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326 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 327

also been observed in phase I clinical trials in patients with AML. opposing strands of the DNA helix and may contribute to the specific-
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Irinotecan and topotecan differ substantially in their profile of toxicities ity of sites of DNA breakage. In addition to their inhibition of Topo II,
and pharmacokinetic behavior. Irinotecan is a water-soluble prodrug anthracyclines generate free radicals by virtue of the oxidation-reduc-
that is converted to the active species, SN-38, by carboxyl esterase- tion cycling of their quinone group, an action catalyzed by the binding
2+
mediated cleavage. Irinotecan and SN-38 are both eliminated by glu- of Fe . Free radical generation is thought to be responsible for their
curonidation and biliary excretion. Therefore, irinotecan must be used cardiac toxicity.
with caution and at lower doses in patients with Gilbert disease (and The importance of the presence of Topo II in determining response
lacking glucuronyl transferase 1A1) or in those with hepatic dysfunc- to anthracyclines is best illustrated by the greater benefit of anthracy-
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tion. In contrast to the hepatic extraction and excretion of irinotecan, cline-based breast cancer treatment in patients with amplification of
approximately two-thirds of the dose of topotecan is eliminated by renal the target enzyme on chromosome 17, near the HER2 gene with which
101
excretion, with the remainder being cleared by biliary excretion. Dose it coamplifies. Anthracycline-containing regimens are particularly
adjustment proportional to CrCl is indicated in patients with renal fail- effective in HER2-amplified breast cancers. 102
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ure. Topotecan toxicity consists mainly of myelosuppression and, to a Anthracyclines enter cells through a passive transport process.
lesser degree, mucositis, whereas irinotecan causes a profound diarrhea, Their lipophilic structure allows them to achieve high intracellular con-
which is responsive to loperamide, and a more modest myelosuppres- centrations. Anthracyclines are pumped out of the cell by a series of
sion. The maximum tolerated dose of topotecan for the 5-day schedule ATP-dependent transporters, including the P-glycoprotein MDR trans-
2
of 30-minute intravenous infusions/day is 4.5 mg/m per day in patients porter, the breast cancer resistance protein transporter (BCRP) and
with leukemia. This is considerably greater than the approved dose for related efflux pumps. Other mechanisms for anthracycline resistance
11
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solid tumors, and gastrointestinal side effects, such as mucositis and include decreased Topo II activity or Topo II mutations in the enzyme
diarrhea, become dose-limiting at these higher doses. that inhibit drug binding, as well as defects in apoptosis or impaired
checkpoint recognition of DNA strand breaks.
ANTHRACYCLINE ANTIBIOTICS Clinical Pharmacology
The anthracyclines are a unique class of natural products that inhibit Daunorubicin and idarubicin are readily converted to active hydroxyl
topoisomerase II (Topo II), an enzyme important in DNA strand pas- metabolites, whereas doxorubicin produces limited amounts of alco-
sage allowing the untangling of DNA prior to replication or repair. Dox- hol metabolite. The alcohols of daunorubicin and doxorubicin are less
orubicin, daunorubicin, idarubicin, and epirubicin are closely related active as antitumor agents, but do possess cardiotoxic activity.
in structure, each possessing a rigid planar core to which is linked a All anthracyclines are eliminated by the formation of inactive met-
daunosamine sugar. The molecules differ in side-chain substitutions abolic products (aglycons, side-chain-modified products, glucuronides,
attached to the anthracycline ring system, and exhibit different spectra sulphates, and oxidative metabolite) in the liver. Only a minor fraction
of antitumor activity and toxicity. Mitoxantrone, a closely related, nong- of the dose of any of the anthracyclines is excreted in the urine as the
lycosidic anthracenedione, has very similar pharmacologic properties to parent drug or alcohol metabolite. The pharmacokinetics of the clini-
those of the anthracyclines. The anthracyclines are produced by a Strep- cally useful anthracyclines are predominantly influenced by their termi-
tomyces species, whereas mitoxantrone is a synthetic compound. Doxo- nal disposition phase, which exceeds 24 hours. Although prolongation
rubicin (Adriamycin) has broad activity against solid and hematologic of the half-life of doxorubicin has been reported in studies of patients
malignancies. It is an important component of the standard multidrug with compromised liver function, no clear correlations of liver function
regimens used to treat Hodgkin lymphoma (doxorubicin, bleomycin, with toxicity have been established. However, in patients with elevated
vinblastine, and dacarbazine [ABVD]) and aggressive non-Hodgkin serum bilirubin levels, initial doses of doxorubicin and daunorubicin
lymphoma (cyclophosphamide, doxorubicin, vincristine, and pred- should be reduced by 50 percent, and adjust there after according to
nisone). Daunorubicin and idarubicin are used almost exclusively in tolerance. Idarubicin, the only anthracycline amenable to oral admin-
combination with ara-C for the treatment of AML, whereas epirubicin istration, has a bioavailability of 20 percent for the parent drug and 40
is primarily effective against solid tumors. Mitoxantrone is employed for percent for parent drug plus idarubicinol, the primary active metabo-
the treatment of AML and breast cancer, and as an immunosuppressive lite. Idarubicinol has a very prolonged biologic half-life, ranging from
for patients with multiple sclerosis. Liposome-encapsulated doxoru- 50 to 60 hours, and is likely responsible for the antitumor activity of this
bicin (Doxil) and daunorubicin derivatives are approved for treatment drug. In contrast to the metabolites of doxorubicin and daunorubicin,
of solid tumors; they provide a more prolonged, lower peak concen- idarubicinol is eliminated primarily by renal excretion. No dose adjust-
tration of drug, and have decreased cardiac toxicity. The daunorubicin ment for hepatic dysfunction is indicated.
liposome is of interest in treating AML. A novel anthracycline, pixan- Mitoxantrone has a long terminal half-life of 23 to 42 hours. Only
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trone, which has lesser cardiotoxicity, has received conditional approval a minor fraction of unchanged drug is excreted in the urine (<10 per-
in Europe for refractory non-Hodgkin B-cell lymphoma. 100 cent) or stool (<20 percent). The majority of the drug is metabolized or
bound to tissues. Patients with impaired hepatic function may have a
Mechanism of Action more prolonged elimination of mitoxantrone.
Anthracyclines target the replication and structural integrity of DNA. The usual dose of doxorubicin when administered as a single agent
Their primary mechanism of toxicity stems from their interaction by bolus intravenous injection is 45 to 75 mg/m every 3 to 4 weeks,
2
with Topo II, an enzyme that creates DNA strand breaks and promotes depending on the tumor treated and the drug combination. Less car-
strand passage through those breaks. Strand passage is essential in diac toxicity may result from schedules that avoid high peak plasma
untangling DNA in preparation for replication and repair. Once the concentrations, such as weekly doses (15 to 25 mg/m ) or continuous
2
strand passage and unwinding is complete, Topo II reseals the broken intravenous infusion over 48 to 96 hours, as in the EPOCH (etoposide,
DNA strands. The anthracyclines inhibit the resealing step by forming a prednisone, vincristine, cyclophosphamide, and doxorubicin) regi-
complex with Topo II and the broken DNA strand to which the enzyme men. When given in combination with other myelotoxic agents such
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is linked. Accumulation of strand breaks activates apoptosis. The planar as cyclophosphamide, the dose of doxorubicin is usually decreased
molecular structure of these drugs promotes their intercalation between because of overlapping marrow toxicity. Daunorubicin has been used as

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