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Fludarabine-Mediated Inhibition of Nucleotide Excision Repair Induces Apoptosis in Quiescent Human Lymphocytes1

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Fludarabine-Mediated Inhibition of Nucleotide Excision Repair Induces Apoptosis in Quiescent Human Lymphocytes1 Vol. 2, 1731-1741, October 1996 Clinical Cancer Research 1731 Fludarabine-mediated Inhibition of Nucleotide Excision Repair Induces Apoptosis in Quiescent Human Lymphocytes1 Alex Sandoval, Ugo Consoli, and 2). The deoxyadenosine analogue fludarabine is currently used William Plunkett2 alone and in combination for treating hematological malignan- cies such as chronic lymphocytic leukemia (3-5), low-grade Departments of Clinical Investigation [A. S., W. P.] and Hematology bymphoma (6, 7), acute myebogenous leukemia (8-10), and EU. C.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 mycosis fungoides/S#{233}zary syndrome (1 1). Previous studies in- dicate that the nucleoside of fludarabine, F-ara-A,3 is a potent inhibitor of cellular DNA synthesis. This inhibition is brought ABSTRACT about by actions of the triphosphate F-ara-ATP. Indirect inhi- Incorporation of fludarabine, 941-D-arabinofuranosyl- bition occurs through the action of F-ara-AIP on ribonucleotide 2-fluoroadenine (F-ara-A), into replicating DNA inhibits reductase, causing a decrease in cellular deoxynucleotide further chain elongation and is the critical event in F-ara- triphosphate pools required for DNA synthesis (12). Reducing A-mediated cytotoxicity. We have used the normal cellular deoxynucleotide triphosphate bevels facilitates the use of F-ara- process of nucleotide excision repair to create an opportu- ATP by DNA polymerases for incorporation of F-ara-A-AMP nity for F-ara-A incorporation into the DNA of noncycling into DNA, which is the critical event in F-ara-A-mediated cells. Irradiation of quiescent lymphocytes with UV light cytotoxicity (13, 14). F-ara-ATP is also known to be a potent (254 nm, 0.5-30 J/m2) in the presence of [3H]F-ara-A pro- inhibitor of DNA primase activity (15). In CCRF-CEM lym- duced a dose-dependent increase in F-ara-A monophosphate phoblastoid cells, 95% of the F-ara-AMP incorporated into incorporation into DNA that reflected a 60-70% inhibition DNA was located in the 3-terminal position ( 14). In vitro DNA of DNA repair at 2 h. Lymphocytes pretreated with 3 pi primer extension assays have demonstrated that incorporation of F-ara-A for 2 h before irradiation with 0.5 or 2.0 JIm2 were F-ara-AMP is capable of terminating strand elongation mediated incubated for 24 h in the presence or absence of F-ara-A. by DNA polymerases a and #{128}and that this inhibition is reduced Morphological features of apoptosis and DNA cleavage into by the addition of dATP, which competes for insertion into the high molecular weight fragments were increased in cells elongating DNA strand (14). The incorporated F-ara-AMP, treated with UV plus F-ara-A compared to those treated which cannot be extended, is resistant to excision by DNA with UV or F-ara-A alone. FACScan analysis confirmed the pobymerase-associated 3’-5’ exonuclease (16) and also inhibits morpholcgical and biochemical results. A 2-h pulse of F- ligation by DNA ligase I ( 17). Cell death occurs by apoptosis ara-A produced intracellular F-ara-ATP bevels of 40 riM, and is cell cycle rebated; F-ara-A-induced cell death was shown and removal of F-ara-A from the media resulted in a to be S-phase specific in a synchronized population of cells (13). monophasic elimination (r 0.88) in F-ara-AIP levels with These results lead to the question of how F-ara-A-termi- a half-life of 5.6 h. Lymphocytes undergoing apoptosis dem- nated DNA might be repaired. It has been reported that cells that onstrated a G0 DNA content, indicating that entry into the survive F-ara-A treatment have a higher frequency of gene cell cycle was not required. This study demonstrates that deletions (18), indicating some attempt to repair the lesion. At F-ana-AMP is incorporated into DNA during UV-induced the moment, little is known about the recognition and repair of repair in quiescent lymphocytes and that this is associated nucleoside analogues in DNA. Because enzymes involved in with the inhibition of ongoing DNA repair and an increased DNA replication are also involved in DNA repair, it is likely incidence of apoptosis Combinational therapies involving that F-ara-A is capable of inhibiting DNA repair as it does fludarabine with agents and modalities that initiate DNA replication. If so, there would be clinical relevance for protocols repair may have clinical relevance in the treatment of hu- that combine fiudarabine with agents and modalities that initiate man malignancies. DNA repair. The ability of nucleoside analogues to inhibit DNA repair processes at the polymerization step has been reported INTRODUCTION previously ( I 9 -22) with some combinational therapies currently Nucleoside analogues are potent antimetabobites that dem- employed in the clinic (23). Unlike agents used previously to onstrate antitumor activities against a variety of malignancies ( 1, inhibit DNA repair, such as ara-C and hydroxyurea, the nude- otide metabobites of F-ara-A interfere with multiple reactions that are required for DNA replication; this suggests that a Received 4/1/96; revised 6/27/96; accepted 7/3/96. ) Supported in part by Grant CA28596 from the National Cancer Insti- tute, the Department of Health and Human Services, and Grant DHP- 1 from the American Cancer Society. 3 The abbreviations used are: F-ara-A, 9-3-o-arabinofuranosyl-2-fiuoroad- 2 To whom requests for reprints should be addressed, at Department of enine; NER, nucleotide excision repair; am-C. l-3-D-arabinofuranosylcy- Clinical Investigation, Box 71, The University oflexas M. D. Anderson tosine: ISEL, In situ end labeling; F-ara-ATP, 9-3-D-arabinofuranosyl-2- Cancer Center, Houston, TX 77030. Phone: (713) 792-3335; Fax: (713) fluoroadenine-5’-triphosphate; F-ara-AMP, 943-D-arabinofuranosyl-2- 794-4316. fluoroadenine-5 ‘-monophosphate. Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 1996 American Association for Cancer Research. 1732 Apoptosis in Quiescent Lymphocytes strategy of combining F-ara-A with an agent that evokes a DNA diluted 1:3 with cold PBS [(0.135 si NaC1, 2.7 msvi KC1, 1.5 mM repair response might have more profound effects on cell via- KH2PO4, and 8 mi Na2HPO4 (pH 7.4)] and layered onto bility. Ficoll-Hypaque (specific gravity, 1 .086). Blood was centrifuged NER is conducted by a complex system of proteins (at least at 1500 rpm for 20 mm, and mononuclear cells were removed 20 peptides are believed to be involved), many with dual func- from the interphase. Cells were washed twice with cold PBS and tions, that work in four basic steps (24-26). Irradiation of resuspended in 10 ml RPM! 1640 without phenol red, supple- cellular DNA by UV light, for example, induces the formation mented with 10% fetal calf serum and peniciblin-streptomycin of pyrimidine dimers and photoproducts that are identified by (Life Technologies, Inc., Grand Island, NY). Cells were counted NER recognition proteins (step 1). Step 2 involves incision of and diluted to a concentration of 2 X 106 cells/mI and incubated the damaged strand by endonucleases and local unwinding of at 37#{176}Covernight to remove monocytes and acclimate the cells the region by helicase activity. In step 3, the damaged strand is to culture conditions. Lymphocytes were collected carefully, removed, and the resulting gap is stabilized by repair proteins. counted, and resuspended at a concentration of 2 X 106 cells/mb. Step 4 results in synthesis of the DNA patch, presumably by Drug Exposure and Irradiation. Preliminary studies DNA polymerases #{128}or (27), using the complementary strand demonstrated that 3 p.M F-ara-A was the highest concentration as a template and strand ligation by DNA ligase. It is in step 4, that induced minimal apoptosis at 24 h of incubation and was the polymerizing step, that the action of F-ara-A as a chain the dosage used throughout these experiments. Lymphocytes terminator is exploited and in which NER would presumably be were incubated with 3 JiM F-ara-A for 2 h before irradiation and inhibited. Two general pathways are involved in NER, tran- continuously throughout the incubation periods. Other samples scription-coupled repair and global repair. The former involves were incubated with 3 J.M F-ara-A for 2 h, then washed free of the removal of lesions that block ongoing transcription (28 -31), media containing F-ara-A and resuspended in media without whereas the latter recognizes and repairs damage occurring in F-ara-A before irradiation. Lymphocytes were transferred to the genome overall. Because F-ara-A would affect the polym- 30-mm or 60-mm dishes and irradiated with UV light (254 nm) erization step of NER, both pathways would be affected by from a UVGL-25 lamp (UVP, Inc., San Gabriel, CA). Radiation F-ara-AMP incorporation into the repair patch. intensity was measured by a UVX-25 UV meter (UVP, Inc.). The purpose of this study was to use the normal cellular Immediately after irradiation, 1 ml of media was added to each function of NER to exploit the cytotoxic potential of F-ara-A. dish and samples were incubated for the indicated times at 37#{176}C. With an understanding of the molecular actions of F-ara-A, we Examination of Cell Morphology. At the indicated hypothesized that the induction of DNA repair processes by UV times, 5 X l0 cells were centrifuged onto glass slides, fixed irradiation would permit F-ara-A incorporation into the DNA with methanol, and stained with Wright’s Giemsa. Cell mor- repair patch. Incorporated F-ara-AMP would resist excision and phology was examined by light microscopy using a Nikon terminate polymerization, causing irreversible damage recog- HFX-II microscope.
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