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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 895

2′-Deoxycoformycin responsible for 6-TG cytotoxicity, although DNA incorporation
appears to play a significant role. 6-TG is considered to be an
Chemistry and Mechanism of Action: 2′-Deoxycoformycin S-phase–specific agent.
(pentostatin; DCF) is an adenosine analog that is a highly effective
inhibitor of the purine biosynthetic enzyme adenosine deaminase Absorption, Fate, and Excretion: After oral administration, the
(ADA). It is transported across cell membranes by facilitated nucleo- bioavailability of 6-TG is variable, ranging from 14% to 46% of the
side diffusion, where it binds tightly to ADA. Inhibition of ADA administered dose (mean: 30%). Peak plasma levels are achieved 8
results in accumulation of deoxyadenosine metabolites, most notably hours after administration and decline slowly thereafter. The average
dATP. dATP exerts its toxic effects through inhibition of ribonucleo- plasma disappearance of 6-TG is approximately 80 minutes, with a
tide reductase and induction of global imbalances in dNTP pools. range of 25–240 minutes. Relatively little unchanged material appears
These result in interference with DNA synthesis and repair. in the urine; the major excreted product is the methylated derivative
2′-Deoxycoformycin is particularly toxic to certain lymphoid cells 2-amino-6-methyl thiopurine. CNS penetrance after parenteral
with low levels of ADA activity. It is also toxic to both cycling and administration is minimal.
resting cells; the mechanism underlying its cytotoxicity toward qui-
escent cells is unknown. Preparation and Administration: 6-TG is available in tablet
form for oral administration. Each tablet contains 40 mg of 6-TG
Absorption, Fate, and Excretion: After IV injection of 2′- and inactive ingredients, including gum acacia, lactose, magnesium
deoxycoformycin, the plasma clearance follows a biphasic pattern, stearate, potato starch, and stearic acid. IV preparations are available
with a terminal elimination half-life of 3–15 hours. Protein binding only in experimental settings.
is limited. The drug is only partially metabolized, with approximately
60%–80% of the drug appearing unchanged in the urine after 24 Toxic Effects: The major dose-limiting toxicity of 6-TG is myelo-
hours. The total-body clearance of 2′-deoxycoformycin correlates well suppression. Other less common toxicities include gastrointestinal
with creatinine clearance. Patients with impaired renal function may disturbances (nausea and vomiting, anorexia, diarrhea), jaundice, and
require reductions in the 2′-deoxycoformycin dose. elevated liver function test results.

Preparation and Administration: 2′-Deoxycoformycin is Potential Drug Interactions: In contrast to 6-MP, the metabo-
unstable when reconstituted in solutions of pH less than 5.0. Conse- lism of 6-TG is not modified by allopurinol; consequently, dose
quently, it is customarily reconstituted in normal saline. 2′-Deoxyco- adjustments do not have to be made when these agents are adminis-
formycin is provided in vials containing 10 mg of drug, 50 mg of tered concurrently.
mannitol, and sodium hydroxide to adjust the pH to less than 7.0.
It is administered as an IV infusion over 20–30 minutes. Hydration Therapeutic Indications in Hematology: The primary indica-
is recommended before and after 2′-deoxycoformycin administration. tion for 6-TG is in the treatment of AML, generally in conjunction
with other agents (e.g., daunorubicin and ara-C). However, it has not
Toxic Effects: The major toxicities of 2′-deoxycoformycin include been firmly established that addition of 6-TG to such regimens
myelosuppression, nausea and vomiting, immunosuppression, acute improves therapeutic efficacy. 6-TG also has activity in chronic
renal failure, keratoconjunctivitis, fever, and elevations of liver func- myeloid leukemia, although it has been supplanted by other agents
tion enzymes. At high doses, neurologic toxicity, including somno- (e.g., hydroxyurea, IFN-α in this disorder.
lence, seizures, and coma, have been reported, although these are seen
infrequently in patients receiving standard dose therapy. When 6-Mercaptopurine
2
administered at such doses (e.g., 4 mg/m biweekly), side effects are
relatively minor. Chemistry and Mechanism of Action: 6-Mercaptopurine
(1,7-dihydro-6H-purine 6-thione monohydrate; 6-MP; purinethol)
Potential Drug Interactions: 2′-Deoxycoformycin may augment is an analog of the purine bases adenine and hypoxanthine. It is both
the toxicity of ara-A as a consequence of inhibition of ADA. an antineoplastic and immunosuppressive agent. Similar to 6-TG,
6-MP and its metabolites act at multiple levels to interfere with
Therapeutic Indications in Hematology: 2′-Deoxycoformycin purine biosynthesis and interconversions. It competes with hypoxan-
is primarily used in the treatment of hairy cell leukemia, in which thine and guanine for hypoxanthine–guanine phosphoribosyltrans-
response rates of up to 90% have been reported, even in patients ferase, and after conversion to thioinosinic acid (TIMP), blocks
refractory to other therapy, including interferon-α (IFN-α). Activity conversion of IMP to xanthylic acid and IMP to AMP. Both TIMP
has also been reported in other lymphoid malignancies, such as T-cell and another metabolite, 6-methylthioinosinate (MTIMP), inhibit
lymphoma, CLL, prolymphocytic leukemia, and Waldenström glutamine-5-phosphoribosylpyrophosphate aminotransferase. 6-MP
macroglobulinemia, although its precise role in the treatment of these is also incorporated into RNA and DNA, thereby functioning as a
disorders remains to be fully evaluated. fraudulent base. It is unknown which of these actions is primarily
responsible for the lethal actions of 6-MP, although available evidence
6-Thioguanine points to DNA incorporation as a prime determinant of
cytotoxicity.
Chemistry and Mechanism of Action: Thioguanine (6-TG) is
a guanine analog in which the 6′-hydroxyl group is replaced by a Fate, Absorption, and Excretion: After oral administration, the
sulfhydryl group. It interferes with de novo purine biosynthesis at bioavailability of 6-MP is highly variable, presumably because of
multiple levels. After transport across the cell membrane by facilitated interpatient differences in gastrointestinal absorption, which averages
diffusion, 6-TG competes with hypoxanthine and guanine for phos- 50% of the administered dose. Extensive catabolism by hepatic
phorylation by hypoxanthine–guanine phosphoribosyltransferase and xanthine oxidase also contributes to drug elimination. Approximately
is converted to its nucleotide form, 6-thioguanylic acid (TGMP), 50% of the administered 6-MP or its metabolites are recovered in the
which accumulates within cells. TGMP inhibits several purine bio- urine. The volume of distribution generally exceeds the total body
synthetic enzymes, including glutamine-5-phosphoribosylpyrophos- water. After IV administration, the plasma disappearance half-life was
phate aminotransferase and IMP dehydrogenase. 6-TG nucleotides 47 minutes in adults. Plasma protein binding is modest (approxi-
are also incorporated in DNA and RNA, where they function as mately 19%), and CNS penetrance is minimal.
fraudulent bases. It is presently unknown which of these actions
(interference with purine interconversions, blockade of de novo Preparation and Administration: 6-MP is supplied as tablets
purine biosynthesis, or nucleic acid incorporation) is primarily for oral administration. Each tablet contains 50 mg of 6-MP and the