The anthracycline antibiotics
are fermentation products of Streptomyces
peucetius. Daunorubicin (Cerubidine)
is used to treat acute leukemias, while its structural ana-logue, doxorubicin (Adriamycin) is extensively em-ployed
against a broad spectrum of cancers. Although the two drugs have similar
pharmacological and toxico-logical properties, doxorubicin is more potent
against most animal and human tumors and will be discussed in greater detail.
Doxorubicin binds tightly to
DNA by its ability to intercalate between
base pairs and therefore is prefer-entially concentrated in nuclear structures.
Inter-calation results in steric hindrance, hence production of single-strand
breaks in DNA and inhibition of DNA synthesis and DNA-dependent RNA synthesis.
The en-zyme topoisomerase II is thought to be involved in the generation of DNA
strand breaks by the anthracyclines. Cells
in S-phase are most sensitive to doxorubicin, al-though cytotoxicity also
occurs in other phases of the cell cycle.
In addition to the intercalation
mechanism de-scribed, the anthracycline ring of doxorubicin can un-dergo a
one-electron reduction to form free radicals and participate in further
electron transfer. These highly active substances can then react with tissue
macromol-ecules. This type of interaction suggests an alternative mechanism of
cytotoxicity for the anthracyclines. In particular, the cardiac toxicity of
anthracyclines may re-sult from the generation of free radicals of oxygen.
Resistance to the
anthracyclines usually involves de-creased drug accumulation due to enhanced active efflux of drug. This
form of drug resistance is common among the large, heterocyclic naturally
derived anticancer agents. It is termed multidrug
resistance because of the high degree of cross-resistance among the
anthracy-clines, vinca alkaloids, dactinomycin, and podophyllo-toxins .
Doxorubicin is not absorbed
orally, and because of its ability to cause tissue necrosis must not be
injected intramuscularly or subcutaneously. Distribution studies indicate rapid
uptake in all tissues except the CNS. Extensive tissue binding, primarily
intranuclear, ac-counts for the prolonged elimination half-life. The drug is
extensively metabolized in the liver to hydroxylated and conjugated metabolites
and to aglycones that are primarily excreted in the bile.
Doxorubicin is one of the
most effective agents used in the treatment of carcinomas of the breast, ovary,
en-dometrium, bladder, and thyroid and in oat cell cancer of the lung. It is
included in several combination regi-mens for diffuse lymphomas and Hodgkin’s
disease. Doxorubicin can be used as an alternative to daunoru-bicin in acute
leukemias and is useful in Ewing’s sar-coma, osteogenic sarcoma, soft-tissue
sarcomas, and neuroblastoma. Some activity has been reported in non–oat cell
lung cancer, multiple myeloma, and adeno-carcinomas of the stomach, prostate,
The most important toxicities
caused by doxoru-bicin involve the heart and bone marrow. Acutely, doxo-rubicin
may cause transient cardiac arrhythmias and depression of myocardial function.
Doxorubicin may cause radiation recall reactions, with flare-ups of
der-matitis, stomatitis, or esophagitis that had been pro-duced previously by
radiation therapy. Less severe tox-icities include phlebitis and sclerosis of
veins used for injection, hyperpigmentation of nail beds and skin creases, and
conjunctivitis. Because of its intense red color, doxorubicin will impart a
reddish color to the urine for 1 or 2 days after administration.
Idarubicin (Idamycin) differs from its parent
com-pound, daunorubicin, by the absence of the methoxy group in the
anthracycline ring structure. Its mecha-nisms of action and resistance are
similar to those of doxorubicin and daunorubicin; however, it is more
lipophilic and more potent than these other anthracy-clines. Idarubicin
undergoes extensive hepatic metabo-lism and biliary excretion. Adverse
reactions of idaru-bicin are similar to those of its congeners.
The bleomycins are a group of
glycopeptides that are isolated from Streptomyces
verticillus. The clinical preparation, bleomycin sulfate (Blenoxane), is a mix-ture of several
components. Bleomycin binds to DNA, in part through an intercalation mechanism,
without markedly altering the secondary structure of the nucleic acid. The drug
produces both single- and double-strand scission and fragmentation of DNA. It
is thought that the bleomycins, which are avid metal-chelating agents, form a
bleomycin–Fe complex that can donate elec-trons to molecular oxygen, thus
forming the superoxide and hydroxyl free radicals. It is these highly reactive
in-termediates that attack DNA and produce DNA strand breakage and maximum
cytotoxicity in the late G2 and early M-phases of the cell cycle.
Bleomycin is poorly absorbed
orally, but it can be given by various parenteral routes. Its plasma half-life
is not affected by renal dysfunction as long as creatinine clearance is greater
than 35 mL/minute.
Bleomycin hydrolase, which
inactivates bleomycin, is an enzyme that is abundant in liver and kidney but
virtually absent in lungs and skin; the latter two organs are the major targets
of bleomycin toxicity. It is thought that bleomycin-induced dermal and
pulmonary toxici-ties are related to the persistence of relatively high local
concentrations of active drug.
Bleomycin, in combination
with cisplatin or etopo-side, is important as part of the potentially curative
combination chemotherapy of advanced testicular car-cinomas. Bleomycin is used
in some standard regimens for the treatment of Hodgkin’s and non-Hodgkin’s
lym-phomas, and it is useful against squamous cell carcino-mas of the head and
neck, cervix, and skin.
A potentially fatal lung
toxicity occurs in 10 to 20% of patients receiving bleomycin. Patients
particularly at risk are those who are over 70 years of age and have had
radiation therapy to the chest. Rarely, bleomycin also may cause allergic
pneumonitis. Bleomycin skin toxicity is manifested by hyperpigmentation, erythe-matosus
rashes, and thickening of the skin over the dorsum of the hands and at dermal
pressure points, such as the elbows. Many patients develop a low-grade
transient fever within 24 hours of receiving bleomycin. Less common adverse
effects include mucositis, alope-cia, headache, nausea, and arteritis of the
Mitomycin (mitomycin C, Mitocin-C, Mutamycin) is an antibiotic
that is derived from a species of Streptomyces.
It is sometimes classified as an alkylating agent because it can covalently
bind to and cross-link DNA. Mitomycin is thought to inhibit DNA synthesis
through its ability to alkylate double-strand DNA and bring about interstrand
cross-linking. There is evidence that enzymatic reduction by a reduced
nicotinamide– adenine dinucleotide phosphate (NADPH) dependent reductase is
necessary to activate the drug.
The drug is rapidly cleared
from serum after intra-venous injection but is not distributed to the brain.
Mitomycin has limited
palliative effects in carcino-mas of the stomach, pancreas, colon, breast, and
The major toxicity associated
with mitomycin ther-apy is unpredictably long and cumulative myelosup-pression
that affects both white blood cells and platelets. A syndrome of
microangiopathic hemolytic anemia, thrombocytopenia, and renal failure also has
been described. Renal, hepatic, and pulmonary toxicity may occur. The drug is
teratogenic and carcinogenic, and it can cause local blistering.
Dactinomycin (actinomycin D, Cosmegen) is one of a family of
chromopeptides produced by Streptomyces.
It is known to bind noncovalently to double-strand DNA by partial
intercalation, inhibiting DNA-directed RNA synthesis. The drug is most toxic to
proliferating cells, but it is not specific for any one phase of the cell
cycle. Resistance to dactinomycin is
caused by decreased abil-ity of tumor cells to take up and retain the drug, and
it is associated with cross-resistance to vinca alkaloids, the anthracyclines,
and certain other agents (multidrug re-sistance).
Dactinomycin is cleared
rapidly from plasma, does not enter the brain, is not appreciably metabolized
or protein bound, and is gradually excreted in both bile and urine. Virtually
no drug is detected in CSF.
Dactinomycin is used in
curative combined treat-ment of Wilms’ tumor, Ewing’s sarcoma,
rhabdomyosar-coma, and gestational choriocarcinoma. It is active in testicular
tumors, lymphomas, melanomas, and sarco-mas, although its use in most of these
malignancies has been supplanted by other agents.
The major side effects of
dactinomycin are severe nausea, vomiting, and myelosuppression. Mucositis,
di-arrhea, alopecia, and radiation recall reactions may oc-cur. The drug is
immunosuppressive and carcinogenic.
Plicamycin (mithramycin, Mithracin) is one of the chro-momycin
group of antibiotics produced by Streptomyces
tanashiensis. Plicamycin binds to DNA
and inhibits tran-scription. It also inhibits resorption of bone by
os-teoblasts, thus lowering serum calcium levels.Very little is known about its
distribution, metabolism, and excretion. Because of its severe toxicity,
plicamycin has limited clin-ical utility. The major indication for plicamycin
therapy is in the treatment of life-threatening hypercalcemia asso-ciated with
malignancy. Plicamycin also can be used in the palliative therapy of metastatic
testicular carcinoma when all other known active drugs have failed.