Page 1016 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 899

A P P E N D I X 57.4

TOPOISOMERASE I INHIBITORS AND
TOPOISOMERASE II INHIBITORS

TOPOISOMERASE II INHIBITORS vomiting are usually mild and easily prevented with antiemetics.
Rapid infusion of etoposide (<30 minutes) may cause hypotension.
Etoposide (Vepesid), Etoposide Phosphate (Etopophos), Anaphylactoid reactions (e.g., bronchospasm) occur in fewer than
Teniposide (Vumon) 2% of patients and may be related to the Cremophor vehicle. Alopecia
occurs in approximately 20% of patients treated with etoposide. This
Chemistry and Mechanism of Action: Etoposide (VP-16), side effect is more common with teniposide. When the drug is given
etoposide phosphate, and teniposide (VM-26) are semisynthetic in bone marrow transplantation doses, mucositis and diarrhea are
derivatives of epipodophyllotoxin. The mechanism of action of these prominent and may be dose limiting.
drugs appears to be related to their ability to stabilize a topoisomerase
II–DNA cleavable complex, which acts as a replication fork barrier Potential Drug Interactions: Theoretically, any drug that
and leads to the generation of irreversible DNA damage and cell increases the S-phase fraction will increase the cytotoxicity of epi-
death in proliferating cells. podophyllotoxins and other topoisomerase inhibitors. Conversely,
drugs that inhibit DNA synthesis antagonize the effect of etoposide
Absorption, Fate, and Excretion: Etoposide has an oral bio- and teniposide (e.g., 5-fluoro-2′-deoxyuridine given before etoposide
availability of 25%–75%. Its terminal half-life is 6–8 hours, with in some human cancer cell lines decreases the cytotoxicity of the
approximately 30%–40% excreted in the urine, two-thirds as latter). More recent in vitro data suggest that synergistic cytotoxic
unchanged drug. There is no accumulation with consecutive daily effects are seen when VP-16 is given after a topoisomerase I inhibitor,
administration, but cytotoxicity has strict schedule dependency. which appears to upregulate the amount of topoisomerase II enzyme.
Clinical studies suggest that in patients with a plasma creatinine level Antagonistic effects have been reported when a topoisomerase II
greater than 130 mol/L, the etoposide dose should be reduced by inhibitor is given before a topoisomerase I inhibitor. In hematology,
more than 25%. etoposide and teniposide may inhibit intracellular ara-CTP forma-
Etoposide phosphate is rapidly and completely converted in vivo tion leading to reduced ara-C cytotoxicity. Potentiation of teniposide
to VP-16 by the activity of phosphatase and has been shown to have activity has been seen with methotrexate and dipyridamoles. There is
the same pharmacokinetics as VP-16. Because of its increased water at least a twofold increase in the clearance of teniposide with con-
solubility, etoposide phosphate can be given IV in much less volume. comitant administration of phenobarbital or phenytoin. Cyclosporine
In addition, the metabolic acidosis and hypotension seen with the and other PGP antagonists (PSC 833) potentiate the cytotoxic effects
infusion of VP-16 are not seen with this prodrug. of etoposide.
Teniposide has a multiphasic pattern of clearance from plasma
with a terminal half-life of 9.5–21 hours. Unlike those of etoposide, Therapeutic Indications: Etoposide is used in the treatment of
metabolites of teniposide account for greater than 80% of the drug NHL and as a second-line treatment for Hodgkin lymphoma. It is
excreted in the urine. Similar to etoposide, there is significant inter- also incorporated in the preparatory regimens for bone marrow
patient and intrapatient variation in clinical pharmacokinetics. There transplantation of refractory lymphomas (CBV) and acute leukemia.
are currently no formal recommendations for dose modification in Teniposide has been approved as a front-line agent with combination
patients with renal insufficiency. chemotherapy for childhood ALL. Combination chemotherapy with
teniposide has been used successfully in some cases of refractory adult
Preparation and Administration: Etoposide is commercially ALL and acute monocytic leukemia, but the duration of remission is
available as 50-mg capsules and in vials of 50 and 100 mg at a not significantly different from that with other standard salvage regi-
concentration of 20 mg/mL. When the drug is diluted with normal mens. In NHL, teniposide has shown comparable activity to vincris-
saline or 5% dextrose in water to a concentration of 0.2 or 0.4 mg/ tine. Etoposide phosphate has been given in both standard-dose and
mL, it is stable for 96 or 48 hours, respectively. Etoposide must be high-dose (as a single agent) chemotherapy regimens and appears to
administered slowly over more than 30 minutes to prevent have the same pharmacokinetics and antitumor activity as VP-16.
hypotension.
Etoposide phosphate is available commercially as single-dose vials Daunorubicin
containing etoposide phosphate equivalent to 100 mg of etoposide.
When it is diluted with water, 5% dextrose, or normal saline to a Chemistry and Mechanism of Action: Daunorubicin is an
concentration of 10–20 mg/mL, it can be administered without dilu- anthracycline that inhibits DNA topoisomerase II, acting as a poison
tion over 5–10 minutes. When reconstituted, etoposide phosphate is at lower concentrations and a suppressor of cleavable complex forma-
stable for 24 hours at room temperature or under refrigeration. tion at higher doses. Daunorubicin is also a DNA intercalator and
Teniposide is supplied in 50-mg vials for IV use only. The IV generates reactive oxygen intermediates.
solution may be taken orally but is unpalatable. Currently, no oral
preparation is available in the market; however, for investigational Absorption, Fate, and Excretion: After IV injection, daunoru-
purposes, each 50-mg vial may be dissolved in 50–100 mL of syrup bicin undergoes rapid tissue uptake and concentration. It is rapidly
or juice. To achieve optimal absorption, a single oral dose of 60 mg/ metabolized in the liver, where approximately 25% of the drug
2
m , which may be repeated at 6-hour intervals, is advised. As with concentrates and has a half-life of 20–50 hours. The principal
etoposide, rapid infusion can produce hypotension. metabolite is daunorubicinol, which also displays antineoplastic
activity. Biliary excretion accounts for approximately 75% of the drug
Toxic Side Effects: Myelosuppression, especially leukopenia, is and metabolite elimination. Patients with significant hepatic dysfunc-
the dose-limiting toxic effect of etoposide and teniposide. Nausea and tion should receive an attenuated dose of daunorubicin.