pentostatin and Nervous-System-Diseases

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.

Topics: Adenosine Deaminase Inhibitors; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Synergism; Enzyme Inhibitors; Forecasting; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Kidney Diseases; Mice; Molecular Structure; Neoplasm Proteins; Nervous System Diseases; Pentostatin; Vidarabine

The purine analogs, fludarabine, cladribine, and pentostatin, are active against a broad spectrum of indolent lymphoid malignancies. They also have similar toxicities, including myelosuppression, immunosuppression, and sporadic neurotoxicity. This review compares the spectrum of neurotoxicity of each of these agents. Now that these drugs are commercially available and are being widely used, physicians should be aware of potentially serious side effects that may be encountered.. The literature was searched using MedLine and Cancerline, as well as the bibliographies of published reports through the fall of 1993. In addition, case records from National Cancer Institute (NCI) Group C protocols were reviewed for fludarabine in chronic lymphocytic leukemia (CLL), and cladribine and pentostatin in hairy cell leukemia (HCL), as well as adverse drug reactions reported to the NCI from January 1980 through September 1993.. At higher than recommended doses, life-threatening and fatal neurotoxicity were encountered with all three drugs. At the recommended doses, each agent induced neurotoxicity in approximately 15% of patients, mostly mild and reversible. However, severe neurologic complications were reported; these were occasionally delayed, sometimes fatal, but often at least partially reversible.. The doses of these three agents should not be increased above the recommended levels. Development of moderate or worse neurotoxicity should result in discontinuation of that drug.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Female; Humans; Male; Middle Aged; Nervous System; Nervous System Diseases; Pentostatin; Purine Nucleosides; Vidarabine

Deoxycoformycin (DCF) is a tight-binding inhibitor of adenosine deaminase (ADA) currently undergoing phase I--II evaluation. Neurological toxicity has been a frequent and occasionally severe complication of treatment with this drug. A T-cell leukemia patient with an Ommaya reservoir was treated with DCF, and the pharmacokinetics of the drug in the cerebrospinal fluid and plasma were studied. DCF penetrates the cerebrospinal fluid and achieves levels as high as 1/10 the concurrent plasma levels. The accumulation of adenosine and deoxyadenosine in plasma, cerebrospinal fluid, and urine was monitored; the neuropharmacological effect of these metabolites is discussed.

Topics: Adenosine; Adult; Coformycin; Deoxyadenosines; Electroencephalography; Humans; Male; Nervous System Diseases; Pentostatin; Ribonucleosides