| Reference | 1. Leuk Lymphoma. 2011 Jun;52 Suppl 2:43-5. doi: 10.3109/10428194.2011.570394. Epub
2011 Apr 4.
<br>
Mechanism of action of pentostatin and cladribine in hairy cell leukemia.
<br>
Johnston JB(1).
<br>
Author information: <br>
(1)Manitoba Institute of Cell Biology, Section of Hematology/Oncology, University
of Manitoba, Winnipeg, Manitoba, Canada. [email protected]
<br>
Pentostatin (2/’-deoxycoformycin; dCF) and cladribine (2-chlorodeoxyadenosine;
CdA) are highly effective agents for the treatment of hairy cell leukemia.
Although their precise mechanisms of action in this disease are still unknown, a
number of mechanisms have been postulated. dCF is a potent inhibitor of adenosine
deaminase (ADA), and treatment results in the accumulation of deoxyadenosine
(dAdo) and adenosine (Ado) in the plasma. dAdo is phosphorylated by deoxycytidine
kinase in lymphocytes to deoxyadenosine monophosphate (dAMP), which is
subsequently converted to deoxyadenosine triphosphate (dATP). CdA is the
chlorinated derivative of deoxyadenosine, is resistant to degradation by ADA, and
accumulates in lymphocytes as CdATP. Both dATP and CdATP cause an initial
accumulation of DNA strand breaks in lymphocytes and this results in the
activation of p53, the release of cytochrome c from mitochondria, and apoptosis.
CdA has several unique mechanisms of action over dAdo and these include the
incorportation of CdATP into DNA, the inhibition of DNA polymerase β, and the
phosphorylation of CdA to CdATP by deoxyguanosine kinase in mitochondria. These
additional modes of action produce further DNA breaks in CdA-treated cells and
explain the more potent activity of CdA compared to dCF and the greater
myelosuppression with this agent. The cells die by apoptosis, but the DNA strand
breaks also cause the activation of poly(ADP-ribose) polymerase (PARP), with
resultant cellular depletion of nicotinamide adenine dinucleotide (NAD) and ATP.
The induction of necrosis by PARP activation may explain the activity of these
analogs in some patients with p53 mutations.
<br>
2. Haematologia (Budap). 1996;27(2):55-84.
<br>
Deoxycoformycin (pentostatin): clinical pharmacology, role in the chemotherapy of
cancer, and use in other diseases.
<br>
Spiers AS(1).
<br>
Author information: <br>
(1)Division of Medical Oncology and Hematology, H. Lee Moffitt Cancer Center and
Research Institute, University of South Florida, Tampa, Florida, USA.
<br>
Pentostatin (2/’-deoxycoformycin, dCF) is a purine nucleoside analog and a product
of the fermentation of Streptomyces antibioticus. It is a tight-binding inhibitor
of adenosine deaminase (ADA), an enzyme essential in the cellular metabolism of
purines. Children with congenital absence of ADA suffer from atrophy of lymphoid
tissues and severe combined immune deficiency (SCID) syndrome. It was
hypothesized that pentostatin would be lymphocytotoxic and this proved to be
true; this finding prompted its investigation in lymphoid neoplasms. It was
anticipated that pentostatin would be most active in neoplasms with high
intracellular concentrations of ADA, e.g. acute lymphocytic leukemia (ALL),
particularly of the T-cell variety. Although pentostatin proved to be active in
ALL, large doses were required and major toxic effects outweighed therapeutic
benefits. By contrast, pentostatin proved to be exceptionally active in hairy
cell leukemia (HCL), a B-cell neoplasm with low intracellular concentrations of
ADA. Pentostatin has since been shown to possess activity in chronic lymphocytic
leukemia, prolymphocytic leukemia, cutaneous T-cell lymphomas, adult T-cell
lymphoma-leukemia, and low grade non-Hodgkin/’s lymphomas. It potentiates the
activity of vidarabine against viruses and against the cells of acute myeloid
leukemia. Pentostatin is inactive in melanoma and renal carcinoma, but has not
been adequately evaluated in other solid tumors. The toxic effects of pentostatin
include renal failure, central nervous system (CNS) depression, immunosuppresion,
keratoconjunctivitis, and opportunistic infections. In the absence of
pre-existing bone marrow compromise, pentostatin produces only mild
myelosuppression. Aside from its use as an antineoplastic agent, pentostatin has
potential applications as an immunosuppressive drug, as an antiviral agent, as an
antimalarial compound, and in the protection of cells of the CNS from damage
induced by ischemia and anoxia. Clinical studies with pentostatin are ongoing,
and its roles in the management of neoplastic and non-neoplastic diseases have
yet to be fully defined.
<br>
3. Ann Pharmacother. 1992 Jul-Aug;26(7-8):939-47.
<br>
Pentostatin: an adenosine deaminase inhibitor for the treatment of hairy cell
leukemia.
<br>
Kane BJ(1), Kuhn JG, Roush MK.
<br>
Author information: <br>
(1)Department of Pharmacology and Clinical Pharmacy, University of Texas Health
Science Center, San Antonio 78284.
<br>
OBJECTIVE: To review the pharmacology, pharmacokinetics, adverse effects, and
various dosage regimens of pentostatin, and to evaluate the role of pentostatin
in the treatment of hairy cell leukemia (HCL).
DATA IDENTIFICATION: Articles were identified via an English-language literature
search of MEDLINE (1966-91) and an extensive search of bibliographies from
identified articles.<br>
STUDY SELECTION: Human clinical trials and case reports were selected for
evaluation.<br>
DATA EXTRACTION: The literature was assessed for quality, methodology, and
outcome information.<br>
DATA SYNTHESIS: At dosages of 4 mg/m2 administered every other week for 6-9
months, pentostatin has been shown to successfully induce a complete response in
58-90 percent of patients and to produce a partial response in up to 30 percent
of patients with HCL. The median time to achieve a response is 4.7 months.
Long-term remissions of at least 14 months/’ duration have occurred in some
patients. Compared with interferon alfa alone, total response rates are not
significantly different when pentostatin and interferon alfa are used in
combination. When dosed appropriately, pentostatin is generally well tolerated.
Common adverse effects include nausea, vomiting, myelosuppression, fever, and
infection.<br>
CONCLUSIONS: Pentostatin is a purine analog that inhibits adenosine deaminase, a
key enzyme necessary for purine salvage. Pentostatin has received labeling
approval for the treatment of HCL refractory to a minimum of three to six months
of treatment with interferon alfa. Based on current data, pentostatin will be a
useful addition to the therapeutic agents presently available to patients with
HCL. Ongoing trials are evaluating the effectiveness of pentostatin as first-line
therapy for patients with HCL.<br>
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