Impact of cytidine deaminase activity on intrinsic resistance to cytarabine in carcinoma cells.
Cytarabine (araC) is a highly active antimetabolite against hematological malignancy while the agent shows limited activity against carcinomas. In this study, we focused on cellular transport and catalysis of the nucleoside in order to elucidate the mechanism of intrinsic resistance to araC in carcinomas. Activities of two metabolizing enzymes for araC, deoxycytidine kinase (DCK) and cytidine deaminase (CDA), and cellular transport of the agent were examined in 9 carcinoma cell lines. These variables in carcinoma lines were compared with those in 14 araC-sensitive leukemia lines and one leukemia line with acquired resistance. The mean IC50 in 9 carcinoma lines was 3 x 10(3)-fold higher than that in 14 leukemia lines (4.6 x 10(3) vs. 1.3 microM, p<0.01). A cell line with acquired resistance (U937R), which was established from U937 monocytoid leukemia cells, showed more than 10(3)-fold higher IC50 than the parent cells (1.6 x 10(3) vs. 1.3 microM). The resistance in carcinomas was associated with higher CDA activity and lower influx when compared to araC sensitive leukemias. Especially, these two types of malignant cell lines were clearly distinguished by CDA activity. The acquired resistance in U937R cells was followed by increase in cytidine deaminase (CDA) activity, decrease in DCK activity and decrease in influx of the drug. In conclusion, carcinomas are intrinsically resistant to cytarabine through high CDA activity and low cellular transport, but not low DCK activity. This finding suggests that treatment of carcinoma with deoxycytidine analogues should conquer the high CDA activity.
Ohta
Takuya
T
Department of Pediatrics, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Hori
Hiroki
H
Ogawa
Masahiro
M
Miyahara
Masazumi
M
Kawasaki
Hajime
H
Taniguchi
Norihisa
N
Komada
Yoshihiro
Y
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001692:Biological Transport; D003561:Cytarabine / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000378:metabolism*; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003842:Deoxycytidine Kinase; D003564:Cytidine Deaminase