Adenosine deaminase treatment

Pentostatin (2 -deoxycoformycin) is an adenosine analog that is a potent inhibitor of adenosine deaminase. Pentostatin particularly useful for treating T-cell leukemia since malignant T cells have higher levels of adenosine deaminase than most cells. Similar to individuals who are genetically deficient in adenosine deaminase, treatment with pentostatin produces immunosuppression of bofh T and B lymphocytes, with minimal effect on other tissues. As a result, severe opportunistic infections are often associated with its clinical use. 

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

Poly(ethylene glycol) (PEG) molecules attached to adenosine deaminase (ADA) have been used in patients exhibiting symptoms of the severe combined immunodeficiency syndrome (SCID) caused by ADA deficiency. The modified enzyme has a plasma half-life of weeks as compared to the unmodified enzyme (minutes) (248). PEG-L-asparaginase has induced remissions in patients with non-Hodgkin s lymphoma (248). However, one disadvantage of PEG-enzyme treatment is its expense, ie, a year s treatment costs about 60,000 (248). 

Use adenosine deaminase inhibitor (for hairy cell leucemia treatment)... 

It is not clear that inhibition of adenosine deaminase is the basis for the clinical efficacy of Trazodone for the treatment of depression. 

Adenosine deaminase (ADA) deficiency, an autosomal recessive disorder, produces severe combined immunodeficiency (SCID). Lacking both B-cell and T-cell function, children are multiply infected with many organisms Pneumocystis carinii, Candida) and do not survive without treatment. Enzyme replacement therapy and bone marrow transplantation may be used. Experimental gene therapy trials have not yet yielded completely successfiil cures. 

Gene engineering is the basis of gene therapy where genes are removed, replaced, or altered producing new proteins for the treatment of diseases such as muscular dystrophy, some cancers, adenosine deaminase deficiency, cystic fibrosis, and emphysema. 

Mutation in the adenosine deaminase gene on chromosome 20 can cause severe combined immunodeficiency due to absence of T cells, B cells, and natural killer cells (T cell-negative, B cell-negative, natural killer cell-negative autosomal recessive SCID). The lack of the enzyme adenosine deminase results in the accumulation of adenosine and toxic deoxyadenosine nucleotides. The latter can cause apoptosis of lymphocytes. Lymphocyte counts can be as low as 0.5 x 10 /L, affecting primarily T cells which are absent (105). While therapy of missing enzyme has been shown to effect improvement, bone marrow transplantation is the preferred treatment. Milder forms of adenosine deaminase deficiency have been reported (116). 

Hershfield, M.S., R.H. Buckley, M.L. Greenberg, A.L. Melton, R. Schiff) C. Hatem, J. Kurtzberg, M.L. Markert, R.H. Kobayashi, A.L. Kobayashi, et al., Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N Engl J Med, 1987. 316(10) 589-96. 

Dunbar, C., L. Chang, C. Mullen, et al.. Amendment to Clinical Research Project. Project 90-C-195. April 1,1993. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with autologous lymphocytes transduced with a human ADA gene. Hum Gene Ther, 1999.10(3) 477-88. 

Gene therapy holds great promise for the treatment of many diseases (e.g., cancer, AIDS, cystic fibrosis, adenosine deaminase deficiency, cardiovascular diseases, Gaucher disease, a 1-antitrypsin deficiency, rheumatoid arthritis, and several others) (1,2). Advances in genomics and molecular biology have revealed that almost all diseases have a genetic component. In some cases, such as cystic fibrosis or hemophilia,... 

Retrovirus vectors were subjected to the first clinical trial on human gene therapy to correct adenosine deaminase (ADA) deficiency (32). White-blood cells isolated from patients were infected ex vivo with an MLV-based vector expressing ADA and a neomycin marker gene. After selection with G418, neomycin-resistant cells were isolated and reintroduced into patients. The treatment improved the physical condition of the patients and the ADA-containing provirus was stable in the blood for several years. 

Volume III, Pharmacology and Therapy, addresses developments in basic science, translational and clinical research that are underway to bring stem cell research to therapy, particularly for the treatment of Batten s diseases, graft-versus-host disease and adenosine deaminase deficiency. This volume covers the importance of stem cell research for the understanding of drug activities and design. It also addresses the ethical issues and constraints involved in stem cell research, and its commercial applications. 

San Raffaele Telethon Institute for Gene Therapy is developing an adenosine deaminase transduced hematopoietic stem cell therapy for the potential intravenous treatment of adenosine deaminase deficiency in severe combined immunocompromised individuals (ADA-SCID). 

T-lymphocyte ontogeny in adenosine deaminase-deficient severe combined immune deficiency after treatment with polyethylene glycol-modified adenosine deaminase. Weinberg, K., Hershfield, M.S., Bastian, J., Kohn, D., Sender, L., Parkman, R., Lenarsky, C. (1993).JClin Invest, 2 596-602. 

Adagen (adenosine deaminase) approved for treatment of severe combined immunodeficiency disease. 

Levy, Y., Hershfield, M. S., Fernandez-Mejia, C., et al. Adenosine deaminase deficiency with late onset of recurrent infections Response to treatment with polyethylene glycol-modified adenosine deaminase. J. Pediatr. 113(2) 312-317. 1988. 

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