Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We show that the adenylate cyclase activating diterpine, forskolin, the phosphodiesterase inhibitor, aminophylline, and the permeant cAMP analog dibutyryl cAMP inhibit the in vitro clonogenic growth of leukemic B-cell precursors. We also used a SCID mouse xenograft model of refractory human B-cell precursor leukemia to evaluate the anti-leukemic effect of aminophylline in vivo. Treatment with aminophylline (6 mg/kg bolus followed by 0.1-0.5 mg/kg/hour x 7 days) significantly prolonged the event-free survival of SCID mice (median survival of control mice, 39 days, N = 79; median survival of aminophylline-treated mice, 60 days, N = 10; P < 0.0001 by log-rank test) and it was more effective than treatment with vincristine (median survival = 51 days, N = 5) or L asparaginase (median survival = 44 days, N = 5). However, aminophylline was not as effective as methylprednisolone (median survival: 103 days, N = 5). These results indicate that cAMP modulating agents may be useful in treatment of refractory human B-cell precursor leukemia.
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PMID:In vitro and in vivo anti-leukemic efficacy of cyclic AMP modulating agents against human leukemic B-cell precursors. 881 74

We have examined the role of adenylate cyclase-hemolysin (CyaA) by constructing an in-frame deletion in the Bordetella bronchiseptica cyaA structural gene and comparing wild-type and cyaA deletion strains in natural host infection models. Both the wild-type strain RB50 and its adenylate cyclase toxin deletion (DeltacyaA) derivative efficiently establish persistent infections in rabbits, rats, and mice following low-dose inoculation. In contrast, an inoculation protocol that seeds the lower respiratory tract revealed significant differences in bacterial numbers and in polymorphonuclear neutrophil recruitment in the lungs from days 5 to 12 postinoculation. We next explored the effects of disarming specific aspects of the immune system on the relative phenotypes of wild-type and DeltacyaA bacteria. SCID, SCID-beige, or RAG-1(-/-) mice succumbed to lethal systemic infection following high- or low-dose intranasal inoculation with the wild-type strain but not the DeltacyaA mutant. Mice rendered neutropenic by treatment with cyclophosphamide or by knockout mutation in the granulocyte colony-stimulating factor locus were highly susceptible to lethal infection by either wild-type or DeltacyaA strains. These results reveal the significant role played by neutrophils early in B. bronchiseptica infection and by acquired immunity at later time points and suggest that phagocytic cells are a primary in vivo target of the Bordetella adenylate cyclase toxin.
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PMID:Probing the function of Bordetella bronchiseptica adenylate cyclase toxin by manipulating host immunity. 1002 99