Lippincott Chapter 46: Anticancer Drugs Flashcards
ANTIMETABOLITES
Azacitidine VIDAZA
Capecitabine XELODA
Cladribine LEUSTATIN
Cytarabine CYTOSINE ARABINOSIDE (ARA-C)
Fludarabine FLUDARA
5-Fluorouracil ADRUCIL
Gemcitabine GEMZAR
6-Mercaptopurine PURINETHOL
Methotrexate (MTX) TREXALL
Pemetrexed ALIMTA
Pralatrexate FOLOTYN
ANTIBIOTICS
Bleomycin BLENOXANE
Daunorubicin CERUBIDINE
Doxorubicin ADRIAMYCIN
Epirubicin ELLENCE
Idarubicin IDAMYCIN
Mitoxantrone
ALKYLATING AGENTS
Busulfan MYLERAN
Carmustine BICNU
Chlorambucil LEUKERAN
Cyclophosphamide CYTOXAN
Dacarbazine DTIC-DOME
Ifosfamide IFEX
Lomustine CEENU
Melphalan ALKERAN
Temozolomide TEMODAR
MICROTUBULE INHIBITORS
Docetaxel TAXOTERE
Paclitaxel TAXOL
Vinblastine
Vincristine VINCASAR PFS
Vinorelbine NAVELBINE
STEROID HORMONES AND THEIR
ANTAGONISTS
Anastrozole ARIMIDEX
Bicalutamide CASODEX
Estrogens VARIOUS
Exemestane AROMASIN
Flutamide
Goserelin ZOLADEX
Letrozole FEMARA
Leuprolide LUPRON
Megestrol acetate MEGACE
Nilutamide NILANDRON
Prednisone
Tamoxifen
Triptorelin TRELSTAR
Raloxifene
Fulvestrant FASLODEX
MONOCLONAL ANTIBODIES
Bevacizumab AVASTIN
Cetuximab ERBITUX
Rituximab RITUXAN
Trastuzumab HERCEPTIN
TYROSINE KINASE INHIBITORS
Dasatinib
TARCEVA
Imatinib GLEEVEC
Nilotinib TASIGNA
Sorafenib NEXAVAR
Erlotinib
Sunitinib
SPRYCEL
SUTENT
OTHERS
Abiraterone ZYTIGA
Carboplatin
Cisplatin PLATINOL
Enzalutamide XTANDI
Interferons PEG-INTRON
Irinotecan CAMPTOSAR
Oxaliplatin ELOXATIN
Procarbazine MATULANE
Topotecan HYCAMTIN
Asparaginase ERWINAZE
Etoposide TOPOSAR, VEPESID
ANTIMETABOLITES
Methotrexate, pemetrexed, and pralatrexate
Antimetabolites are structurally related to normal compounds that exist
within the cell (Figure 46.8). They generally interfere with the availability
of normal purine or pyrimidine nucleotide precursors, either by inhibit-
ing their synthesis or by competing with them in DNA or RNA synthesis.
Their maximal cytotoxic effects are in S-phase and are, therefore, cell
cycle specific.
A. Methotrexate, pemetrexed, and pralatrexate
The vitamin folic acid plays a central role in a variety of metabolic
reactions involving the transfer of one-carbon units and is essential
for cell replication. Folic acid is obtained mainly from dietary sources
and from that produced by intestinal flora. Methotrexate [meth-oh-
TREK-sate] (MTX), pemetrexed [pem-e-TREX-ed], and pralatrexate
[pral-a-TREX-ate] are antifolate agents.
1. Mechanism of action: MTX is structurally related to folic acid and
acts as an antagonist of the vitamin by inhibiting mammalian dihy-
drofolate reductase (DHFR), the enzyme that converts folic acid to
its active, coenzyme form, tetrahydrofolic acid (FH4
) (Figure 46.9).
The inhibition of DHFR can only be reversed by a 1000-fold excess
of the natural substrate, dihydrofolate (FH2
), or by administration of
leucovorin, which bypasses the blocked enzyme and replenishes
the folate pool (Figure 46.9). [Note: Leucovorin, or folinic acid, is
the N5
-formyl group–carrying form of FH4
.] MTX is specific for the
S-phase of the cell cycle. Pemetrexed is an antimetabolite similar
in mechanism to methotrexate. However, in addition to inhibiting
DHFR, it also inhibits thymidylate synthase and other enzymes
involved in folate metabolism and DNA synthesis. Pralatrexate is a
newer antimetabolite that also inhibits DHFR.
- Therapeutic uses: MTX, usually in combination with other drugs,
is effective against acute lymphocytic leukemia, Burkitt lymphoma
in children, breast cancer, bladder cancer, and head and neck car-
cinomas. In addition, low-dose MTX is effective as a single agent
against certain inflammatory diseases, such as severe psoriasis
and rheumatoid arthritis, as well as Crohn disease. All patients
receiving MTX require close monitoring for possible toxic effects.
Pemetrexed is primarily used in non–small cell lung cancer.
Pralatrexate is used in relapsed or refractory T-cell lymphoma. - Resistance: Nonproliferating cells are resistant to MTX, probably
because of a relative lack of DHFR, thymidylate synthase, and/
or the glutamylating enzyme. Decreased levels of the MTX
polyglutamate have been reported in resistant cells and may be due
to its decreased formation or increased breakdown. Resistance in
neoplastic cells can be due to amplification (production of additional
copies) of the gene that codes for DHFR, resulting in increased
levels of this enzyme. The enzyme affinity for MTX may also be
diminished. Resistance can also occur from a reduced influx of MTX, apparently caused by a change in the carrier-mediated
transport responsible for pumping the drug into the cell. - Pharmacokinetics: MTX is variably absorbed at low doses from
the GI tract, but it can also be administered by intramuscular, intra-
venous (IV), and intrathecal routes (Figure 46.10). Because MTX
does not easily penetrate the blood–brain barrier, it can be adminis-
tered intrathecally to destroy neoplastic cells that are thriving in the
sanctuary of the CNS. High concentrations of the drug are found
in the intestinal epithelium, liver, and kidney, as well as in asci-
tes and pleural effusions. MTX is also distributed to the skin. High
doses of MTX undergo hydroxylation at the 7 position and become
7-hydroxymethotrexate. This derivative is much less active as an
antimetabolite. It is less water soluble than MTX and may lead to
crystalluria. Therefore, it is important to keep the urine alkaline and
the patient well hydrated to avoid renal toxicity. Excretion of the
parent drug and the 7-OH metabolite occurs primarily via urine,
although some of the drug and its metabolite appear in feces due
to enterohepatic excretion. - Adverse effects: Adverse effects of MTX are outlined in Figure
46.8. Pemetrexed should be given with folic acid and vitamin B12
supplements to reduce hematologic and GI toxicities. It is also rec-
ommended to pretreat with corticosteroids to prevent cutaneous
reactions. One of the more common side effects of pralatrexate is
mucositis. Doses must be adjusted or withheld based on the sever-
ity of mucositis. Pralatrexate also requires supplementation with
folic acid and vitamin B12.
6-Mercaptopurine
6-Mercaptopurine [mer-kap-toe-PYOOR-een] (6-MP) is the thiol ana-
log of hypoxanthine. 6-MP and 6-thioguanine were the first purine
analogs to prove beneficial for treating neoplastic disease. [Note:
Azathioprine, an immunosuppressant, exerts its cytotoxic effects after
conversion to 6-MP.] 6-MP is used principally in the maintenance of
remission in acute lymphoblastic leukemia. 6-MP and its analog, aza-
thioprine, are also beneficial in the treatment of Crohn disease.
1. Mechanism of action:
a. Nucleotide formation: To exert its antileukemic effect, 6-MP
must penetrate target cells and be converted to the nucleotide
analog, 6-MP-ribose phosphate (better known as 6-thioinosinic
acid or TIMP; Figure 46.11). The addition of the ribose phosphate
is catalyzed by the salvage pathway enzyme, hypoxanthine–
guanine phosphoribosyltransferase (HGPRT).
b. Inhibition of purine synthesis: A number of metabolic pro-
cesses involving purine biosynthesis and interconversions are
affected by the nucleotide analog, TIMP. Similar to nucleotide
monophosphates, TIMP can inhibit the first step of de novo
purine ring biosynthesis (catalyzed by glutamine phosphoribo-
syl pyrophosphate amidotransferase). TIMP also blocks the for-
mation of adenosine monophosphate and xanthinuric acid from
inosinic acid.
c. Incorporation into nucleic acids: TIMP is converted to thio-
guanine monophosphate, which after phosphorylation to di- and
triphosphates can be incorporated into RNA. The deoxyribo-
nucleotide analogs that are also formed are incorporated into
DNA. This results in nonfunctional RNA and DNA.
2. Resistance: Resistance is associated with 1) an inability to
biotransform 6-MP to the corresponding nucleotide because of
decreased levels of HGPRT, 2) increased dephosphorylation,
or 3) increased metabolism of the drug to thiouric acid or other
metabolites.
3. Pharmacokinetics: Oral absorption is erratic and incomplete.
Once it enters the blood circulation, the drug is widely distributed
throughout the body, except for the cerebrospinal fluid (CSF). The
bioavailability of 6-MP can be reduced by first-pass metabolism in
the liver. 6-MP is converted in the liver to the 6-methylmercapto-
purine derivative or to thiouric acid (an inactive metabolite). [Note:
The latter reaction is catalyzed by xanthine oxidase.] The parent
drug and its metabolites are excreted by the kidney.
Fludarabine
Fludarabine [floo-DARE-a-been] is the 5′-phosphate of 2-fluoro-
adenine arabinoside, a purine nucleotide analog. It is useful in the
treatment of chronic lymphocytic leukemia, hairy cell leukemia, and
indolent non-Hodgkin lymphoma. Fludarabine is a prodrug, the phos-
phate being removed in the plasma to form 2-F-araA, which is taken up
into cells and again phosphorylated (initially by deoxycytidine kinase).
Although the exact cytotoxic mechanism is uncertain, the triphosphate
is incorporated into both DNA and RNA. This decreases their synthe-
sis in the S-phase and affects their function. Resistance is associ-
ated with reduced uptake into cells, lack of deoxycytidine kinase, and
decreased affinity for DNA polymerase, as well as other mechanisms.
Fludarabine is administered IV rather than orally, because intestinal
bacteria split off the sugar to yield the very toxic metabolite, fluoroad-
enine. Urinary excretion accounts for partial elimination.
Cladribine
Another purine analog, 2-chlorodeoxyadenosine or cladribine [KLA-
dri-been], undergoes reactions similar to those of fludarabine, and it
must be phosphorylated to a nucleotide to be cytotoxic. It becomes
incorporated at the 3′-terminus of DNA and, thus, hinders elonga-
tion. It also affects DNA repair and is a potent inhibitor of ribonucleo-
tide reductase. Resistance may be due to mechanisms analogous
to those that affect fludarabine, although cross-resistance is not
observed. Cladribine is effective against hairy cell leukemia, chronic
lymphocytic leukemia, and non-Hodgkin lymphoma. The drug is given
as a single, continuous infusion. Cladribine distributes throughout the
body, including into the CSF.
5-Fluorouracil
5-Fluorouracil
5-Fluorouracil [flure-oh-YOOR-ah-sil] (5-FU ), a pyrimidine analog, has
a stable fluorine atom in place of a hydrogen atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic
acid to thymidylic acid, thus depriving the cell of thymidine, one of the
essential precursors for DNA synthesis. 5-FU is employed primarily in
the treatment of slowly growing solid tumors (for example, colorectal,
breast, ovarian, pancreatic, and gastric carcinomas). When applied
topically, 5-FU is also effective for the treatment of superficial basal
cell carcinomas.
1. Mechanism of action: 5-FU itself is devoid of antineoplastic
activity. It enters the cell through a carrier-mediated transport
system and is converted to the corresponding deoxynucleotide
(5-fluorodeoxyuridine monophosphate [5-FdUMP]; Figure 46.12),
which competes with deoxyuridine monophosphate for thymidylate
synthase, thus inhibiting its action. DNA synthesis decreases
due to lack of thymidine, leading to imbalanced cell growth and
“thymidine-less death” of rapidly dividing cells. [Note: Leucovorin
is administered with 5-FU, because the reduced folate coenzyme
is required in the thymidylate synthase inhibition. For example,
a standard regimen for advanced colorectal cancer is irinotecan
plus 5-FU/leucovorin.] 5-FU is also incorporated into RNA, and
low levels have been detected in DNA. In the latter case, a glyco-
sylase excises the 5-FU, damaging the DNA. 5-FU produces the
anticancer effect in the S-phase of the cell cycle.
2. Resistance: Resistance is encountered when the cells have
lost their ability to convert 5-FU into its active form (5-FdUMP)
or when they have altered or increased thymidylate synthase
levels.
3. Pharmacokinetics: Because of its severe toxicity to the GI tract,
5-FU is given IV or, in the case of skin cancer, topically. The drug
penetrates well into all tissues, including the CNS. 5-FU is rapidly
metabolized in the liver, lung, and kidney. It is eventually con-
verted to fluoro-β-alanine, which is removed in the urine. The dose
of 5-FU must be adjusted in impaired hepatic function. Elevated
levels of dihydropyrimidine dehydrogenase (DPD) can increase
the rate of 5-FU catabolism and decrease its bioavailability. The
DPD level varies from individual to individual and may differ by
as much as sixfold in the general population. Patients with DPD
deficiency may experience severe toxicity manifested by pancy-
topenia, mucositis, and life-threatening diarrhea. Knowledge of
an individual’s DPD activity should allow more appropriate dosing
of 5-FU.
Capecitabine
Capecitabine [cape-SITE-a-been] is a novel, oral fluoropyrimidine car-
bamate. It is used in the treatment of colorectal and metastatic breast
cancer. After being absorbed, capecitabine, which is itself nontoxic,
undergoes a series of enzymatic reactions, the last of which is hydro-
lysis to 5-FU. This step is catalyzed by thymidine phosphorylase, an
enzyme that is concentrated primarily in tumors (Figure 46.13). Thus,
the cytotoxic activity of capecitabine is the same as that of 5-FU and
is tumor specific. The most important enzyme inhibited by 5-FU (and,
thus, capecitabine) is thymidylate synthase. Capecitabine is well
absorbed following oral administration. It is extensively metabolized to 5-FU and is eventually biotransformed into fluoro-β-alanine.
Metabolites are primarily eliminated in the urine.
Cytarabine
Cytarabine
Cytarabine [sye-TARE-ah-been] (cytosine arabinoside or ara-C) is
an analog of 2′-deoxycytidine in which the natural ribose residue is
replaced by d-arabinose. Cytarabine acts as a pyrimidine antago-
nist. The major clinical use of cytarabine is in acute nonlymphocytic
(myelogenous) leukemia (AML). Cytarabine enters the cell by a
carrier-mediated process and, like the other purine and pyrimidine
antagonists, must be sequentially phosphorylated by deoxycytidine
kinase and other nucleotide kinases to the nucleotide form (cyto-
sine arabinoside triphosphate or ara-CTP) to be cytotoxic. Ara-CTP
is an effective inhibitor of DNA polymerase. The nucleotide is also
incorporated into nuclear DNA and can terminate chain elongation.
It is, therefore, S-phase (and, hence, cell cycle) specific.
1. Resistance: Resistance to cytarabine may result from a defect
in the transport process, a change in activity of phosphorylating
enzymes (especially deoxycytidine kinase), or an increased pool
of the natural dCTP nucleotide. Increased deamination of the drug
to uracil arabinoside (ara-U) can also cause resistance.
2. Pharmacokinetics: Cytarabine is not effective when given orally,
because of its deamination to the noncytotoxic ara-U by cytidine
deaminase in the intestinal mucosa and liver. Given IV, it distrib-
utes throughout the body but does not penetrate the CNS in suf-
ficient amounts. Therefore, it may also be injected intrathecally.
A liposomal preparation that provides slow release into the CSF is
also available. Cytarabine undergoes extensive oxidative deamina-
tion in the body to ara-U, a pharmacologically inactive metabolite.
Both cytarabine and ara-U are excreted in urine.
Azacitidine
Azacitidine [A-zuh-SITE-i-dine] is a pyrimidine nucleoside analog of
cytidine. It is used for the treatment of myelodysplastic syndromes
and AML. Azacitidine undergoes activation to the nucleotide metabo-
lite azacitidine triphosphate and gets incorporated into RNA to inhibit
RNA processing and function. It is S-phase cell cycle specific. The
mechanism of resistance is not well described.
Gemcitabine
Gemcitabine [jem-SITE-ah-been] is an analog of the nucleoside deoxy-
cytidine. It is used most commonly for pancreatic cancer and non–
small cell lung cancer. Gemcitabine is a substrate for deoxycytidine
kinase, which phosphorylates the drug to 2′,2′-difluorodeoxycytidine
triphosphate (Figure 46.14). Resistance to the drug is probably due
to its inability to be converted to a nucleotide, caused by an altera-
tion in deoxycytidine kinase. In addition, the tumor cell can produce
increased levels of endogenous deoxycytidine that compete for the
kinase, thus overcoming the inhibition. Gemcitabine is infused IV.
It is deaminated to difluorodeoxyuridine, which is not cytotoxic, and
is excreted in urine
Anthracyclines: Doxorubicin, daunorubicin, idarubicin,
epirubicin, and mitoxantrone
Doxorubicin [dox-oh-ROO-bi-sin] and daunorubicin [daw-noe-ROO-
bi-sin] are classified as anthracycline antibiotics. Doxorubicin is the
hydroxylated analog of daunorubicin. Idarubicin [eye-da-ROO-bi-sin],
the 4-demethoxy analog of daunorubicin, epirubicin [eh-pee-ROO-
bih-sin], and mitoxantrone [mye-toe-ZAN-trone] are also available.
Applications for these agents differ despite their structural similarity
and their apparently similar mechanisms of action. Doxorubicin is one
of the most important and widely used anticancer drugs. It is used in
combination with other agents for treatment of sarcomas and a vari-
ety of carcinomas, including breast and lung, as well as for treatment
of acute lymphocytic leukemia and lymphomas. Daunorubicin and
idarubicin are used in the treatment of acute leukemias, and mitoxan-
trone is used in prostate cancer.
1. Mechanism of action: Doxorubicin and other anthracyclines
induce cytotoxicity through several different mechanisms. For
example, doxorubicin-derived free radicals can induce membrane lipid peroxidation, DNA strand scission, and direct oxidation of
purine or pyrimidine bases, thiols, and amines (Figure 46.16).
2. Pharmacokinetics: All these drugs must be administered IV,
because they are inactivated in the GI tract. Extravasation is a seri-
ous problem that can lead to tissue necrosis. The anthracycline
antibiotics bind to plasma proteins as well as to other tissue com-
ponents, where they are widely distributed. They do not penetrate
the blood–brain barrier or the testes. These agents undergo exten-
sive hepatic metabolism, and dosage adjustments are needed
in patients with impaired hepatic function. Biliary excretion is the
major route of elimination. Some renal excretion also occurs, but
dosage adjustments are generally not needed in renal dysfunc-
tion. Because of the dark red color of the anthracycline drugs, the
veins may become visible surrounding the site of infusion, and red
discoloration of urine may occur.
3. Adverse effects: Irreversible, dose-dependent cardiotoxicity, appar -
ently a result of the generation of free radicals and lipid peroxida-
tion, is the most serious adverse reaction and is more common with
daunorubicin and doxorubicin than with idarubicin and epirubicin.
Addition of trastuzumab to protocols with doxorubicin or epirubicin
increases congestive heart failure. There has been some success
with the iron chelator dexrazoxane in protecting against the cardio-
toxicity of doxorubicin. The liposomal-encapsulated doxorubicin is
reported to be less cardiotoxic than the usual formulation.
Bleomycin
Bleomycin [blee-oh-MYE-sin] is a mixture of different copper-chelating
glycopeptides that, like the anthracycline antibiotics, cause scission
of DNA by an oxidative process. Bleomycin is cell cycle specific and
causes cells to accumulate in the G2
phase. It is primarily used in the
treatment of testicular cancers and Hodgkin lymphoma.
1. Mechanism of action: A DNA–bleomycin–Fe2+ complex appears
to undergo oxidation to bleomycin–Fe3+. The liberated electrons
react with oxygen to form superoxide or hydroxyl radicals, which, in
turn, attack the phosphodiester bonds of DNA, resulting in strand
breakage and chromosomal aberrations (Figure 46.17).
2. Resistance: Although the mechanisms of resistance have not
been elucidated, increased levels of bleomycin hydrolase (or
deaminase), glutathione S-transferase, and possibly, increased
efflux of the drug have been implicated. DNA repair also may
contribute.
3. Pharmacokinetics: Bleomycin is administered by a number of
routes. The bleomycin-inactivating enzyme (a hydrolase) is high in
a number of tissues (for example, liver and spleen) but is low in the
lung and is absent in skin (accounting for the drug’s toxicity in those
tissues). Most of the parent drug is excreted unchanged in the
urine, necessitating dose adjustment in patients with renal failure.
4. Adverse effects: Mucocutaneous reactions and alopecia are
common. Hypertrophic skin changes and hyperpigmentation of the hands are prevalent. There is a high incidence of fever and
chills and a low incidence of serious anaphylactoid reactions.
Pulmonary toxicity is the most serious adverse effect, progressing
from rales, cough, and infiltrate to potentially fatal fibrosis. The
pulmonary fibrosis that is caused by bleomycin is often referred as
“bleomycin lung.” Bleomycin is unusual in that myelosuppression
is rare.
ALKYLATING AGENTS
Cyclophosphamide and ifosfamide
Cyclophosphamide and ifosfamide
These drugs are very closely related mustard agents that share most
of the same primary mechanisms and toxicities. They are cytotoxic
only after generation of their alkylating species, which are produced
through hydroxylation by cytochrome P450 (CYP450). These agents
have a broad clinical spectrum, being used either singly or as part of
a regimen in the treatment of a wide variety of neoplastic diseases,
such as non-Hodgkin lymphoma, sarcoma, and breast cancer.
1. Mechanism of action: Cyclophosphamide [sye-kloe-FOSS-fah-
mide] is the most commonly used alkylating agent. Both cyclophos-
phamide and ifosfamide [eye-FOSS-fah-mide] are first biotrans-
formed to hydroxylated intermediates primarily in the liver by the
CYP450 system (Figure 46.19).The hydroxylated intermediates
then undergo breakdown to form the active compounds, phos-
phoramide mustard and acrolein. Reaction of the phosphoramide
mustard with DNA is considered to be the cytotoxic step. The par-
ent drug and its metabolites are primarily excreted in urine.
2. Pharmacokinetics: Cyclophosphamide is available in oral or IV
preparations, whereas ifosfamide is IV only. Cyclophosphamide
is metabolized in the liver to active and inactive metabolites, and
minimal amounts are excreted in the urine as unchanged drug.
Ifosfamide is metabolized primarily by CYP450 3A4 and 2B6 iso-
enzymes. It is mainly renally excreted.
3. Resistance: Resistance results from increased DNA repair,
decreased drug permeability, and reaction of the drug with thiols
(for example, glutathione). Cross-resistance does not always occur.
4. Adverse effects: A unique toxicity of both drugs is hemorrhagic
cystitis, which can lead to fibrosis of the bladder. Bladder
toxicity has been attributed to acrolein in the urine in the case of
cyclophosphamide and to toxic metabolites of ifosfamide. Adequate
hydration as well as IV injection of mesna (sodium 2-mercaptoethane
sulfonate), which neutralizes the toxic metabolites, can minimize
this problem. A fairly high incidence of neurotoxicity has been
reported in patients on high-dose ifosfamide, probably due to the
metabolite, chloroacetaldehyde.
Nitrosoureas
Carmustine
Carmustine [KAR-mus-teen, BCNU] and lomustine [LOE-mus-teen,
CCNU] are closely related nitrosoureas. Because of their ability to
penetrate the CNS, the nitrosoureas are primarily employed in the
treatment of brain tumors.
1. Mechanism of action: The nitrosoureas exert cytotoxic effects
by an alkylation that inhibits replication and, eventually, RNA
and protein synthesis. Although they alkylate DNA in resting
cells, cytotoxicity is expressed primarily on cells that are actively
dividing. Therefore, nondividing cells can escape death if DNA
repair occurs. Nitrosoureas also inhibit several key enzymatic
processes by carbamoylation of amino acids in proteins in the
targeted cells.
- Pharmacokinetics: In spite of the similarities in their struc-
tures, carmustine is administered IV and as chemotherapy wafer
implants, whereas lomustine is given orally. Because of their lipo-
philicity, they distribute widely in the body, but their most striking
property is their ability to readily penetrate the CNS. The drugs
undergo extensive metabolism. Lomustine is metabolized to active
products. The kidney is the major excretory route for the nitro-
soureas (Figure 46.20).
Dacarbazine
Dacarbazine [dah-KAR-bah-zeen] is an alkylating agent that must
undergo biotransformation to an active metabolite, methyltriazeno-
imidazole carboxamide (MTIC). This metabolite is responsible for the
drug’s activity as an alkylating agent by forming methylcarbonium
ions that can attack the nucleophilic groups in the DNA molecule.
Thus, similar to other alkylating agents, the cytotoxic action of dacar-
bazine has been attributed to the ability of its metabolite to methylate
DNA on the O6
position of guanine. Dacarbazine has found use in the
treatment of melanoma and Hodgkin lymphoma.
Temozolomide
The treatment of tumors in the brain is particularly difficult.
Temozolomide [te-moe-ZOE-loe-mide], a triazene agent, has been
approved for use against glioblastomas and anaplastic astrocytomas.
It is also used in metastatic melanoma. Temozolomide is related
to dacarbazine, because both must undergo biotransformation to
an active metabolite, MTIC, which probably is responsible for the
methylation of DNA on the 6 position of guanine. Unlike dacarbazine,
temozolomide does not require the CYP450 system for metabolic
transformation, and it undergoes chemical transformation at normal
physiological pH. Temozolomide also has the property of inhibiting
the repair enzyme, O6
-guanine-DNA alkyltransferase. Temozolomide
differs from dacarbazine in that it crosses the blood–brain barrier.
Temozolomide is administered intravenously or orally and has
excellent bioavailability after oral administration. The parent drug and
metabolites are excreted in urine (Figure 46.21).
Other alkylating agents
Mechlorethamine
Mephalan
Chlorambucil
Busulfan
Mechlorethamine [mek-lor-ETH-ah-meen] was developed as a
vesicant (nitrogen mustard) during World War I. Its ability to cause
lymphocytopenia led to its use in lymphatic cancers. Melphalan [MEL-
fah-lan], a phenylalanine derivative of nitrogen mustard, is used in the
treatment of multiple myeloma. This is a bifunctional alkylating agent
that can be given orally. Although melphalan can be given orally, the
plasma concentration differs from patient to patient due to variation in
intestinal absorption and metabolism. The dose of melphalan is care-
fully adjusted by monitoring the platelet and white blood cell counts.
Chlorambucil [clor-AM-byoo-sil] is another bifunctional alkylating
agent that is used in the treatment of chronic lymphocytic leukemia.
Both melphalan and chlorambucil have moderate hematologic toxici-
ties and upset the GI tract. Busulfan [byoo-SUL-fan] is another oral
agent that is effective against chronic granulocytic leukemia. In aged patients, busulfan can cause pulmonary fibrosis (“busulfan lung”).
Like other alkylating agents, all of these agents are leukemogenic.
