Tumorigenicity, Immunogenicity, and Virus Production in Mouse Melanoma Cells Treated with 5-Bromodeoxyuridine

Silagi, Selma; Beju, Delia; Wrathall, Jean R.; deHarven, Etienne

doi:10.1073/pnas.69.11.3443

Cited by 55 publications

(22 citation statements)

References 11 publications

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“…The parental TK+ and virus+ cell line F4 releases FV complex of NB host range. The major fraction of the inducible virus in B8 and B8/3 cells is, therefore, not LLV-F (NB tropic), but endoge- (22)(23)(24). The yield of endogenous virus in B8, after induction with BrdUrd, also is much higher than in nontransformed cells (2)(3)(4).…”

Section: Inhibition Of Virusmentioning

confidence: 88%

Induction of Endogenous Virus and of Thymidine Kinase by Bromodeoxyuridine in Cell Cultures Transformed by Friend Virus

Ostertag

Roesler

Krieg

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

106

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Thymidine kinase positive (TK+) N type cell lines that had been transformed by spleen focus-forming virus were established by transformation with NB tropic Friend virus complex. Thymidine kinase deficient (TK-) cell clones were isolated. Some of these cell clones release 1000-to 100,000-fold reduced amounts of Friend virus complex as compared to the TK+ parental cell clone. TK-clones were grown in medium without BrdUrd. Some of these TK-clones can be induced to release endogenous helper virus and transforming spleen focus-forming virus on reexposure to 10-10-4 M BrdUrd. BrdUrd inhibits the replication of C-type tumor viruses (1), whereas in some instances BrdUrd or IdUrd can induce endogenous C-type virus (2-4). In order to study the action of BrdUrd on virus replication and its role in the induction of endogenous virus we have used Friend virus (FV) infected and transformed DBA-2 mouse spleen cells in culture. The FV complex consists of two components, the lymphatic leukemia helper virus (LLV-F) and the replication-defective erythroid cell-transforming spleen focus-forming virus (SFFV-F) (5, 6). The RNA of the two virus types is presumably different in size and structure (7). We have established various cell lines transformed by the SFFV-F (8, 9) which, after another thymidine analogue, can be phosphorylated to azidothymidine triphosphate. However, the presence of an No group at the 3' terminal of the deoxysugar interferes with esterification, so presumably azidothymidine can only be added terminally to the growing DNA strand. Both azidothymidine as well as BrdUrd can be used to decrease the virus titer of BrdUrd-sensitive erythroleukemic cells. We have isolated several BrdUrd-resistant clones by treatment of sensitive cells with high doses of BrdUrd (11) and have shown that some of these clones have either decreased or barely detectable thymidine kinase (ATP: thymidine 5'-phosphotransferase, EC 2.7.1.75) activity (11). Furthermore, they have a 108-to 104-fold decreased virus titer. The decrease in C-type virus release can also be shown by electron microscopy.A temporary thymidine kinase activation is observed if BrdUrd is added to some virus negative lines. The same cells release large numbers of endogenous C-type and spleen focusforming virus on exposure to BrdUrd but not to azidothymidine. The RNA tumor virus which is induced by BrdUrd has mainly N-type host range properties unlike the original NB type FV complex which has been used for the transformation of our erythroid cell lines. Thymidine kinase induction and virus induction are always correlated. We have independent evidence (Ostertag, Crozier, and Swetly, unpublished)

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Section: Inhibition Of Virusmentioning

confidence: 88%

Induction of Endogenous Virus and of Thymidine Kinase by Bromodeoxyuridine in Cell Cultures Transformed by Friend Virus

Ostertag

Roesler

Krieg

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

106

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“…The parental tumor line for the transfectants is the C57BL/6-derived B78H1 melanoma, which is a poorly metastatic, amelanotic variant that was originally derived from the melanotic, B16 melanoma (31 (20,32). Because coexpression of Ii inhibits presentation of MHC II-restricted endogenously synthesized Ag in the tumor vaccines, we have tested whether B78H1 cells express Ii.…”

Section: B78h1 and B78h1/tap Transfectants Express I-a K The Model mentioning

confidence: 99%

Presentation of Endogenously Synthesized MHC Class II-Restricted Epitopes by MHC Class II Cancer Vaccines Is Independent of Transporter Associated with Ag Processing and the Proteasome

Dissanayake

Tuera

Ostrand‐Rosenberg

2005

The Journal of Immunology

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Cell-based vaccines consisting of invariant chain-negative tumor cells transfected with syngeneic MHC class II (MHC II) and costimulatory molecule genes are prophylactic and therapeutic agents for the treatment of murine primary and metastatic cancers. Vaccine efficacy is due to direct presentation of endogenously synthesized, MHC II-restricted tumor peptides to CD4+ T cells. Because the vaccine cells lack invariant chain, we have hypothesized that, unlike professional APC, the peptide-binding groove of newly synthesized MHC II molecules may be accessible to peptides, allowing newly synthesized MHC II molecules to bind peptides that have been generated in the proteasome and transported into the endoplasmic reticulum via the TAP complex. To test this hypothesis, we have compared the Ag presentation activity of multiple clones of TAP-negative and TAP-positive tumor cells transfected with I-Ak genes and the model Ag hen egg white lysozyme targeted to the endoplasmic reticulum or cytoplasm. Absence of TAP does not diminish Ag presentation of three hen egg white lysozyme epitopes. Likewise, cells treated with proteasomal and autophagy inhibitors are as effective APC as untreated cells. In contrast, drugs that block endosome function significantly inhibit Ag presentation. Coculture experiments demonstrate that the vaccine cells do not release endogenously synthesized molecules that are subsequently endocytosed and processed in endosomal compartments. Collectively, these data indicate that vaccine cell presentation of MHC II-restricted endogenously synthesized epitopes occurs via a mechanism independent of the proteasome and TAP complex, and uses a pathway that overlaps with the classical endosomal pathway for presentation of exogenously synthesized molecules.

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“…Extending the former hypothesis LIN and RIGGS have proposed that cellular functions which are subject to regulation are selectively inhibited by BUdR because BUdR-substituted DNA binds regulatory proteins tighter than does normal DNA (35). This may explain not only the high sensitivity to BUdR substitution of differentiating systems, but also the appearance of virus-like particles after growth of guinea pig cells (11), polyoma transformed cells (20), spleen cells (44), rat embryo cells (48) and mouse melanoma cells (49) in BUdR containing media. In all cases altered binding to DNA of regulatory proteins may result in disruption of finely adjusted regulatory systems which normally check viral growth (35).…”

Section: Effects On Enzyme Activities Of Budr Substitution In Dnamentioning

confidence: 99%

Mechanisms of action of 5-bromodeoxyuridine based on studies with tetrahymena pyriformis

Lykkesfeldt

1977

Carlsberg Res. Commun.

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The effect of BUdR on cell multiplication, DNA-, RNA-and protein synthesis in Tetrahymena pyriformis has been studied. Incorporation of BUdR up to 50% of the thymine sites in the DNA has no effect on the DNA synthetic rate at least for two generation times. RNA synthesis is inhibited shortly after addition of BUdR to exponentially growing populations, and experiments with synchronously growing populations have revealed that inhibition of RNA synthesis follows the incorporation of BUdR into the ribosomal RNA genes. A preferential inhibition of the synthesis of 25S and 17S ribosomal RNA has been found to take place at all degrees of BUdR substitution in DNA. Local changes in the structure of the DNA molecule leading to alterations in the pattern of transcription have been proposed as a model for the mode of action of BUdR. CONTENTS

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Tumorigenicity, Immunogenicity, and Virus Production in Mouse Melanoma Cells Treated with 5-Bromodeoxyuridine

Cited by 55 publications

References 11 publications

Induction of Endogenous Virus and of Thymidine Kinase by Bromodeoxyuridine in Cell Cultures Transformed by Friend Virus

Induction of Endogenous Virus and of Thymidine Kinase by Bromodeoxyuridine in Cell Cultures Transformed by Friend Virus

Presentation of Endogenously Synthesized MHC Class II-Restricted Epitopes by MHC Class II Cancer Vaccines Is Independent of Transporter Associated with Ag Processing and the Proteasome

Mechanisms of action of 5-bromodeoxyuridine based on studies with tetrahymena pyriformis

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