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Persistent Human Cytomegalovirus Infection Induces Drug Resistance and Alteration of Programmed Cell Death in Human Neuroblastoma Cells¹

Zentrum der Hygiene, Institut für Medizinische Virologie [Ji. C., Ja. C., J-U. V., R. K., H. W. D.], Zentrum für Kinderheilkunde und Jugendmedizin, Abteilung Pädiatrische Hämatologie und Onkologie [Ja. C., J-U. V., R. K., B. K., D. S.], and Abteilung Pädiatrische Neurologie [P. H. D.], Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany, and Clinical KlinLab Stresovice, Praha 6, Czech Republic [H. K.]

Infection with human cytomegalovirus (HCMV) is a common and generally asymptomatic affection in childhood. Its role in neuroblastoma (NB) patients has not yet been elucidated. As evidence grows that HCMV interacts with apoptotic signaling due to the interaction of HCMV gene products with cellular proteins of apoptotic pathways, we used human NB cell line UKF-NB-2 persistently infected with HCMV strain AD169 to study the effects of long-term HCMV infection on programmed cell death of neuroectodermal tumor cells. The cells designated UKF-NB-2^AD169 continued to produce infectious virus in successive subcultures over a period of more than 1 year. Up to 20% of cells expressed viral genes or produced infectious virus after initiation of infection. UKF-NB-2^AD169 cells were significantly less sensitive to the cytotoxic agents cisplatinum and etoposide than parental (noninfected) UKF-NB-2 cells. These effects were associated with decreased ability of UKF-NB-2^AD169 cells to undergo apoptosis and continuous viral replication. UKF-NB-2^AD169 cells showed increased levels of antiapoptosis Bcl-2 protein (up to 12-fold), whereas expression of p53 and c-myc was not changed. Treatment of UKF-NB-2^AD169 cells with ganciclovir, abolishing virus production, reestablished sensitivity to chemotherapy, lowered Bcl-2 expression, and facilitated inducibility of apoptosis to the level of the parental cell line. The results demonstrate that persistent HCMV infection confers resistance to cytotoxic agents on neuroectodermal tumor cells and protects from apoptosis, probably due to increased levels of Bcl-2 protein. Hence, it is conceivable that HCMV infection before or during tumorigenesis may contribute in some NB patients to failure of therapy.

¹ This work was supported by the foundations Hilfe für krebskranke Kinder Frankfurt am Main e.V., Frankfurter Stiftung für krebskranke Kinder, and Paul und Ursula Klein-Stiftung.

² To whom requests for reprints should be addressed, at Institut für Medizinische Virologie, Zentrum der Hygiene, Klinikum der Johann Wolfgang Goethe-Universität, Paul-Ehrlich-Straße 40, D-60596 Frankfurt am Main, Germany.

Received 8/ 5/97. Accepted 11/13/97.

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