In Vitro and in Vivo Anti-Leukemic Efficacy of Cyclic AMP Modulating Agents Against Human Leukemic B-cell Precursors

Abstract

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.

Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21WAF1/CIP1 proteins in human acute lymphoblastic leukemia cells

“…The activities of several nonspecific PDE inhibitors in our assay confirm the results seen with aminophylline on a B-lineage ALL cell line. 43 Our data extend this finding and demonstrate at least additive effects with either a glucocorticoid or an adenylyl cyclase activator. We find that such combinations of drugs induce cell cycle arrest and apoptosis in human ALL cells and that this effect involves inhibition of the PDE4 subclass of PDE inhibitors.…”

“…These findings confirm and extend those demonstrating effectiveness of nonspecific PDE inhibitors in ALL and CLL, and of rolipram in CLL. 42,43,47 Considering the therapeutic importance of glucocorticoids in childhood ALL therapy, the reversal of glucocorticoid resistance by rolipram seen in our data is intriguing. Furthermore, the additive effects of adenylyl cyclase activation and rolipram seen in our results suggest that clinically relevant, specific adenylyl cyclase activators could enhance the potential therapeutic effect of a rolipram-glucocorticoid combination.…”

“…42 The nonspecific PDE inhibitor aminophylline prolongs the survival of mice injected with human ALL cells. 43 Because PDE inhibitors such as caffeine, theophylline, rolipram, and vinpocetine have been used therapeutically in humans, it is attractive to consider whether these agents have significant activity against human ALL cells. In this report we show that PDE inhibitors induce growth suppression and apoptosis in human ALL cells, primarily mediated through inhibition of the PDE4 subclass, and that additive or synergistic effects are induced by adding an activator of adenylyl cyclase.…”

Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies

“…There are several reports in which either ALL cell lines 10,[32][33][34][35][36][37][38][39] or patient biopsies 5,6,[11][12][13][14][15][40][41][42][43][44][45][46] have been engrafted into immunedeficient mice. A limited number of these models have been used to monitor the efficacy of drugs used in the treatment of childhood ALL, 38,40,41,45 or to test novel therapies.…”

“…A limited number of these models have been used to monitor the efficacy of drugs used in the treatment of childhood ALL, 38,40,41,45 or to test novel therapies. [33][34][35][36][39][40][41][44][45][46] Nine of these studies used xenografts established as systemic disease by intravenous or intraperitoneal inoculation of leukemia cells, [34][35][36][38][39][40][44][45][46] whereas others used localized leukemia growth following subcutaneous or intraocular injections. 33,40,41 The majority of studies carried out to monitor the effects of conventional agents or novel therapies on ALL established as systemic disease used leukemiarelated morbidity as the biologic end point.…”