Potentiation of Diabetogenic Effect of L-Asparaginase by Prednisolone

Khan, Amanullah; Adachi, M; Jm, Hill

doi:10.1055/s-0028-1095058

Cited by 23 publications

(14 citation statements)

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“…2; Table 3). Addition of hydrocortisone, however, potentiated the inhibitory effect in analogy with the combined treatment of L-asparaginase and prednisone in man and in rabbits (18). Hydrocortisone was previously shown to influence glucose-induced insulin release and content in a bimodal manner on both mouse (1 9) and rat (20) islets in culture.…”

Section: Resultsmentioning

confidence: 95%

Direct Long-Term Effects of L-Asparaginase on Rat and Human Pancreatic Islets

Clausen

Nielsen

1989

Pediatr Res

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ABSTRACT. L-Asparaginase, an effective agent in the treatment of acute lymphoblastic leukemia, may induce a diabetic state. The pathogenesis of the diabetogenic effect was studied in cultured pancreatic islets. Mean serum concentrations in three children with acute lymphoblastic leukemia were 2.4 U/mL (range 1.4-4.5) before and 31.5 U/mL (range 18.6-51.8) immediately after an intravenous injection of 1000 U/kg L-asparaginase. Glucose-induced insulin release from pancreatic islets of rat and man was measured after 3 and 7 days of culture in media with or without clinically relevant concentrations of Escherichia coli L-asparaginase (0.01-100 U/mL). After culture, the remaining insulin, glucagon, and DNA in the islets were determined. After 7 days of culture of adult rat or human islets, both the accumulation of insulin in the medium and the content of insulin and glucagon in the islets were significantly reduced in the presence of 100 U/mL Lasparaginase compared with controls. Addition of M hydrocortisone to the culture medium enhanced this effect. In newborn rat islets a significant reduction in insulin release and content was observed already in the presence of 0.1 U/mL asparaginase, whereas the glucagon content was unchanged. Removal of the drug resulted in partial recovery of the insulin secretion. To elucidate the mechanisms of action of the drug, insulin biosynthesis was studied in islets cultured in asparagine-free medium with or without asparaginase. No difference in biosynthesis was seen between media with or without asparagine, whereas 0.1 U/ mL asparaginase caused about a 50% reduction under both conditions. These results indicate that the pancreatic Pcells are particularly sensitive to L-asparaginase, suggesting that the diabetogenic effect of the drug is exerted by a direct interaction with the pancreatic P-cell and is not due to lack of exogenous supply of asparagine. (Pediatr Res 26: 158-161,1989) L-Asparaginase is an established drug for the induction or consolidation of remission in children with acute lymphoblastic leukemia. A major side effect of L-asparaginase treatment is nonketotic hyperglycemia and glycosuria, which have been reported in 10% of children receiving 10000 IU/m2 two to four times in the induction treatment in conjunction with prednisone (1). The mechanism of the hyperglycemia is not known, but a rational approach to the treatment of this adverse effect of Lasparaginase requires clarification of the pathogenesis. Decrease in insulin synthesis (2, 3), reduction in insulin release (4), and reduction of the number of insulin receptors (5) proposed. In previous in vitro studies only acute effects were measured, and extremely high doses of the drug were used (6). The aim of our study was, therefore, to elucidate the direct longterm effect of clinically relevant concentrations of L-asparaginase on the insulin release and biosynthesis in isolated rat and human pancreatic islets in culture. MATERIALS AND METHODSAsparaginase activity in treated children. In three children with acute ...

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Section: Resultsmentioning

confidence: 95%

Direct Long-Term Effects of L-Asparaginase on Rat and Human Pancreatic Islets

Clausen

Nielsen

1989

Pediatr Res

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“…Furthermore, two endocrine complications were commonly observed in induction regimen (data not shown), which included a large dose of prednisone. Similarly, the concomitant use of both drugs synergistically increases the occurrence of hyperglycemia and hypertriglyceridemia45.…”

Section: Discussionmentioning

confidence: 99%

Use of PEG-asparaginase in newly diagnosed adults with standard-risk acute lymphoblastic leukemia compared with E. coli-asparaginase: a retrospective single-center study

Liu

Wang²,

Wang³

et al. 2016

Sci Rep

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Acute lymphoblastic leukemia (ALL) is a heterogeneous disease, and the long-term survival varies with different ages. We performed a retrospective analysis of 122 newly diagnosed adults with standard-risk ALL treated with Escherichia coli asparaginase (E. coli-asparaginase, n = 50) and polyethylene glycol-conjugated asparaginase (PEG-asparaginase, n = 72). No treatment-related mortality (TRM) occurred in the E. coli-asparaginase group, and 3 TRM events occurred in the PEG-asparaginase group without relation to asparaginase. In addition, 22 (44.0%) and 48 (66.7%) patients achieved a complete response (CR) on day 14 in the E. coli-asparaginase and PEG-asparaginase groups, respectively (P = 0.032). No different 5-year event-free survival (EFS) or overall survival (OS) rate (P = 0.632 and 0.769) was observed. Multivariate analysis revealed later CR (P = 0.008) and older age (P = 0.049) as adverse prognostic factors for both EFS and OS. In addition, we specifically monitored the known adverse effects of asparaginase, and no asparaginase-related death was observed. Allergy occurred in 9 patients using E. coli-asparaginase, and no patient in the PEG-asparaginase group suffered from allergies (P < 0.001). The incidence of other asparaginase-related toxicities was similar. We conclude that PEG-asparaginase can be safely and effectively used as asparaginase in adults with newly diagnosed standard-risk ALL.

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“…It has been pos tulated that L-asparaginase inhibits insulin biosynthesis or its secretion from B cells [3,5,6], This effect was also observed in neonatal rat islets in vitro [13,14] and in human pancreatic islets [14].…”

Section: Discussionmentioning

confidence: 82%

“…This enzyme can block protein biosynthesis in several cellular types [2,3]. L-Asparaginase toxicity includes hepatocellular dysfunction, hyper sensitivity, coagulation abnormalities, prerenal azotemic syndrome, central nervous system changes, pancreatitis and a syndrome of hyperglycemia [4], L-Asparaginase can block insulin secretion [5] both in vivo and in vitro, and it has been suggested that L-asparaginase inhibits insulin biosynthesis and/or release [6].…”

Section: Introductionmentioning

confidence: 99%

Effect of <i>L</i>-Asparaginase on Insulin Secretion from Isolated Rat Islets of Langerhans

Pou

Cervera²,

Pérez³

et al. 1991

Horm Res

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The effects of L-asparaginase were evaluated on glucose-induced insulin release from isolated rat islets of Langerhans. Islets were obtained by enzymatic digestion of pancreas from Sprague-Dawley rats. The study of L-asparaginase effects on insulin secretion was performed in a static incubation of islets. Insulin secretion was measured at 60 min of incubation with different secretagogues with and without L-asparaginase. L-Asparaginase at concentrations from 310 to 5,000 U/ml could inhibit the glucose-induced insulin secretion in a dose-dependent manner. This effect was not recovered after incubation in the absence of the drug for another 2 h. The half-maximal inhibitory effect of the enzyme on insulin secretion was observed at L-asparaginase concentrations of 1,000 U/ml. Tolbutamide (200 µM) and ketoisocaproic acid (20 µM) did not induce insulin secretion in the presence of moderately high L-asparaginase concentrations. L-Asparaginase did not inhibit glucose-induced insulin secretion in the presence of isobutyl-methyl-xanthine (IBMX) (20 µM) or forskolin (20 µM). L-Asparaginase promoted a decrease in total c-AMP in isolated rat islets at concentrations from 500 to 1,500 U/ml when they were stimulated by glucose. If islets were treated with IBMX or forskolin, L-asparaginase did not inhibit the glucose-induced total c-AMP levels in islets.

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Potentiation of Diabetogenic Effect of L-Asparaginase by Prednisolone

Cited by 23 publications

References 1 publication

Direct Long-Term Effects of L-Asparaginase on Rat and Human Pancreatic Islets

Direct Long-Term Effects of L-Asparaginase on Rat and Human Pancreatic Islets

Use of PEG-asparaginase in newly diagnosed adults with standard-risk acute lymphoblastic leukemia compared with E. coli-asparaginase: a retrospective single-center study

Effect of <i>L</i>-Asparaginase on Insulin Secretion from Isolated Rat Islets of Langerhans

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