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Sensitivity to Gemcitabine and Its Metabolizing Enzymes in Neuroblastoma

Authors' Affiliation: Department of Pediatrics, Mie University School of Medicine, Tsu, Japan

Requests for reprints: Hiroki Hori, Department of Pediatrics, Mie University School of Medicine, 2-174 Edobashi, 514-8507 Tsu, Mie, Japan. Phone: 81-59-232-1111; Fax: 81-59-231-5213; E-mail: hhori{at}clin.medic.mie-u.ac.jp.

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 IC₅₀s for gemcitabine in 11 neuroblastoma lines ranged between 3 nmol/L and 4 µmol/L. The high activity of gemcitabine against neuroblastoma was confirmed in 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 IC₅₀s 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.

Key Words: gemcitabine • neuroblastoma • deoxycytidine kinase • cytidine deaminase • apoptosis

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