Page 1005 - Hematology_ Basic Principles and Practice ( PDFDrive )

888 Part VII Hematologic Malignancies

Streptozocin (Zanosar) Pain along the injection site can occur if the drug is rapidly infused
but can usually be lessened by prolonging the infusion rate. Second-
Chemistry: Streptozocin is a naturally occurring nitrosourea ary leukemias are reported between 3 and 10 years after use.
derived from Streptomyces acromogenes. The drug is a glucosamine-1-
methyl-nitrosourea, which, unlike the other nitrosoureas, methylates Potential Drug Interactions: DTIC activation may be enhanced
DNA and is cytotoxic owing to induced mismatch repair. by phenytoin or phenobarbital, although the clinical significance of
this potential interaction remains uncertain. There may be a potential
Absorption, Fate, and Excretion: After IV administration, the (as yet poorly characterized) drug interaction with levodopa, whereby
drug is rapidly metabolized, with no intact drug detectable in the the response to levodopa is diminished.
plasma after 3 hours. Its half-life is 40 hours. Within the first 24
hours after administration, approximately 10% of the parent com- Therapeutic Indications in Hematology: DTIC is used pri-
pound is excreted in the urine. marily in the treatment of Hodgkin lymphoma as part of the ABVD
(doxorubicin [Adriamycin], bleomycin, vinblastine, and DTIC)
Preparation and Administration: The drug is commercially regimen and for melanoma.
available in 1-g vials and is reconstituted with either 9.5 mL of
normal saline or 5% dextrose in water for injection to form a 100-mg/ Procarbazine
mL solution. IV infusion of the drug over 30–45 minutes usually
prevents discomfort at the injection site. Patients should be kept well Chemistry and Mechanism of Action: Procarbazine is a sub-
hydrated to preclude renal tubular toxicity. stituted hydrazine derivative with a chemical structure similar to that
of the monoamine oxidase inhibitors (MAOIs). Accordingly, procar-
Toxic Effects: Although nausea and vomiting have been consid- bazine exhibits weak MAOI effects. Procarbazine itself is inert and
ered by some investigators to be the limiting toxic effects, in most must undergo metabolic activation to generate cytotoxic reactants,
phase I trials nephrotoxicity was the principal dose-limiting effect. the mode of action of which is not clear. They may inhibit trans-
Nausea and vomiting are severe and require aggressive antiemetic methylation of methyl groups of methionine into tRNA or may also
support. Streptozocin may also aggravate duodenal ulcers. Renal directly damage DNA. Hydrogen peroxide, formed during the
toxicity frequently occurs and includes mild proteinuria, glycosuria, autooxidation of procarbazine, may attack protein sulfhydryl groups
hypophosphatemia, renal tubular acidosis, and occasionally irrevers- contained in residual proteins tightly bound to DNA.
ible azotemia. Although the myelosuppressive effect of streptozocin
is mild, it can potentiate the bone marrow suppression of other Absorption, Fate, and Excretion: Procarbazine is rapidly and
cytotoxic drugs. Slight increases in hepatic enzymes can also occur. completely absorbed by the oral route, with peak plasma levels occur-
Occasionally, patients (primarily those with insulinomas) may experi- ring within 60 minutes. It penetrates well into the cerebrospinal fluid.
ence transient alterations in glucose metabolism. The drug is readily metabolized in the liver and has a plasma half-life
of 10 minutes after IV injection. The major sites of elimination are
Potential Drug Interactions: Streptozocin can potentiate the the kidneys, where approximately 70% of the drug is excreted as
hyperglycemic effect of glucocorticosteroids. Phenytoin therapy N-isopropylterephthalamic acid and less than 5% is excreted
decreases the cytotoxic effect of streptozocin on the pancreatic β-cells, unchanged.
leading to potential interference with its therapeutic effect in patients
with pancreatic islet cell tumors. Streptozocin is a potent renal toxin, Preparation and Administration: Procarbazine is commercially
and every effort should be made to avoid concomitant administration available as 50-mg capsules.
of other nephrotoxins.
Toxic Effects: The usual dose-limiting toxic effect is myelosup-
Therapeutic Indications in Hematology: Streptozocin has pression. Occasionally, nausea and vomiting may be dose limiting,
been used in the initial treatment of Hodgkin lymphoma and, less although tolerance to those effects may develop during continued
commonly, in NHLs. administration. Other less common side effects include paresthesias,
headache, dizziness, depression, apprehension, insomnia, nightmares,
Dacarbazine hallucinations, drowsiness, ataxia, foot drop, decreased reflexes,
tremors, coma, confusion, convulsions, skin rash, alopecia, myalgia,
Chemistry: Dacarbazine is also called DTIC [5-(3,3-dimethyl-1- and arthralgia. Procarbazine may possibly be leukemogenic.
triazeno)imidazole-4-carboxamide]. After undergoing metabolic
activation by microsomal enzymes in the liver, it acts primarily as an Potential Drug Interactions: Combination chemotherapy that
alkylating agent. includes procarbazine may result in a decrease in digoxin plasma
levels. Because procarbazine is a weak MAOI, hypertensive reactions
Absorption, Fate, and Excretion: After IV administration, the could theoretically occur after concurrent ingestion of sympathomi-
drug is extensively metabolized. Activated DTIC has an elimination metics, levodopa, tricyclic antidepressants, or foods with high tyra-
half-life of 5–7 hours. Approximately 40%–50% of the parent drug mine content (e.g., dark beer, yogurt, cheeses, and red wines).
is found in the urine within the first 24 hours after administration. However, such reactions have not been reported. Concomitant use
of narcotics or other strong sedatives may result in exaggerated
Preparation and Administration: DTIC is commercially avail- depressant effects, leading to coma and possibly death. Procarbazine
able in 100- and 200-mg vials, which must be protected from light also interacts with alcohol, causing a disulfiram-like reaction.
and stored at a temperature of 2–8°C. The drug is reconstituted with
normal saline or sterile water to produce a 10-mg/mL solution. It can Therapeutic Indications in Hematology: Procarbazine is often
be administered as a slow IV push or by infusion over 15–30 minutes. used in combination with other cytotoxic agents in the treatment of
Hodgkin lymphoma (MOPP and MOPP derivatives) and to a lesser
Toxic Effects: Myelosuppression, primarily represented by leuko- extent in the treatment of NHL (PROMACE-MOPP).
penia, is the dose-limiting toxic effect. Use of the drug leads to
considerable problems with emesis and requires aggressive antiemetic Temozolomide
support. A flulike syndrome consisting of fever, malaise, and myalgias
may occur. Direct sunlight during the first 2 days after drug admin- Chemistry and Mechanism of Action: Temozolomide is not
istration may result in facial flushing, facial paresthesias, and light- active but undergoes rapid nonenzymatic conversion at physiologic
headedness. Hepatotoxicity and diarrhea have also been reported. pH to the reactive compound monomethyl 5-triazino imidazole