title: Ganciclovir inhibits lymphocyte proliferation by impairing DNA synthesis.
abstract: Cytomegalovirus (CMV) disease-related mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients has dramatically declined because of ganciclovir prophylaxis and preemptive therapeutic strategies. However, ganciclovir has not improved overall survival in randomized studies despite effectively preventing overt CMV disease. Moreover, recurrent posttransplant CMV antigenemia, associated with prolonged ganciclovir exposure, is a predictor of increased relapse of malignancy. We examined the hypothesis that ganciclovir itself may have a negative impact on immune reconstitution by testing the effect of ganciclovir on normal human lymphocytes in vitro. T-lymphocyte activation and proliferation, as measured by PHA-induced (3)H-thymidine uptake, was greatly reduced at therapeutic concentrations of ganciclovir (10 microg/mL) but not for foscarnet (300 microM/L). Moreover, ganciclovir impaired bromodeoxyuridine incorporation in proliferating lymphocytes, but did not impair lymphocyte survival or induce lymphocyte apoptosis. Collectively, these results show that ganciclovir suppresses T-lymphocyte proliferation in vitro by inhibiting DNA synthesis; with implications for T-lymphocyte function following allogeneic BMT.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14202, USA. minoo.battiwalla@roswellpark.org <minoo.battiwalla@roswellpark.org>
authors.forename: Minoo
authors.initials: M
authors.lastname: Battiwalla
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Rajinder P S
authors.initials: RP
authors.lastname: Bajwa
authors.forename: Marija
authors.initials: M
authors.lastname: Radovic
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Almyroudis
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
authors.forename: Paul K
authors.initials: PK
authors.lastname: Wallace
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Theresa
authors.initials: T
authors.lastname: Hahn
authors.forename: Philip L
authors.initials: PL
authors.lastname: McCarthy
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control; D004247:DNA / Q000096:biosynthesis*; D015774:Ganciclovir / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D000998:Antiviral Agents; D004247:DNA; D015774:Ganciclovir