Пентостатин

Описание

Pentostatin, an adenosine deaminase inhibitor, is an orphan drug introduced for the treatment of hairy cell leukemia. The agent is considered a significant advance over alpha-interferon, the only other drug available for this indication. The majority of patients treated with pentostatin have been reported to remain in remission for at least four years. It is also under investigation for the treatment of other kinds of leukemia and in transplant rejection.

Химические свойства

White Solid

Использование

Pentostatin is a potent antitumour antibiotic isolated from a Streptomyces species. Pentostatin is a potent inhibitor of adenine deaminase and has been used therapeutically as an antitumour agent.

Показания

Pentostatin (Nipent, deoxycoformycin) is a purine isolated from fermentation cultures of the microbe Streptomyces antibioticus. Its mechanism of action involves inhibition of the enzyme adenosine deaminase, which plays an important role in purine salvage pathways and DNA synthesis.The resulting accumulation of deoxyadenosine triphosphate (dATP) is highly toxic to lymphocytes.
Pentostatin is effective in the therapy of hairy cell leukemia, producing remissions in 80 to 90% of patients and complete remissions in more than 50%. The major toxic effects of the drug include myelosuppression, nausea, and skin rashes.

Общее описание

The drug is available in 10-mg vials for IV use. The drug isused to treat leukemias such as hairy cell leukemia, chroniclymphocytic leukemia, and lymphoblastic leukemia. Themechanism of action involves inhibition of the enzymeadenosine deaminase yielding increased cellular levels ofdeoxyadenosine and deoxyadenosine triphosphate (dATP).The increased levels of dATP are cytotoxic to lymphocytes.Pentostatin is a fermentation product of Streptomyces antibioticus.Resistance appears to involve decreased cellulartransport or increased expression of catabolic enzymes.Acid instability prevents oral administration, and the drug isonly administered by IV. The drug is distributed in totalbody water but does not enter the CNS. The majority of thedosage is excreted unchanged in the urine. Fatal pulmonary toxicity has occurred when pentostatin and fludarabine areused in combination. Toxicities include myelosuppression,immunosuppression, nausea, vomiting, headache, lethargy,and fatigue.

Биологическая активность

Irreversible inhibitor of adenosine deaminase (K i = 2.5 pM). Anticancer agent.

Механизм действия

Pentostatin is the most potent inhibitor of adenosine deaminase, an important and ubiquitous cellular enzyme. Inhibition of this enzyme leads to the accumulation of dATP, which inhibits ribonucleotide reductase and thus DNA synthesis.

Клиническое использование

Pentostatin is a ring-expanded purine ribonucleoside that inhibits adenosine deaminase and is used in the treatment of hairy cell leukemia. The elevated levels of deoxyadenosine triphosphate that result from inhibition of this degradative enzyme inhibit the action of ribonucleotide reductase (the enzyme that converts ribose diphosphate to deoxyribose diphosphate), thus halting DNA synthesis within the tumor cell.

Профиль безопасности

Poison by intravenous route. An experimental teratogen. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOx.