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Pentostatin


ACCESSION NB: DB00552 (APRD00202)


TYPE: small molecule


GROUP: approved


DESCRIPTION:
A potent inhibitor of adenosine deaminase. The drug is effective in the treatment of many lymphoproliferative malignancies, particularly hairy-cell leukemia. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity. [PubChem]

CATEGORIES:
Antineoplastic Agents Enzyme Inhibitors Immunosuppressive Agents Antibiotics

ABSORPTION: Not absorbed orally, crosses blood brain barrier.

INDICATION:
For the treatment of hairy cell leukaemia refractory to alpha interferon.

PHARMACODYNAMICS:
Pentostatin is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia and hairy cell leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase).

MECHANISM OF ACTION:
Pentostatin is a potent transition state inhibitor of adenosine deaminase (ADA), the greatest activity of which is found in cells of the lymphoid system. T-cells have higher ADA activity than B-cells, and T-cell malignancies have higher activity than B-cell malignancies. The cytotoxicity that results from prevention of catabolism of adenosine or deoxyadenosine is thought to be due to elevated intracellular levels of dATP, which can block DNA synthesis through inhibition of ribonucleotide reductase. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase).

PROTEIN BINDING:
4%

METABOLISM:
Primarily hepatic, but only small amounts are metabolized.

TOXICITY:
LD50=128 mg/kg (mouse), side effects include lethargy, rash, fatigue, nausea and myelosuppression.

AFECTED ORGANISMS:
Humans and other mammals