Deoxycoformycin

Pentostatin (or 2′-deoxycoformycin, trade name Nipent, manufactured by SuperGen) is an anticancer chemotherapeutic drug.

Medical uses

Pentostatin is used to treat hairy cell leukemia. It is given by intravenous infusion once every two weeks for three to six months.

Additionally, pentostatin has been used to treat steroid-refractory acute and chronic graft-versus-host disease.

Pentostatin is also used in chronic lymphocytic leukemia (CLL) patients who have relapsed.

Mechanism of action

It is classified as a purine analog, which is a type of antimetabolite.

It mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, interfering with the cell's ability to process DNA.

Cancer cells generally divide more often than healthy cells; DNA is highly involved in cell division (mitosis) and drugs which target DNA-related processes are therefore more toxic to cancer cells than healthy cells.

Production

Pentostatin was originally made by ''Streptomyces antibioticus'' fermentation. Current production likely uses chemical synthesis.

Fermentation

Pentostatin was originally discovered in a fermentation broth of ''Streptomyces antibioticus'' in 1977, when labor-intensive purification of 9500 liters of fermentation broth ("beer") yields 8 grams of the crystalline substance. A "practical process" published in 1992 greatly simplified the purification method of ''Streptomyces'' broth, making it somewhat economical to produce despite the low concentration found in the broth. The paper seems to imply that the labor-intensive purification method was used to supply all pentostatin used for clinical trials required for the FDA approval in 1991.

Another line of process improvement came from the discovery that the cordycepin producer ''Aspergillus nidulans'' Y176-2 also produces pentostatin, which was reported in a 1976 Japanese patent and a 1979 Japanese paper. It is, however, unclear whether the patent was put into practice.

Total synthesis

The structure of natural products is often confirmed by total synthesis. Such a synthesis would not initially be economical, but provides good assurance that the product is indeed of the intended structure. If the product then proves identical to the natural isolate, the proposed structure for the natural product is considered confirmed. Total synthesis was originally achieved in 1979, with many improvements published thereafter. Based on the recency of some of these patents, it may be fair to assume that they are indeed in use.

Natural occurrence

Pentostatin is produced by:
* ''Streptomyces antibioticus'' NRRL 3238, which also produces vidarabine using the same gene cluster. The gene cluster encodes completely separate pathways for vidarabine and pentostatin synthesis with no genes shared between them. Inside of the bacterium, pentostatin protects vidarabine from being destroyed by the adenosine deaminase, a kind of "protector-protégé" strategy.
* ''Cordyceps militaris'' and '' Cordyceps kyusyuensis'' , both of which also produces cordycepin using the same gene cluster. Here pentostatin protects cordycepin from deamination. The pathways are not as cleanly separated as in ''Streptomyces'': of the four proteins encoded by the cluster, one (Cns3) is shared for both pathways, though this is mostly because Cns3 is a bifunctional protein with two catalytic domains.
* ''Aspergillus nidulans'' Y176-2, which also produces cordycepin. Pentostatin probably also serves to protect cordycepin here. The biosynthetic gene cluster is fully syntenic with the ''Cordyceps'' version.
* Probably ''Samsoniella hepiali'', which is known to produce cordycepin. Cordycepin production is known to be coupled with pentostatin production.

Natural analogues

* ''Actinomadura'' sp. ATCC 39365 produces 2′-chloropentostatin to protect 2′-amino-2′-deoxyadenosine.

References

{{Chemotherapeutic agents

Nucleosides
Purine antagonists
Adenosine deaminase inhibitors