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Medical Pharmacology Chapter 33-34: Anticancer Drugs
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Antimetabolites
Purine Analogues:
Pentostatin (Nipent)
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Pentostatin is a purine nucleotide analog antibiotic that is found in the bacterium Streptomyces antibioticus.9
It is also known as 2-' deoxycoformycin.9
Pentostatin (Nipent) is an analog of an intermediate in the adenosine deaminase reaction.1
The
action of this intermediate is to inhibit the enzyme adenosine
deaminase (ADA).
This effect is comparable to phenotypic expression of a genetic ADA deficiency which is manifest as severe mmunodeficiency that affect both T-cell and B-cell physiology and function.1
A consequence of adenosine deaminase inhibition is accumulation of both intracellular adenosine and deoxyadenosine nucleotides.1,9
Elevated concentration of these nucleotides have the effect of blocking DNA synthesis through inhibition of ribonucleotide reductase (RNR).1
Pentostatin
effects on purine nucleotide pools may account for the drug's
antineoplastic activity in hairy cell leukemia and T-cell
lymphoma.
Deoxyadenosine is an inactivator of S-adenosyl homocysteine hydrolase..1
Accumulation
of S-adenosyl homocysteine is a lymphocyte toxicant.
Pentostatin is also an RNA synthesis inhibitor.
The triphosphate derivative a pentostatin can cause strand breakage following incorporation into DNA..1
Absorption, Distribution, Biotransformation, Excretion:
The route of administration for pentostatin is by IV infusion.
Pentostatin administered by IV infusion every other week exhibits a mean terminal half-life (t1/2) of about 6 hours.
Adequate hydration is important during drug administration and is accomplished by infusion of 500-1000 ml dextrose in half-normal (0.45%) saline.
Following drug administration an additional 0.5 L of fluid is administered.
Drug elimination is almost completely by renal excretion and reduction of pentostatin dosage may be appropriate in patients exhibiting renal dysfunction as assessed by reduced creatinine clearance.
Pentostatin may be used to treat hairy cell leukemia.1
In that setting complete remission (about 60%) and partial responses (about 30%) may be expected with pentostatin administration..
However,
cladribine has replaced pentostatin in most circumstances.1
Pentostatin may be used also in the treatment of other lymphoproliferative malignancies.10
Toxicities associated with pentostatin administration include:
Myelosuppression
GI symptoms
Abnormal liver enzyme studies
Skin rashes
Depletion of T cells associated with drug administration may lead to both neutropenic fever and opportunistic infectious disease.
Following drug discontinuation, a persistent, long duration immunosuppression may be observed.
Renal and neurological side effects due to pentostatin administration is more likely observed at higher doses.
Combined with fludarabine phosphate pentostatin administration may cause severe pulmonary toxicity.
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