++
The alkylating agents include nitrogen mustards (cyclophosphamide, mechlorethamine), nitrosoureas
(carmustine, lomustine), and alkylsulfonates
(busulfan). Other drugs that act in part as alkylating agents
include cisplatin, dacarbazine, and procarbazine. The alkylating agents
are CCNS drugs. Some are active as given, whereas others are prodrugs that
are converted to active metabolites in the body. The reactive molecules
covalently bind with one of the four nucleotides in DNA. This binding
(alkylation) usually follows intramolecular cyclization in the
drug, which creates an intermediate that forms a covalent bond with
DNA. When two nucleotides in the double helix DNA are alkylated
by the same drug molecule, the two DNA strands are cross-linked. The resulting cross-linked
DNA cannot be separated and replicated in mitosis, halting cell
division. Alkylating agents may also exert cytotoxic effects by
forming covalent bonds with other cellular constituents such as
proteins. Alkylation of DNA also results in abnormal base pairing
and DNA strand breakage. Several alkylating agents and their acute
and delayed toxicities are listed in Table 31–2. DNA alkylation
probably represents the major interaction that leads to cell death.
Some of the more commonly used alkylating drugs are discussed below.
++
++
Cyclophosphamide is a prodrug that is converted to one or more
highly reactive metabolites by hepatic cytochrome P450 enzymes.
Clinical uses of cyclophosphamide include non-Hodgkin’s lymphoma,
breast and ovarian cancers, and neuroblastoma. One advantage of
the drug is that it can be taken orally. Toxicities observed with
cyclophosphamide include cardiac dysfunction, pulmonary toxicity,
and a syndrome of inappropriate antidiuretic hormone release.
+++
Cisplatin, Carboplatin,
and Oxaliplatin
++
These drugs are rarely used alone in cancer chemotherapy, but
are included as part of a larger drug treatment regimen. Their
mechanism of action is not completely understood, but they are thought
to act like alkylating agents. These drugs are used intravenously.
They distribute to most tissues and are cleared in unchanged form
by the kidney. Cisplatin is commonly used as a component of regimens
for cancers of the testicle, bladder, lung, and ovary. Carboplatin
has similar uses. Oxaliplatin has activity against colorectal cancer.
Their toxicities are listed in Table 31–2. In the case
of cisplatin, drug-induced renal damage may be reduced by the use
of mannitol (an osmotic diuretic) and forced hydration. Carboplatin
and oxaliplatin are less nephrotoxic than cisplatin, but they are
more neurotoxic and have greater myelosuppressant actions.
++
Procarbazine is orally active and penetrates into most tissues,
including the cerebrospinal fluid. The drug is eliminated via hepatic
metabolism. Procarbazine forms hydrogen peroxide, which generates
free radicals that cause DNA strand scission (breaks). The drug
is used as a component of regimens for Hodgkin’s disease
and non-Hodgkin’s lymphomas (common cancers of lymphatic
tissue) and for some brain tumors. Procarbazine has multiple toxicities,
including peripheral neuropathy and skin reactions. Procarbazine
also inhibits many enzymes, including monoamine oxidase and those
involved in hepatic drug metabolism. Disulfiram-like reactions have
occurred with ethanol.
+++
Other Alkylating
Agents
++
Busulfan is sometimes used in chronic
myelogenous leukemia. Carmustine and lomustine are highly lipid-soluble
drugs used as adjuncts in the management of brain tumors. Dacarbazine is used in regimens for
Hodgkin’s disease. Additional toxicities include skin rash,
phototoxicity, and a flu-like syndrome.
++
Antimetabolites used in cancer are structurally similar to endogenous
compounds that are important in rapidly dividing cells. They include
antagonists of folic acid (methotrexate),
purines (mercaptopurine, thioguanine),
and pyrimidines (fluorouracil, cytarabine).
Antimetabolites are CCSdrugs that act primarily in the S phase
of the cell cycle (Figure 31–2). Their sites of action
on DNA synthetic pathways are shown in Figure 31–3. In
addition to cytotoxic effects on neoplastic cells, the antimetabolites
also have immunosuppressant effects (Chapter 32). Commonly used
antimetabolites and delayed toxicities of these drugs are presented
in Table 31–3.
++
++
++
Both oral and intravenous administration of methotrexate afford
good tissue distribution except to the CNS. Methotrexate is not
metabolized, and its clearance is dependent on renal function. Adequate
hydration is needed to prevent crystallization in renal tubules.
Methotrexate acts as an inhibitor of dihydrofolate reductase. This
action decreases synthesis of thymidylate, purine nucleotides, and
several amino acids, thus interfering with nucleic acid and protein
metabolism. The formation of polyglutamate derivatives of methotrexate
appears to be important for cytotoxic actions. Tumor cell resistance
mechanisms include decreased drug accumulation, changes in the activity
of dihydrofolate reductase or its drug sensitivity, and decreased
formation of polyglutamates. Clinically, methotrexate is effective
in choriocarcinoma, acute leukemias, non-Hodgkin’s and
cutaneous T-cell lymphomas, and breast cancer. Methotrexate is also
used as an immune suppressant in rheumatoid arthritis, psoriasis,
and transplant rejection. In combination with mifepristone, it is
an effective abortifacient. The most common toxicities are listed
in Table 31–3. Long-term use of methotrexate has caused
hepatotoxicity and pulmonary infiltrates and fibrosis. Salicylates,
nonsteroidal anti-inflammatory drugs, sulfonamides, and sulfonylureas enhance
the toxicity of methotrexate.
++
Both mercaptopurine (6-MP) and thioguanine (6-TG) have low oral
bioavailability because of first-pass metabolism. Mercaptopurine
and thioguanine act as purine antimetabolites. Both drugs are activated
by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic nucleotides
that inhibit several enzymes involved in purine metabolism. Resistant
tumor cells may have decreased HGPRTase activity, or they may have
increased production of alkaline phosphatases that inactivate the
toxic nucleotides. Clinical uses of these purine antimetabolites
are mainly in the acute leukemias and chronic myelocytic leukemia.
Bone marrow suppression is the dose-limiting toxicity. Hepatic dysfunction
includes cholestasis, jaundice, and necrosis. The metabolism of
6-MP by xanthine oxidase is inhibited by allopurinol, a drug used
in the treatment of gout (Chapter 34).
++
When given intravenously, fluorouracil (5-FU) is widely distributed,
including into the cerebrospinal fluid. Elimination is mainly by
metabolism. Fluorouracil is converted in cells to 5-fluoro-2′-deoxyuridine-5′-monophosphate,
which inhibits thymidylate synthase and leads to “thymineless
death” of cells. Resistance mechanisms include decreased
activation of 5-FU, increased thymidylate synthase activity, and
reduced drug sensitivity of this enzyme. Fluorouracil is used clinically
in bladder, breast, colon, head and neck, liver, and ovarian cancers.
The drug is also used topically for keratoses and superficial basal
cell carcinoma. In addition to the toxicities listed in Table 31–3,
alopecia may occur.
++
Cytabarine (cytosine arabinoside, ARA-C) is used parenterally
and (with slow intravenous infusion) may reach appreciable levels
in the cerebrospinal fluid. Cytarabine is eliminated via hepatic metabolism.
Cytarabine acts as a pyrimidine antimetabolite; it is activated
by kinases to ara-cytidine triphosphate (AraCTP), an inhibitor of
DNA polymerases. Of all the antimetabolites, cytarabine is the most
specific for the S phase of the tumor cell cycle. Resistance to
cytarabine can occur as a result of decreased uptake or decreased
conversion to AraCTP. Clinically, cytarabine is a major drug for
the treatment of acute myelogenous leukemia. Neurotoxicity is associated
with high doses and includes cerebellar dysfunction and peripheral
neuritis.
++
These important CCSdrugs include vinca alkaloids (vinblastine, vincristine), podophyllotoxins
(etoposide, teniposide), camptothecins
(topotecan, irinotecan), and taxanes
(paclitaxel, docetaxel). These drugs
act in S, G2, and M phases of the cell cycle (Figure 31–2).
The acute and delayed toxicities associated with these anticancer
drugs are presented in Table 31–4.
++
++
Vinblastine and vincristine are natural alkaloids, whereas vinorelbine
is semisynthetic. These drugs are given parenterally. They penetrate
most tissues, but not the cerebrospinal fluid, and are cleared mainly
via biliary excretion. These agents block mitotic spindle formation
by preventing the assembly of tubulin dimers into microtubules.
They act primarily in the M phase of the cell cycle. Resistance
can occur from increased drug efflux from tumor cells via overexpression
of membrane drug transporters. Clinically, vincristine is used in
acute leukemias, lymphomas, Wilms’ tumor, and choriocarcinoma.
Vinblastine is used for lymphomas, neuroblastoma, testicular carcinoma,
and Kaposi’s sarcoma. Vinorelbine is used mainly in lung
and breast cancers.
++
Etoposide and teniposide are extracted from the root of the May
apple plant. They are usually used parenterally, but etoposide is
also well absorbed after oral administration and distributes to most
tissues. Elimination is mainly via the kidneys, and dose reductions
should be made in patients with renal impairment. Their mechanisms
of action are similar: they increase DNA degradation (possibly via
interaction with topoisomerase II) and inhibit mitochondrial electron
transport. The drugs are most active in the late S and early G2 phases
of the cell cycle. Clinically, these drugs are used in combination
drug regimens for therapy of lung (small cell), prostate, and testicular
carcinomas. The toxicities of etoposide and teniposide are similar.
++
Topotecan inhibits the activity of topoisomerase I, the key enzyme
responsible for cutting and religating (i.e., joining) single DNA
strands, processes that are essential for normal DNA replication
and repair. Inhibition of topoisomerase I results in DNA damage.
Topotecan is indicated in the treatment of patients with advanced
ovarian cancer and small cell lung cancer. The main route of elimination
is renal excretion, and dosage reduction is required in patients
with abnormal renal function. Irinotecan is a prodrug converted
by the liver into an active metabolite that is also a potent inhibitor
of topoisomerase I. Irinotecan is indicated in metastatic colorectal
cancer. Diarrhea associated with irinotecan therapy can be severe,
leading to significant electrolyte imbalance and dehydration.
++
Although paclitaxel and docetaxel were originally extracted from
the bark of the yew tree, these taxanes are now produced synthetically.
Paclitaxel and docetaxel are given intravenously. The mechanism
of action is interference with the mitotic spindle. In contrast
to vinca alkaloids, taxanes prevent microtubule disassembly into
tubulin monomers. Clinical uses include treatment for several solid
tumors, including advanced breast and ovarian cancers. The toxicities
of these drugs are not identical to each other (Table 31–4).
++
This category of antineoplastic drugs comprises several structurally
dissimilar agents, including doxorubicin,daunorubicin, bleomycin, dactinomycin, and mitomycin. A major mechanism of action
of these antibiotics is binding to DNA through intercalation between
specific bases. This results in blocking synthesis of RNA, DNA,
or both and DNA strand scission, thus interfering with cell replication.
Acute and delayed toxicities associated with these anticancer drugs
are listed in Table 31–5.
++
++
Bleomycin is a mixture of glycopeptides that must be given parenterally.
The drug is inactivated by tissue aminopeptidases, but some renal
clearance of intact drug also occurs. Bleomycin generates free radicals
that bind to DNA, causing strand breaks and inhibiting DNA replication.
Bleomycin is a CCS drug active in the G2 phase of the tumor
cell cycle (Figure 31–2). Clinically, bleomycin is an important
component of drug regimens for Hodgkin’s disease and testicular
cancer. The drug is also used for treatment of non-Hodgkin’s
lymphomas and for squamous cell carcinomas. Pulmonary fibrosis develops slowly,
but is the dose-limiting toxicity. Hypersensitivity manifestations
are common and include chills, fever, and anaphylaxis. Mucocutaneous
reactions are also common and include alopecia, blister formation,
and hyperkeratosis.
+++
Doxorubicin,
Daunorubicin, and Idarubicin
++
Doxorubicin and daunorubicin must be given intravenously. They
are metabolized in the liver, and the products are excreted in the
bile and urine. These anthracyclines have multiple mechanisms of
action, including intercalation between base pairs in DNA, inhibition
of topoisomerase II, and generation of free radicals. As a result,
they block DNA and RNA synthesis and cause DNA strand scission.
Membrane disruption also occurs. The anthracyclines are CCNSdrugs. Clinically,
doxorubicin is used in Hodgkin’s disease, myelomas, sarcomas,
and breast, endometrial, lung, ovarian, and thyroid cancers. The
main use of daunorubicin is in the treatment of acute leukemias.
Idarubicin, a newer anthracycline, is approved for use in acute
myelogenous leukemia. These drugs demonstrate similar toxicities,
including gastrointestinal distress and severe alopecia. Cardiotoxicity
includes initial electrocardiographic abnormalities, with the possibility
of arrhythmias, and a cumulative dose-dependent, slowly developing
cardiomyopathy and congestive heart failure. Dexrazoxane, an inhibitor
of iron-mediated free radical generation, may protect against cardiotoxicity.
Liposomal formulations of doxorubicin
may be less cardiotoxic.
++
Dactinomycin must be given parenterally. Intact drug and metabolites
are excreted in the bile. Dactinomycin is a CCNS drug that binds
to double-stranded DNA and inhibits DNA-dependent RNA synthesis.
Clinically, dactinomycin is used in melanoma and Wilms’ tumor.
++
Mitomycin is given intravenously and is rapidly cleared via hepatic
metabolism. The drug is a CCNS agent that is converted by liver
enzymes to an alkylating agent that cross-links DNA. Mitomycin is
used occasionally in combination regimens for adenocarcinomas of
the cervix, stomach, pancreas, and lung. Myelosuppression is severe,
and the drug is toxic to the heart, liver, lung, and kidney.
+++
Hormonal Anticancer
Agents
++
Many of these drugs are discussed in other chapters and are mentioned
here only in relation to their clinical application in cancer chemotherapy.
The toxicities associated with the hormonally active anticancer
drugs are presented in Table 31–6.
++
+++
Gonadal Hormone
Antagonists
++
Breast cancer and prostate cancer, two common neoplasms, are
usually present in a hormone dependent form. Agents that inhibit
estrogen or progesterone synthesis or the receptors for these ligands
are extremely useful in many patients with breast cancer. Similarly,
antiandrogenic drugs have proven to be useful in men with advanced
prostate cancer.
++
Tamoxifen, a selective estrogen
receptor modulator (Chapter 22), acts as an estrogen antagonist
in estrogen-sensitive breast cancer cells. It is used in estrogen
receptor–positive breast carcinoma. Women with a strong
family history of breast cancer are at high risk for breast cancer.
Because tamoxifen appears to have a preventive effect in women at
high risk for breast cancer, it is now approved as a chemopreventive
agent in this population. Toremifene is
a newer estrogen receptor antagonist that is used in advanced breast
cancer.
++
Flutamide is an androgenreceptor antagonist used in prostatic carcinoma. Bicalutamide and nilutamide are similar in mechanism
and application. These drugs are often used in combination with
the gonadotropin-releasing hormone (GnRH) analogs (see below) to
prevent the initial tumor flare (i.e., short-lived increase in tumor
growth and symptoms) caused by GnRH, and to prevent the action of
androgens produced by extragonadal tissues. For additional information,
see Chapter 22.
+++
Gonadotropin-Releasing
Hormone Analogs
++
Leuprolide, goserelin, andnafarelin are GnRH agonists (Chapter 22) that are effective in advanced prostatic carcinoma. When administered
in constant doses to maintain stable blood levels, they inhibit
release from the pituitary of luteinizing hormone (LH) and follicle-stimulating
hormone (FSH). As a result, androgen production drops to castration
levels and tumor growth may be slowed.
++
Aminoglutethimide, anastrozole, exemestane, and letrozole inhibit
steroid synthesis. Whereas aminoglutethimide inhibits synthesis
of all steroid hormones, the other agents inhibit aromatase, the
enzyme that converts precursor steroids into estrogens. Aromatase
inhibitors are used commonly now in the treatment of estrogen receptor-positive breast
cancer. Aminoglutethimide is used for some cases of metastatic
breast cancer or advanced prostate cancer.
++
Glucocorticoids are useful in the treatment of acute leukemia,
lymphoma, multiple myeloma, and other hematologic malignancies as
well as in advanced breast cancer. Anticancer actions probably involve
multiple mechanisms. In addition, they are effective as supportive
therapy in the management of cancer-related hypercalcemia. Prednisone is the most commonly used
glucocorticoid in cancer chemotherapy. For additional information, see
Chapter 23.
+++
Miscellaneous
Anticancer Agents
++
Additional anticancer drugs not associated with the previous
drug classes are presented below, and their acute and delayed toxicities
are listed in Table 31–7.
++
++
Asparaginase is an enzyme that depletes serum asparagine by hydrolyzing
circulating l-asparagine to aspartic
acid and ammonia. The drug is used in the treatment of T-cell auxotrophic cancers (certain pediatric leukemias
and lymphomas) that require exogenous asparagine for growth. Asparaginase
is given intravenously.
++
Imatinib is an example of a selective anticancer drug whose development
was guided by knowledge of a specific oncogene. Imatinib inhibits
tyrosine kinase activity of the protein product of the BCR-ABL oncogene that is commonly
expressed in chronic myelogenous leukemia (CML). Durable remissions
and apparent cures have occurred in patients treated with this drug.
Resistance may occur because of mutation of the BCR-ABL gene. Imatinib is also effective
for treatment of gastrointestinal stromal tumors that express the
c-kit tyrosine kinase.
+++
Monoclonal Antibodies
++
Trastuzumab is a monoclonal antibody
that binds to a surface growth factorreceptor protein on cells
that overexpress the human epidermal growth factor receptor-2 (HER2) gene in advanced breast cancers.
Binding of trastuzumab to the HER2 receptor causes receptor uptake
into the cell, thereby preventing receptors from being activated
by the circulating ligand. Acute toxicity includes nausea and vomiting,
chills, fevers, and headache. Rituximab is
a monoclonal antibody with high affinity for a surface protein in
non-Hodgkin’s lymphoma cells. The drug is currently used
with conventional anticancer drugs (e.g., cyclophosphamide plus vincristine
plus prednisone) in some types of lymphomas. Use of rituximab is
associated with hypersensitivity reactions and myelosuppression.
++
The interferons are endogenous glycoproteins with antineoplastic,
immunosuppressive, and antiviral actions. Alpha interferons (Chapter 32) are effective against a number of neoplasms, including hairy
cell leukemia, early-stage CML, and T-cell lymphomas. Toxic effects
of the interferons include myelosuppression and neurologic dysfunction.