Induction of intracellular and plasma 2',5'-oligoadenylate synthetase by pentostatin.
Similar to interferon alpha, pentostatin is highly effective in hairy cell leukemia and moderately active in other chronic lymphoid malignancies. In ten patients with hairy cell leukemia (HCL) and seven patients with other B-cell chronic leukemias (BCL), we have studied the intracellular 2',5'-oligoadenylate synthetase (2,5OAS) activity of the mononuclear cells before, 4 h, 24 h, and 48 h after pentostatin administration. In patients with HCL the median level of intracellular 2,5OAS increased 4.6-fold at 4 h and 11.5-fold at 24 h compared to the pretreatment value. Among the other seven patients, the median intracellular 2,5OAS remained unchanged in three patients and rose slightly by 2 to 14 times in four patients. Eleven patients (eight with HCL and two with BCL) responded to pentostatin. The median increase in 2,5OAS among the responders was 13.0-fold (range 4.8-30.0) whereas that among non-responders was 2.2-fold (range 0.2-6.3). The difference was highly significant (p less than 0.0001). In five of the total seventeen patients, the plasma levels of 2,5OAS activity were also determined and changes in plasma levels paralleled those measured intracellularly. To determine if the elevation of 2,5OAS is mediated by induction of interferon alpha, the expressions of mRNA for interferon alpha and beta were investigated by means of reverse transcription and polymerase chain reaction using the corresponding sense primers. In none of the five patients thus studied could we find an induction of mRNA for interferon alpha or beta in the leukemic cells during treatment with pentostatin. Thus, response to pentostatin correlates with induction of 2,5OAS directly and the 2',5'-oligoadenylate system seems to be involved in cytotoxicity.
Ho
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AD
Northeastern Ontario Regional Cancer Centre, Sudbury, Canada.
Klotzbücher
A
A
Gross
A
A
Dietz
G
G
Mestan
J
J
Jakobsen
H
H
Hunstein
W
W
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis* / Q000097:blood; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D007943:Leukemia, Hairy Cell / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D015649:Pentostatin / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012074:Remission Induction
D016898:Interferon-alpha; D012333:RNA, Messenger; D015649:Pentostatin; D016899:Interferon-beta; D015088:2',5'-Oligoadenylate Synthetase