Sensitivity to Gemcitabine and Its Metabolizing Enzymes in Neuroblastoma

Abstract

Purpose: We examined the activity of gemcitabine against neuroblastoma in vitro and in vivo. In addition, we investigated the cellular mechanisms of high sensitivity to the agent in neuroblastoma cells. Experimental Design: We examined 11 neuroblastoma cell lines for sensitivity to gemcitabine and other chemotherapeutic agents used clinically for neuroblastoma. The in vivo sensitivity of neuroblastoma to gemcitabine was determined in xenograft models. Furthermore, the major metabolic enzymes of gemcitabine were assessed and compared in leukemia and carcinoma cells. Apoptosis and mitochondrial membrane potentials were also evaluated. Results: The IC 50 s for gemcitabine in 11 neuroblastoma lines ranged between 3 nmol/L and 4 Amol/L.The high activity of gemcitabine against neuroblastoma was confirmedin animal models. Interestingly, enzymes in neuroblastoma cells involved in the metabolism of deoxycytidine analogue have unique characteristics among solid tumors.The median of deoxycytidine kinase activity in neuroblastoma lines was similar to that in leukemia lines, which have low IC 50 s for cytarabine. Cytidine deaminase (CDA) activity in neuroblastoma was hardly detectable and significantly lower than that in carcinoma. The defect of CDA activity was associated with negative expression of mRNA. Furthermore, gemcitabine-induced apoptosis was observed irrespective of the caspase-8 status of neuroblastoma cells, which indicates that apoptosis depends on the mitochondrial pathway. Conclusions: Neuroblastoma is highly sensitive to gemcitabine. Although the cellular mechanism involved in sensitivity to gemcitabine is multifactorial, low CDA activity may contribute high sensitivity in neuroblastoma cells.These results suggest that clinical application of gemcitabine to the treatment of neuroblastoma is warranted.

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G1 checkpoint‐defective neuroblastoma

“…The best synergy was found between AZD7762 and gemcitabine, as observed in other tumor systems. 4,5 Although gemcitabine is not yet a standard agent for the treatment of neuroblastoma, 31 our data strongly support the potential of combination therapy with checkpoint kinase inhibitor like AZD7762 and gemcitabine for recurrent tumors and for preventing the emergence of resistant clones.…”

nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer

“…Cda is ubiquitously expressed in mice and humans and can inactivate dFdC into dFdU in both plasma and cells (32, 33). Notably, recent in vitro and in vivo data have provided the first evidence that high Cda expression is associated with gemcitabine resistance and a small study in pancreatic cancer patients showed that Cda ultrametabolizers were five times more likely to progress after gemcitabine-based therapy (30, 34, 35). Conversely, patients with functionally deficient Cda were associated with an increased risk of experiencing severe or even lethal adverse effects (36, 37).…”

Novel Blood-Based, Five-Gene Biomarker Set for the Detection of Colorectal Cancer

“…Studies of acute myeloid leukemia in children with and without Down syndrome indicate that elevated CDA transcript levels correlate with poor outcome in Ara-C -based chemotherapy (29,30). CDA gene expression/activity and outcome of gemcitabine-based treatment also correlate in neuroblastoma cell lines (31) and pancreatic cancer (32). Ara-C and gemcitabine have been used in CRC treatment (33 -36), but the correlation between CDA and treatment effectiveness has not been studied.…”