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Cancer Chemotherapy

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CANCER CHEMOTHERAPY: INTRODUCTION

Cancer chemotherapy remains an intriguing area of pharmacology. On the one hand, use of anticancer drugs
produces high rates of cure of diseases, which, without chemotherapy, result in extremely high mortality rates
(eg, acute lymphocytic leukemia in children, testicular cancer, and Hodgkin's lymphoma). On the other hand,
some types of cancer are barely affected by currently available drugs. Furthermore, as a group, the anticancer
drugs are more toxic than any other pharmaceutic agents, and thus their benefit must be carefully weighed
against their risks. Many of the available drugs are cytotoxic agents that act on all dividing cells, cancerous or
normal. The ultimate goal in cancer chemotherapy is to use advances in cell biology to develop drugs that
selectively target specific cancer cells. A few such agents are in clinical use, and many more are in development.

HIGH-YIELD TERMS TO LEARN

Cell cycle-nonspecific
(CCNS) drug

An anticancer agent that acts on tumor stem cells when they are traversing the
cell cycle and when they are in the resting phase

Cell cycle-specific (CCS)

drug

An anticancer agent that acts selectively on tumor stem cells when they are
traversing the cell cycle and not when they are in the G0 phase

Growth fraction

The proportion of cells in a tumor population that are actively dividing

Myelosuppressant

A drug that suppresses the formation of mature blood cells such as erythrocytes,
leukocytes, and platelets. This effect is also known as "bone marrow suppression"

Oncogene

A mutant form of a normal gene that is found in naturally occurring tumors and
which, when expressed in noncancerous cells, causes them to behave like cancer
cells

CANCER CELL CYCLE KINETICS

Cell Cycle Kinetics
Cancer cell population kinetics and the cancer cell cycle are important determinants of the actions and clinical
uses of anticancer drugs. Some anticancer drugs exert their actions on cells undergoing cycling (cell cyclespecific [CCS] drugs), and others (cell cycle-nonspecific [CCNS] drugs) kill tumor cells in both cycling and resting

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phases of the cell cycle (although cycling cell are more sensitive). CCS drugs are usually most effective when
cells are in a specific phase of the cell cycle (Figure 541). Both types of drugs are particularly effective when a
large proportion of the tumor cells are proliferating (ie, when the growth fraction is high).

FIGURE 541

Phases of the cell cycle that are susceptible to the actions of cell cycle-specific (CCS) drugs. All dividing cellsnormal and
neoplasticmust traverse these cell cycle phases before and during cell division. Tumor cells are usually most responsive
to specific drugs (or drug groups) in the phases indicated. Cell cycle-nonspecific (CCNS) drugs act on tumor cells while
they are actively cycling and while they are in the resting phase (G0).
(Reproduced and modified, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGrawHill, 2009: Fig. 542.)

The Log-Kill Hypothesis

Cytotoxic drugs act with first-order kinetics in a murine model of leukemia. In this model system, in which all the
cells are actively progressing through the cell cycle, a given dose kills a constant proportion of a cell population
rather than a constant number of cells. The log-kill hypothesis proposes that the magnitude of tumor cell kill by
anticancer drugs is a logarithmic function. For example, a 3-log-kill dose of an effective drug reduces a cancer
cell population of 1012 cells to 109 (a total kill of 999 x 109 cells); the same dose would reduce a starting
population of 106 cells to 103 cells (a kill of 999 x 103 cells). In both cases, the dose reduces the numbers of
cells by 3 orders of magnitude, or "3 logs." A key principle that stems from this finding and that is applicable to

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hematologic malignancies is an inverse relationship between tumor cell number and curability (Figure 542).
Mathematical modeling data suggest that most human solid tumors do not grow in such an exponential manner
and rather that the growth fraction of the tumor decreases with time owing to blood supply limitations and other
factors. In drug-sensitive solid tumors, the response to chemotherapy depends on where the tumor is in its
growth curve.

FIGURE 542

Relationship, based on the log-kill hypothesis, of tumor cell number to 3 approaches to drug treatment and to no
treatment (dashed line). In the protocol diagrammed at the top, infrequent treatment (indicated by arrows) prolongs
survival but with recurrence of symptoms between treatments and eventual death. With the regimen diagrammed in the
middle section that is more intensive and begun earlier, cure results after many cycles of therapy. In the treatment
diagrammed near the bottom of the graph, early surgery removes much of the tumor burden, and intensive adjuvant
chemotherapy has been used long enough to produce a cure.
(Reproduced with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig.
541.)

Resistance to Anticancer Drugs

Drug resistance is a major problem in cancer chemotherapy. Mechanisms of resistance include the following:

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INCREASED DNA REPAIR

An increased rate of DNA repair in tumor cells can be responsible for resistance and is particularly important for
alkylating agents and cisplatin.

FORMATION OF TRAPPING AGENTS

Some tumor cells increase their production of thiol trapping agents (eg, glutathione), which interact with
anticancer drugs that form reactive electrophilic species. This mechanism of resistance is seen with the
alkylating agent bleomycin, cisplatin, and the anthracyclines.

CHANGES IN TARGET ENZYMES

Changes in the drug sensitivity of a target enzyme, dihydrofolate reductase, and increased synthesis of the
enzyme are mechanisms of resistance of tumor cells to methotrexate.

DECREASED ACTIVATION OF PRODRUGS

Resistance to the purine antimetabolites (mercaptopurine, thioguanine) and the pyrimidine antimetabolites
(cytarabine, fluorouracil) can result from a decrease in the activity of the tumor cell enzymes needed to convert
these prodrugs to their cytotoxic metabolites.

INACTIVATION OF ANTICANCER DRUGS

Increased activity of enzymes capable of inactivating anticancer drugs is a mechanism of tumor cell resistance to
most of the purine and pyrimidine antimetabolites.

DECREASED DRUG ACCUMULATION

This form of multidrug resistance involves the increased expression of a normal gene (MDR1) for a cell surface
glycoprotein (P-glycoprotein). This transport molecule is involved in the accelerated efflux of many anticancer
drugs in resistant cells.

STRATEGIES IN CANCER CHEMOTHERAPY

Cancer Treatment Modalities
Chemotherapy is used in three main clinical settings:

PRIMARY INDUCTION CHEMOTHERAPY

Drug therapy is administered as the primary treatment for many hematologic cancers and for advanced solid
tumors for which no alternative treatment exists. Although primary induction can be curative in a small number
of patients who present with advanced metastatic disease (eg, lymphoma, acute myelogenous leukemia, germ
cell cancer, choriocarcinoma, and several childhood cancers), in many cases the goals of therapy are palliation of
cancer symptoms, improved quality of life, and increased time to tumor progression.

NEOADJUVANT CHEMOTHERAPY
The use of chemotherapy in patients who present with localized cancer for which alternative local therapy, such
as surgery, exist is known as neoadjuvant chemotherapy. The goal is to render the local therapy more effective.

ADJUVANT CHEMOTHERAPY
In the treatment of many solid tumors, chemotherapy serves as an important adjuvant to local treatment
procedures such as surgery or radiation. The goal is to reduce the risk of local and systemic recurrence and to
improve disease-free and overall survival.

Principles of Combination Therapy

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Chemotherapy with combinations of anticancer drugs usually increases log-kill markedly, and in some cases
synergistic effects are achieved. Combinations are often cytotoxic to a heterogeneous population of cancer cells
and may prevent development of resistant clones. Drug combinations using CCS and CCNS drugs may be
cytotoxic to both dividing and resting cancer cells. The following principles are important for selecting
appropriate drugs to use in combination chemotherapy:
(1) Each drug should be active when used alone against the particular cancer.
(2) The drugs should have different mechanisms of action.
(3) Cross-resistance between drugs should be minimal.
(4) The drugs should have different toxic effects (Table 541).

TABLE 541 Selected examples of cancer chemotherapy.

Diagnosis

Examples of Commonly-Used Anticancer Drugs

Acute lymphocytic leukemia in Prednisone, vincristine, and asparaginase or an anthracycline, plus intrathecal
children
methotrexate
Acute myelogenous leukemia
in adults

Cytarabine and idarubicin or daunorubicin

Breast carcinoma

Cytotoxic agents, hormonal therapy with tamoxifen or an aromatase inhibitor

(eg, anastrozole), trastuzumab

Chronic myelogenous
leukemia

Imatinib, newer tyrosine kinase inhibitors, interferon

Colon carcinoma

Fluorouracil plus leucovorin plus oxaliplatin

Hodgkin's lymphoma

ABVD regimen: doxorubicin (Adriamycin), bleomycin, vincristine, dacarbazine,

and prednisone

Non-Hodgkin's lymphoma

CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone)

plus rituximab

Ovarian carcinoma

Paclitaxel and carboplatin

Pancreatic carcinoma

Gemcitabine and erlotinib

Prostate carcinoma

GnRH agonist (eg, leuprolide) or antagonist (eg, abarelix) and androgen

receptor antagonist (eg, flutamide)

Lung carcinoma

Carboplatin, paclitaxel, and bevacizumab

Testicular carcinoma

PEB regimen: cisplatin (Platinol), etoposide, and bleomycin

GnRH, gonadotropin-releasing hormone.

Rescue Therapy
Toxic effects of anticancer drugs can sometimes be alleviated by rescue strategy. For example, high doses of
methotrexate may be given for 3648 h to cells of the gastrointestinal tract and bone marrow and terminated
before severe toxicity occurs. Leucovorin, a form of tetrahydrofolate that is accumulated more readily by
normal than by neoplastic cells, is then administered. This results in rescue of the normal cells because
leucovorin bypasses the dihydrofolate reductase step in folic acid synthesis.
Mercaptoethanesulfonate ( mesna ) "traps" acrolein released from cyclophosphamide and thus reduces the
incidence of hemorrhagic cystitis. Dexrazoxane inhibits free radical formation and affords protection against the
cardiac toxicity of anthracyclines (eg, doxorubicin).

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ALKYLATING AGENTS
The alkylating agents include nitrogen mustards ( chlorambucil, cyclophosphamide, mechlorethamine ),
nitrosoureas ( carmustine, lomustine ), and alkyl sulfonates ( busulfan ). Other drugs that act in part as
alkylating agents include cisplatin, dacarbazine, and procarbazine.
The alkylating agents are CCNS drugs. They form reactive molecular species that alkylate nucleophilic groups on
DNA bases, particularly the N-7 position of guanine. This leads to cross-linking of bases, abnormal base-pairing,
and DNA strand breakage. Tumor cell resistance to the drugs occurs through increased DNA repair, decreased
drug permeability, and the production of trapping agents such as thiols.

Cyclophosphamide
PHARMACOKINETICS
Hepatic cytochrome P450-mediated biotransformation of cyclophosphamide is needed for antitumor activity. One
of the breakdown products is acrolein.

CLINICAL USE
Uses of cyclophosphamide include leukemia, non-Hodgkin's lymphoma, breast and ovarian cancers, and
neuroblastoma.

TOXICITY
Gastrointestinal distress, myelosuppression, and alopecia are expected adverse effects of cyclophosphamide.
Hemorrhagic cystitis resulting from the formation of acrolein may be decreased by vigorous hydration and by
use of mercaptoethanesulfonate ( mesna ). Cyclophosphamide may also cause cardiac dysfunction, pulmonary
toxicity, and a syndrome of inappropriate antidiuretic hormone (ADH) secretion.

Mechlorethamine
MECHANISM AND PHARMACOKINETICS
Mechlorethamine spontaneously converts in the body to a reactive cytotoxic product.

CLINICAL USE
Mechlorethamine is best known for use in regimens for Hodgkin's and non-Hodgkin's lymphoma.

TOXICITY
Gastrointestinal distress, myelosuppression, alopecia, and sterility are common. Mechlorethamine has marked
vesicant actions.

Platinum Analogs (Cisplatin, Carboplatin, Oxaliplatin)

PHARMACOKINETICS
Cisplatin is used intravenously; the drug distributes to most tissues and is cleared in unchanged form by the
kidney.

CLINICAL USE
Cisplatin is commonly used as a component of regimens for testicular carcinoma and for cancers of the bladder,
lung, and ovary. Carboplatin has similar uses. Oxaliplatin is used in advanced colon cancer.

TOXICITY

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Cisplatin causes gastrointestinal distress and mild hematotoxicity and is neurotoxic (peripheral neuritis and
acoustic nerve damage) and nephrotoxic. Renal damage may be reduced by the use of mannitol with forced
hydration. Carboplatin is less nephrotoxic than cisplatin and is less likely to cause tinnitus and hearing loss, but
it has greater myelosuppressant actions. Oxaliplatin causes dose-limiting neurotoxicity.

Procarbazine
MECHANISMS
Procarbazine is a reactive agent that forms hydrogen peroxide, which generates free radicals that cause DNA
strand scission.

PHARMACOKINETICS
Procarbazine is orally active and penetrates into most tissues, including the cerebrospinal fluid. It is eliminated
via hepatic metabolism.

CLINICAL USE
The primary use of the drug is as a component of regimens for Hodgkin's and non-Hodgkin's lymphoma, and
brain tumors.

TOXICITY
Procarbazine is a myelosuppressant and causes gastrointestinal irritation, CNS dysfunction, peripheral
neuropathy, and skin reactions. Procarbazine inhibits many enzymes, including monoamine oxidase and those
involved in hepatic drug metabolism. Disulfiram-like reactions have occurred with ethanol. The drug is
leukemogenic.

Other Alkylating Agents

Busulfan is sometimes used in chronic myelogenous leukemia. It causes adrenal insufficiency, pulmonary
fibrosis, and skin pigmentation. 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 lymphoma. It causes alopecia,
skin rash, gastrointestinal distress, myelosuppression, phototoxicity, and a flu-like syndrome.

ANTIMETABOLITES
The antimetabolites are structurally similar to endogenous compounds and are antagonists of folic acid
( methotrexate ), purines ( mercaptopurine, thioguanine ), or pyrimidines ( fluorouracil, cytarabine,
gemcitabine ). Antimetabolites are CCS drugs acting primarily in the S phase of the cell cycle. In addition to
their cytotoxic effects on neoplastic cells, the antimetabolites also have immunosuppressant actions (see
Chapters 36, 54, and 55).

Methotrexate
MECHANISMS OF ACTION AND RESISTANCE
Methotrexate is an inhibitor of dihydrofolate reductase. This action leads to a decrease in the synthesis of
thymidylate, purine nucleotides, and amino acids and thus interferes with nucleic acid and protein metabolism
(see Figure 332 for folate-dependent enzymatic reactions). 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 drug sensitivity or activity of dihydrofolate reductase, and
decreased formation of polyglutamates.

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PHARMACOKINETICS
Oral and intravenous administration of methotrexate affords 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.

CLINICAL USE
Methotrexate is effective in choriocarcinoma, acute leukemias, non-Hodgkin's and primary central nervous
system lymphomas, and a number of solid tumors, including breast cancer, head and neck cancer, and bladder
cancer. Methotrexate is used also in rheumatoid arthritis psoriasis (Chapter 36) and ectopic pregnancy.

TOXICITY
Common adverse effects of methotrexate include bone marrow suppression and toxic effects on the skin and
gastrointestinal mucosa (mucositis). The toxic effects of methotrexate on normal cells may be reduced by
administration of folinic acid (leucovorin); this strategy is called leucovorin rescue. Long-term use of
methotrexate has led to hepatotoxicity and to pulmonary infiltrates and fibrosis.

Mercaptopurine (6-MP) and Thioguanine (6-TG)

MECHANISMS OF ACTION AND RESISTANCE
Mercaptopurine and thioguanine are 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 have a decreased activity of HGPRTase, or they may increase their production
of alkaline phosphatases that inactivate the toxic nucleotides.

PHARMACOKINETICS
Mercaptopurine and thioguanine have low oral bioavailability because of first-pass metabolism by hepatic
enzymes. The metabolism of 6-MP by xanthine oxidase is inhibited by the xanthine oxidase inhibitors allopurinol
and febuxostat.

CLINICAL USE
Purine antimetabolites are used mainly in the acute leukemias and chronic myelocytic leukemia.

TOXICITY
Bone marrow suppression is dose limiting, but hepatic dysfunction (cholestasis, jaundice, necrosis) also occurs.

Fluorouracil (5-FU)
MECHANISMS
Fluorouracil is converted in cells to 5-fluoro-2'-deoxyuridine-5'-monophosphate (5-FdUMP), which inhibits
thymidylate synthase and leads to "thymineless death" of cells. Incorporation of FdUMP into DNA inhibits DNA
synthesis and function while incorporation of 5-fluorouridine-5'-triphosphate (FUTP), another 5-FU metabolite,
into RNA interferes with RNA processing and function. Tumor cell resistance mechanisms include decreased
activation of 5-FU, increased thymidylate synthase activity, and reduced drug sensitivity of this enzyme.

PHARMACOKINETICS
When given intravenously, fluorouracil is widely distributed, including into the cerebrospinal fluid. Elimination is
mainly by metabolism.

CLINICAL USE

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Fluorouracil is used in bladder, breast, colon, anal, head and neck, liver, and ovarian cancers. The drug can be
used topically for keratoses and superficial basal cell carcinoma.

TOXICITY
Gastrointestinal distress, myelosuppression, and alopecia are common.

Cytarabine (ARA-C)
MECHANISMS OF ACTION AND RESISTANCE
Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite. The drug is activated by kinases to AraCTP, an
inhibitor of DNA polymerases. Of all the antimetabolites, cytarabine is the most specific for the S phase of the
cell cycle. Resistance to cytarabine can occur as a result of its decreased uptake or its decreased conversion to
AraCTP.

Gemcitabine
MECHANISMS
Gemcitabine is a deoxycytidine analog that is converted into the active diphosphate and triphosphate nucleotide
form. Gemcitabine diphosphate appears to inhibit ribonucleotide reductase and thereby diminish the pool of
deoxyribonucleoside triphosphates required for DNA synthesis. Gemcitabine triphosphate can be incorporated
into DNA, where it causes chain termination.

PHARMACOKINETICS
Elimination is mainly by metabolism.

CLINICAL USE
Gemcitabine was initially approved for pancreatic cancer and now is used widely in the treatment of non-small
cell lung cancer, bladder cancer, and non-Hodgkin's lymphoma.

TOXICITY
Primarily myelosuppression occurs, mainly as neutropenia. Pulmonary toxicity has been observed.

NATURAL PRODUCT ANTICANCER DRUGS

The most important of these plant-derived, CCS drugs are the vinca alkaloids (vinblastine, vincristine,
vinorelbine), the podophyllotoxins (etoposide, teniposide), the camptothecins (topotecan, irinotecan),
the taxanes (paclitaxel, docetaxel).

Vinblastine, Vincristine, and Vinorelbine

MECHANISMS
The vinca alkaloids block the formation of the mitotic spindle by preventing the assembly of tubulin dimers into
microtubules. They act primarily in the M phase of the cancer cell cycle. Resistance can occur from increased
efflux of the drugs from tumor cells via the membrane drug transporter.

PHARMACOKINETICS
These drugs must be given parenterally. They penetrate most tissues except the cerebrospinal fluid. They are
cleared mainly via biliary excretion.

CLINICAL USE
Vincristine is used in acute leukemias, lymphomas, Wilms' tumor, and neuroblastoma. Vinblastine is used for

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lymphomas, neuroblastoma, testicular carcinoma, and Kaposi's sarcoma. Vinorelbine is used in non-small cell
lung cancer and breast cancer.

TOXICITY
Vinblastine and vinorelbine cause gastrointestinal distress, alopecia, and bone marrow suppression. Vincristine
does not cause serious myelosuppression but has neurotoxic actions and may cause areflexia, peripheral
neuritis, and paralytic ileus.

Etoposide and Teniposide

MECHANISMS
Etoposide , a semisynthetic derivative of podophyllotoxin, induces DNA breakage through its inhibition of
topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an
analog with very similar pharmacologic characteristics.

PHARMACOKINETICS
Etoposide is well absorbed after oral administration and distributes to most body tissues. Elimination of
etoposide is mainly via the kidneys, and dose reductions should be made in patients with renal impairment.

CLINICAL USE
These agents are used in combination drug regimens for therapy of lymphoma, and lung, germ cell, and gastric
cancers.

TOXICITY
Etoposide and teniposide are gastrointestinal irritants and cause alopecia and bone marrow suppression.

Topotecan and Irinotecan

MECHANISMS
The 2 camptothecins, topotecan and irinotecan , produce DNA damage by inhibiting topoisomerase I. They
damage DNA by inhibiting an enzyme that cuts and relegates single DNA strands during normal DNA repair
processes.

PHARMACOKINETICS
Irinotecan is a prodrug that is converted in the liver into an active metabolite. Topotecan is eliminated renally,
whereas irinotecan and its metabolite are eliminated in the bile and feces.

CLINICAL USE
Topotecan is used as second-line therapy for advanced ovarian cancer and for small cell lung cancer. Irinotecan
is used for metastatic colorectal cancer.

TOXICITY
Myelosuppression and diarrhea are the 2 most common toxicities.

Paclitaxel and Docetaxel

MECHANISMS
Paclitaxel and docetaxel interfere with the mitotic spindle. They act differently from vinca alkaloids, since they
prevent microtubule disassembly into tubulin monomers.

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PHARMACOKINETICS
Paclitaxel and docetaxel are given intravenously.

CLINICAL USE
The taxanes have activity in a number of solid tumors, including breast, ovarian, lung, gastroesophageal,
prostate, bladder, and head and neck cancers.

TOXICITY
Paclitaxel causes neutropenia, thrombocytopenia, a high incidence of peripheral neuropathy, and possible
hypersensitivity reactions during infusion. Docetaxel causes neurotoxicity and bone marrow depression.

ANTITUMOR ANTIBIOTICS
This category of antineoplastic drugs is made up of several structurally dissimilar microbial products and includes
the anthracyclines, bleomycin, and mitomycin.

Anthracyclines
MECHANISMS
The anthracyclines ( doxorubicin , daunorubicin, idarubicin , epirubicin , mitoxantrone ) intercalate
between base pairs, inhibit topoisomerase II, and generate free radicals. They block the synthesis of RNA and
DNA and cause DNA strand scission. Membrane disruption also occurs. Anthracyclines are CCNS drugs.

PHARMACOKINETICS
Doxorubicin and daunorubicin must be given intravenously. They are metabolized in the liver, and the products
are excreted in the bile and the urine.

CLINICAL USE
Doxorubicin is used in Hodgkin's and non-Hodgkin's lymphoma, myelomas, sarcomas, and breast, 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. Epirubicin is used in breast cancer and
gastroesophageal cancer. Mitoxantrone is used in acute myeloid leukemias, non-Hodgkin's lymphoma, breast
cancer, and gastroesophageal cancer.

TOXICITY
These drugs cause bone marrow suppression, gastrointestinal distress, and severe alopecia. Their most
distinctive adverse effect is cardiotoxicity, which includes initial electrocardiographic abnormalities (with the
possibility of arrhythmias) and slowly developing, dose-dependent cardiomyopathy and congestive heart failure.
Dexrazoxane, an inhibitor of iron-mediated free radical generation, may protect against the dose-dependent
form of cardiotoxicity. Liposomal formulations of doxorubicin may be less cardiotoxic.

Bleomycin
MECHANISMS
Bleomycin is a mixture of glycopeptides that generates free radicals, which bind to DNA, cause strand breaks,
and inhibit DNA synthesis. Bleomycin is a CCS drug active in the G2 phase of the tumor cell cycle.

PHARMACOKINETICS
Bleomycin must be given parenterally. It is inactivated by tissue aminopeptidases, but some renal clearance of
intact drug also occurs.

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CLINICAL USE
Bleomycin is a component of drug regimens for Hodgkin's lymphoma and testicular cancer. It is also used for
treatment of lymphomas and for squamous cell carcinomas.

TOXICITY
The toxicity profile of bleomycin includes pulmonary dysfunction (pneumonitis, fibrosis), which develops slowly
and is dose limiting. Hypersensitivity reactions (chills, fever, anaphylaxis) are common, as are mucocutaneous
reactions (alopecia, blister formation, hyperkeratosis).

Mitomycin
MECHANISMS AND PHARMACOKINETICS
Mitomycin is a CCNS drug that is metabolized by liver enzymes to form an alkylating agent that cross-links DNA.
Mitomycin is given intravenously and is rapidly cleared via hepatic metabolism.

CLINICAL USE
Mitomycin acts against hypoxic tumor cells and is used in combination regimens for adenocarcinomas of the
cervix, stomach, pancreas, and lung.

TOXICITY
Mitomycin causes severe myelosuppression and is toxic to the heart, liver, lung, and kidney.

MISCELLANEOUS ANTICANCER AGENTS

Tyrosine Kinase Inhibitors
Imatinib is an example of a selective anticancer drug whose development was guided by knowledge of a
specific oncogene. It inhibits the tyrosine kinase activity of the protein product of the bcr-abl oncogene that is
commonly expressed in chronic myelogenous leukemia (CML). In addition to its activity in CML, imatinib is
effective for treatment of gastrointestinal stromal tumors that express the c-kit tyrosine kinase, which is also
inhibited. Resistance may occur from mutation of the bcr-abl gene. Toxicity of imatinib includes diarrhea,
myalgia, fluid retention, and congestive heart failure. Dasatinib and nilotinib are newer anticancer kinase
inhibitors.

Growth Factor Receptor Inhibitors

Trastuzumab , a monoclonal antibody, recognizes a surface protein in breast cancer cells that overexpress the
HER-2/neu receptor for epidermal growth factor. Acute toxicity of this antibody includes nausea and vomiting,
chills, fevers, and headache. Trastuzumab may cause cardiac dysfunction, including congestive heart failure.
Several drugs inhibit the epidermal growth factor receptor (EGFR), which is distinct from the HER-2/neu receptor
for epidermal growth factor that is targeted by trastuzumab. The EGFR regulates signaling pathways involved in
cellular proliferation, invasion and metastasis, and angiogenesis. It is also implicated in inhibiting the cytotoxic
activity of some anticancer drugs and radiation therapy. Cetuximab is a chimeric monoclonal antibody directed
to the extracellular domain of the EGFR. It is used in combination with irinotecan and oxaliplatin for metastatic
colon cancer and is used in combination with radiation for head and neck cancer. Its primary toxicity is skin rash
and a hypersensitivity infusion reaction. Panitumumab is a fully human monoclonal antibody directed against
the EGFR; it is approved for refractory metastatic colorectal cancer. Gefitinib and erlotinib are small molecule
inhibitors of the EGFR's tyrosine kinase domain. Both are used as second-line agents for non-small cell lung

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cancer, and erlotinib is also used in combination therapy of advanced pancreatic cancer. Rash and diarrhea are
the main toxicities.
Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and
prevents it from interacting with VEGF receptors. VEGF plays a critical role in the angiogenesis required for
tumor metastasis. Bevacizumab has activity in colorectal, breast, non-small cell lung, and renal cancer. Adverse
effects include hypertension, infusion reactions, arterial thrombosis, impaired wound healing, gastrointestinal
perforation, and proteinuria.

Rituximab
Rituximab is a monoclonal antibody that binds to a surface protein in non-Hodgkin's lymphoma cells and
induces complement-mediated lysis, direct cytotoxicity, and induction of apoptosis. It is currently used with
conventional anticancer drugs (eg, cyclophosphamide plus vincristine plus prednisone) in low-grade lymphomas.
Rituximab is associated with hypersensitivity reactions and myelosuppression.

Interferons
The interferons are endogenous glycoproteins with antineoplastic, immunosuppressive, and antiviral actions.
Alpha-interferons (see Chapter 55) are effective against a number of neoplasms, including hairy cell leukemia,
the early stage of chronic myelogenous leukemia, and T-cell lymphomas. Toxic effects of the interferons include
myelosuppression and neurologic dysfunction.

Asparaginase
Asparaginase is an enzyme that depletes serum asparagine; it is used in the treatment of T-cell auxotrophic
cancers (leukemia and lymphomas) that require exogenous asparagine for growth. Asparaginase is given
intravenously and may cause severe hypersensitivity reactions, acute pancreatitis, and bleeding.

HORMONAL ANTICANCER AGENTS

Glucocorticoids
Prednisone is the most commonly used glucocorticoid in cancer chemotherapy and is widely used in
combination therapy for leukemias and lymphomas. Toxicity is described in Chapter 39.

Gonadal Hormone Antagonists

Tamoxifen, a selective estrogen receptor modulator (see Chapter 40), blocks the binding of estrogen to
receptors of estrogen-sensitive cancer cells in breast tissue. The drug is used in receptor-positive breast
carcinoma and has been shown to have a preventive effect in women at high risk for breast cancer. Because it
has agonist activity in the endometrium, tamoxifen increases the risk of endometrial hyperplasia and neoplasia.
Other adverse effects include nausea and vomiting, hot flushes, vaginal bleeding, and venous thrombosis.
Toremifene is a newer estrogen receptor antagonist used in advanced breast cancer. Flutamide is an
androgen receptor antagonist used in prostatic carcinoma (see Chapter 40). Adverse effects include
gynecomastia, hot flushes, and hepatic dysfunction.

Gonadotropin-Releasing Hormone (GnRH) Analogs

Leuprolide, goserelin, and nafarelin are GnRH agonists, effective in prostatic carcinoma. When administered
in constant doses so as to maintain stable blood levels, they inhibit release of pituitary luteinizing hormone (LH)
and follicle-stimulating hormone (FSH). Leuprolide may cause bone pain, gynecomastia, hematuria, impotence,

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and testicular atrophy (see Chapters 37 and 40).

Aromatase Inhibitors
Anastrozole and letrozole inhibit aromatase, the enzyme that catalyzes the conversion of androstenedione (an
androgenic precursor) to estrone (an estrogenic hormone). Both drugs are used in advanced breast cancer.
Toxicity includes nausea, diarrhea, hot flushes, bone and back pain, dyspnea, and peripheral edema.

SKILL KEEPER: MANAGEMENT OF ANTICANCER DRUG

HEMATOTOXICITY
(See Chapter 33)
Bone marrow suppression is a characteristic toxicity of most cytotoxic anticancer drugs. What agents are
available for the treatment of anemia and neutropenia, and for platelet restoration in patients undergoing cancer
chemotherapy? The Skill Keeper Answer appears at the end of the chapter.

SKILL KEEPER ANSWER: MANAGEMENT OF ANTICANCER DRUG

HEMATOTOXICITY
(See Chapter 33)
Recombinant DNA technology has provided several agents that have value in the management of hematotoxicity
caused by anticancer drugs. Erythropoietin stimulates red cell formation by interaction with receptors on
erythroid progenitors in bone marrow. Myeloid growth factors filgrastim (G-CSF) and sargramostim (GM-CSF)
stimulate the production and function of neutrophils. Megakaryocyte growth factor oprelvekin (IL-11) stimulates
the growth of platelet progenitors.

CHECKLIST
When you complete this chapter, you should be able to:
Name 3 anticancer drugs that are cell cycle-specific and act at different phases of the cell cycle.
Describe the relevance of cell cycle kinetics to the modes of action and clinical uses of anticancer drugs.
List the mechanisms by which tumor cells develop drug resistance.
Describe the rationale underlying strategies of combination drug chemotherapy and rescue therapies.
Identify the major subclasses of anticancer drugs and describe the mechanisms of action of the main drugs in
each subclass.
Identify a distinctive "characteristic" toxicity for each of the following anticancer drugs: bleomycin, cisplatin,
cyclophosphamide, doxorubicin, and vincristine.

DRUG SUMMARY TABLE: CANCER CHEMOTHERAPY DRUGS

Subclass

Mechanism of
Action

Clinical Applications Acute Toxicities Chronic Toxicities

Alkylating agents
Cyclophosphamide Forms DNA crosslinks, resulting in
inhibition of DNA
synthesis and
function

Breast cancer, ovarian Nausea and

cancer, non-Hodgkin's vomiting
lymphoma, chronic
lymphocytic leukemia,
neuroblastoma

Myelosuppression,
alopecia, hemorrhagic
cystitis

Other major alkylating agents: Mechlorethamine, procarbazine, busulfan carmustine, lomustine, dacarbazine
Platinum analogs: Cisplatin, carboplatin, oxaliplatin
Antimetabolites

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Methotrexate

Inhibits DHFR,
resulting in inhibition
of synthesis of
thymidylate, purine
nucleotides, serine,
and methionine

Breast cancer, head

and neck cancer,
primary CNS
lymphoma, nonHodgkin's lymphoma,
bladder cancer,
choriocarcinoma

Mucositis,
diarrhea

Myelosuppression

6-Mercaptopurine

Inhibits de novo
purine synthesis

Acute myelogenous
leukemia

Nausea and
vomiting

Myelosuppression,
immunosuppression,
hepatotoxicity

5-Fluorouracil

Inhibits thymidylate
synthase, and its
metabolites are
incorporated into
RNA and DNA, all
resulting in inhibition
of DNA synthesis and
function and in RNA
processing

GI cancers, breast
Nausea,
cancer, head and neck mucositis,
cancer, hepatocellular diarrhea
cancer

Myelosuppression,
neurotoxicity

Other antimetabolites: Cytarabine, gemcitabine

Vinca alkaloids
Vincristine

Interferes with
microtubule function,
resulting in impaired
mitosis

Acute lymphocytic
None
leukemia, Hodgkin's
and non-Hodgkin's
lymphoma, Wilms'
tumor, neuroblastoma

Neurotoxicity with
peripheral neuropathy,
paralytic ileus,
myelosuppression,
alopecia, inappropriate
ADH secretion

Other vinca alkaloids: Vinblastine, vinorelbine

Podophyllotoxins
Etoposide

Inhibits
topoisomerase II,
resulting in DNA
damage

Lung cancer, nonHodgkin's lymphoma,

gastric cancer

Nausea, vomiting Alopecia,

myelosuppression

Other podophyllotoxins: Teniposide

Camptothecins
Topotecan

Inhibits
topoisomerase I,
resulting in DNA
damage

Small cell lung cancer, Nausea,

ovarian cancer
vomiting,
diarrhea

Myelosuppression

Breast, lung, ovarian,

gastroesophageal,
prostate, bladder, and
head and neck cancers

Nausea,
vomiting,
hypotension,
arrhythmias,
hypersensitivity

Myelosuppression,
peripheral sensory
neuropathy

Lymphomas,

Nausea,

Alopecia,

Other camptothecins: Irinotecan

Taxanes
Paclitaxel

Interferes with
microtubule function,
resulting in impaired
mitosis

Other taxanes: Docetaxel

Anthracyclines
Doxorubicin

Oxygen free radicals

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bind to DNA causing

strand breakage;
inhibits
topoisomerase II;
intercalates into DNA

myelomas, sarcomas,
and breast, lung,
ovarian and thyroid
cancers

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arrhythmias

myelosuppression,
cardiomyopathy,
myelosuppression

Other anthracyclines: Daunorubicin, idarubicin, epirubicin, mitoxantrone

Other antitumor antibiotics: Bleomycin, mitomycin
Tyrosine kinase inhibitors
Imatinib

Inhibits bcrabl tyrosine kinase

and other receptor
tyrosine kinases

Chronic myelogenous
leukemia,
gastrointestinal
stromal tumor

Nausea, vomiting Fluid retention with

ankle and periorbital
edema, diarrhea,
myalgias, congestive
heart failure

Other tyrosine kinase inhibitors: Dasatinib, nilotinib

Growth factor receptor inhibitors
Trastuzumab

Inhibits the binding

of EGF to the HER2/neu growth
receptor

HER-2/neu receptor +
breast cancer

Nausea,
vomiting, chills,
fever, headache

Cardiac dysfunction

Other growth factor receptor inhibitors: Cetuximab, panitumumab, gefitinib, erlotinib

Vascular endothelial growth factor (VEGF) inhibitors
Bevacizumab

Inhibits binding of
Colorectal, breast,
VEGF to its receptor, non-small cell lung,
resulting in inhibition and renal cancer
of tumor
vascularization

Hypertensin,
infusion reaction

Arterial thromboembolic
events, gastrointestinal
perforations, wound
healing complications,
proteinuria

Hormone agonists
Prednisone

See Chapter 39

Hormone antagonists
Tamoxifen

See Chapter 40

Other hormonal antagonists: Aromatase inhibitors, GnRH agonist and antagonists, androgen receptor
antagonists (see Chapter 40)
DHFR, dihydrofolate reductase; EGF, epidermal growth factor; GnRH, gonadotropin-releasing hormone; VEGF,
vascular endothelial growth factor.
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