⁷ Alopecia and dermatitis may accompany administration of methotrexate. Folic acid antagonists also interfere with embryogenesis, emphasizing the risk in administering these drugs to pregnant patients. Normal cells can be protected from lethal damage by folate antagonists with sequential administration of folinic acid (leucovorin), thymidine, or both. This approach has been termed the rescue technique.

Pyrimidine Analogues

Pyrimidine analogues have in common the ability to prevent the biosynthesis of pyrimidine nucleotides or to mimic these natural metabolites to such an extent that they interfere with vital cellular activities such as the synthesis and functioning of nucleic acids. Examples of antimetabolite chemotherapeutic drugs that function as pyrimidine analogues are fluorouracil and cytarabine.

Fluorouracil

Fluorouracil blocks production of thymine nucleotides by inhibiting thymidylate synthase. This chemotherapeutic drug lacks significant inhibitory activity on cells and must be converted enzymatically to a 5′-monophosphate nucleotide. Administration of fluorouracil is usually by IV injection because absorption after oral ingestion is unpredictable and incomplete. Metabolic degradation occurs primarily in the liver, with an important metabolite being urea. Only approximately 10% of fluorouracil appears unchanged in urine. Fluorouracil readily enters the cerebrospinal fluid, with therapeutic concentrations being present within 30 minutes after IV administration.

Clinical Uses

Fluorouracil may be of palliative value in certain types of carcinoma, particularly of the breast and gastrointestinal tract. The drug is often used for the topical treatment of premalignant keratoses of the skin and superficial basal cell carcinomas.

Side Effects

Side effects caused by fluorouracil are difficult to anticipate because of their delayed appearance. Fluorouracil-induced myocardial ischemia is a rare cardiac toxicity that may lead to myocardial infarction up to 1 week after treatment.¹⁸ The incidence of this side effect is low in patients without underlying heart disease but may increase to 4.5% of treated patients with preexisting coronary artery disease. Stomatitis manifesting as a white patchy membrane that ulcerates and becomes necrotic is an early sign of toxicity and warns of the possibility that similar lesions may be developing in the esophagus and gastrointestinal tract. Myelosuppression, most frequently manifesting as leukopenia between 9 and 14 days of therapy, is a serious side effect. Thrombocytopenia and anemia may complicate treatment with fluorouracil. Loss of hair progressing to total alopecia, nail changes, dermatitis, and increased pigmentation and atrophy of the skin may occur. Hand-foot syndrome has also been associated with fluorouracil. Neurologic manifestations, including an acute cerebellar syndrome (ataxia), have been reported.

Capecitabine

Capecitabine is an orally administered drug that is metabolized to fluorouracil by thymidine phosphorylase after absorption from the gastrointestinal tract. Because there is more activity of thymidine phosphorylase in cancer cells (especially breast cancer) than in normal cells, capecitabine has the potential to be more selective than fluorouracil.

Pemetrexed

Pemetrexed is a folate antagonist that is effective in the treatment of mesothelioma and lung cancer. This drug inhibits multiple enzymes involved in the folate pathway, including thymidylate synthase and dihydrofolate reductase.

Cytarabine

Cytarabine (cytosine arabinoside), like other pyrimidine antimetabolites, must be activated by conversion to the 5′-monophosphate nucleotide before inhibition of DNA synthesis can occur. Both natural and acquired resistance to cytarabine develops, reflecting the activity of cytidine deaminase, an enzyme capable of converting cytarabine to the inactive metabolite arabinosyl uracil.

Clinical Uses

In addition to its chemotherapeutic activity, particularly in acute leukemia in children and adults, cytarabine has potent immunosuppressive properties. The drug is particularly useful in chemotherapy of acute granulocytic leukemia in adults. IV administration of cytarabine is recommended because oral absorption is poor and unpredictable.

Side Effects

Cytarabine is a potent myelosuppressive drug capable of producing severe leukopenia, thrombocytopenia, and anemia. Cerebellar toxicity and ataxia can occur at high doses. Other side effects include gastrointestinal disturbances, stomatitis, and hepatic dysfunction. Thrombophlebitis at the site of infusion is common. Alternatively, the drug may be given subcutaneously.

Gemcitabine

Gemcitabine resembles cytarabine structurally yet gemcitabine is active in several nonhematologic cancers, whereas cytarabine is not effective. Gemcitabine is also used in solid organ carcinomas, such as of the pancreas, breast, and lung. This most likely reflects unique effects of this chemotherapeutic drug on DNA and RNA metabolism. Common side effects associated with use of gemcitabine include bone marrow suppression, flulike symptoms, fever, fatigue, mild nausea/vomiting, and diarrhea.

Purine Analogues

Antimetabolite chemotherapeutic drugs that function as purine analogues include mercaptopurine, azathioprine, thioguanine, pentostatin (2′-deoxycoformycin), and cladribine (2-chlorodeoxyadenosine). Mercaptopurine and thioguanine are analogues of the natural purines hypoxanthine and guanine, respectively.

Mercaptopurine

Mercaptopurine is incorporated into DNA or RNA strands and either blocks further strand synthesis or causes structural alterations that damage DNA. This drug is useful in the treatment of acute leukemia in children. Oral absorption is prompt, and gastrointestinal epithelium is not damaged. The elimination half-time is brief (about 90 minutes) due to rapid tissue uptake, renal excretion, and hepatic metabolism. One pathway of metabolism is methylation and subsequent oxidation of the methylated derivatives. A second pathway involves the enzyme xanthine oxidase, which oxidizes mercaptopurine to 6-thiouric acid. Allopurinol, as an inhibitor of xanthine oxidase, prevents conversion of mercaptopurine to 6-thiouric acid and thus increases the exposure of cells to mercaptopurine. The dose of mercaptopurine is decreased by about one-third when the drug is combined with allopurinol.

Side Effects

The principal side effect of mercaptopurine is a gradual development of bone marrow depression manifesting as thrombocytopenia, granulocytopenia, or anemia several weeks after initiation of therapy. Anorexia, nausea, and vomiting are common side effects; stomatitis and diarrhea rarely occur. Jaundice occurs in approximately one-third of patients and is associated with bile stasis and occasional hepatic necrosis. Hyperuricemia and hyperuricosuria may occur during treatment with mercaptopurine, presumably reflecting destruction of cells. This effect may require the use of allopurinol.

Thioguanine

Thioguanine is of particular value in the treatment of acute myelogenous leukemia, especially if given with cytarabine. After oral administration, thioguanine appears in the urine as a methylated metabolite and inorganic sulfate. Minimal amounts of 6-thiouric acid are formed, suggesting that deamination is not important in the metabolic inactivation of thioguanine. For this reason, thioguanine may be administered concurrently with allopurinol without a decrease in dosage, unlike mercaptopurine. Toxic manifestations of thioguanine treatment include bone marrow depression and, occasionally, gastrointestinal effects.

Pentostatin and Cladribine

Pentostatin and cladribine are purine analogues that have clinical activity against a variety of indolent lymphoid tumors, with the most dramatic effects occurring in patients with hairy-cell leukemia.¹⁹ These drugs act by irreversibly binding to adenosine deaminase (pentostatin) or by chemical modification of enzyme substrate, rendering it resistant to the action of adenosine deaminase (cladribine). Patients with acute leukemia and cells with high levels of adenosine deaminase activity are most likely to respond to these drugs. Fever, which is likely due to cytokines, is a side effect of treatment with cladribine. Both drugs are capable of producing immunosuppression. The recovery from immunosuppression seems to be more rapid after treatment with cladribine than after treatment with pentostatin, perhaps because of the shorter duration of administration of the former. Indeed, cladribine is emerging as the treatment of choice for hairy cell leukemia because of its minimal toxicity and its ability to induce a complete and sustained response with a single course of therapy.

Hydroxyurea

Hydroxyurea acts on the enzyme ribonucleoside diphosphate reductase to interfere with the synthesis of DNA. Oral absorption is excellent, and approximately 80% of the drug appears in the urine within 12 hours after oral or IV administration. The primary use of hydroxyurea is in the treatment of chronic myelogenous leukemia. Temporary remissions in patients with metastatic malignant melanoma have been reported.

Side Effects

Myelosuppression manifesting as leukopenia, megaloblastic anemia, and occasionally thrombocytopenia is the major side effect produced by hydroxyurea. Nausea and vomiting may accompany administration of this drug. Hyperpigmentation of the skin, stomatitis, and alopecia occur infrequently.

Topoisomerase Inhibitors

Topoisomerases are enzymes that correct alterations in DNA which occur during replication and transcription. Certain chemotherapeutic drugs inhibit either topoisomerase I or topoisomerase II. Because cancer cells possess more topoisomerase activity than normal cells, there is more drug-induced DNA damage and resultant cell death. Toxicity reflects effects of inhibition of topoisomerase enzymes on normal proliferating tissues (myelosuppression, mucositis). Topoisomerase II inhibitors that include doxorubicin, daunorubicin, etoposide, and teniposide are part of most combination chemotherapy treatment regimens. Topoisomerase I inhibitors include topotecan and irinotecan. These drugs exhibit a broad spectrum of chemotherapeutic activity being useful in the treatment of leukemia and lung, colon, and ovarian cancer.

Doxorubicin and Daunorubicin

Doxorubicin and daunorubicin are anthracycline antibiotics that are natural products of certain soil fungi. Structurally, they contain a tetracycline ring attached to the sugar daunosamine by a glycosidic linkage. These drugs most likely act by binding to DNA, resulting in changes in the DNA helix that interfere with the ability of nucleic acids to serve as a template during replication. These drugs are also a likely cause of disruptive effects on cellular membranes. Drug-induced free radicals may overwhelm the heart’s antioxidant defenses, leading to the oxidation of critical cardiac proteins and membrane components (unsaturated free fatty acids), leading to cardiotoxicity.²⁰ Laboratory studies demonstrate that each subsequent dose of doxorubicin appears to diminish the heart’s ability to withstand subsequent oxidant stress. Evidence that free radicals have a role is the protective effect of free radical scavengers.

Daunorubicin and doxorubicin are administered IV, with care taken to prevent extravasation because local vesicant action may result. There is rapid clearance from the plasma into the heart, kidneys, lungs, and liver. These drugs do not cross the blood–brain barrier to any significant extent. The urine may become red for 1 to 2 days after administration of these drugs.

Daunorubicin is metabolized primarily to daunorubiconol, whereas doxorubicin is excreted unchanged and as metabolites, including adriamycinol in the urine. Ultimately, approximately 40% of daunorubicin and doxorubicin are metabolized. Indeed, clinical toxicity may result in patients with hepatic dysfunction.

Clinical Uses

Daunorubicin is used primarily in the treatment of acute lymphocytic and myelocytic leukemia. Doxorubicin, which differs from daunorubicin only by a single hydroxyl group on the number 14 carbon atom, is also effective against a wide range of solid tumors. For example, doxorubicin is one of the most active single drugs for treating metastatic adenocarcinoma of the breast, carcinoma of the bladder, bronchogenic carcinoma, metastatic thyroid carcinoma, oat cell carcinoma, and osteogenic carcinoma.

Resistance is observed to the anthracycline antibiotics, as with other chemotherapeutic drugs. Furthermore, cross-tolerance occurs between daunorubicin and doxorubicin. Cross-resistance also occurs between these antibiotics and the vinca alkaloids, suggesting that an alteration of cellular permeability may be involved.

Side Effects

Cardiomyopathy and myelosuppression are side effects of the chemotherapeutic antibiotics. Leukopenia typically manifests during the second week of therapy. Thrombocytopenia and anemia occur but are usually less pronounced. Stomatitis, gastrointestinal disturbances, and alopecia are common side effects.

Cardiomyopathy

Cardiomyopathy is a unique dose-related and often irreversible side effect of the anthracycline antibiotics. Increased plasma concentrations of troponin T reflect drug-induced injury to myocardial cells. Congestive heart failure develops in less than 3% of patients with a cumulative dose of doxorubicin of less than 400 mg/m², rising to 18% at 700 mg/m² (Fig. 42-2).²¹ Prior mediastinal radiation or previous treatment with cyclophosphamide increases the subsequent risk of cardiomyopathy in response to administration of an anthracycline antibiotic. Marked impairment of left ventricular function for as long as 3 years after discontinuing doxorubicin has been observed. Previous treatment with anthracycline antibiotics may enhance myocardial depressant effects of anesthetic drugs even in patients with normal resting cardiac function.²² Acute left ventricular failure 2 months after cessation of treatment with doxorubicin has been described during general anesthesia.²³