No abstract

Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD.

Tumor cells of Epstein-Barr virus (EBV)-associated Hodgkin's disease (HD) express the viral protein, latent infection membrane protein-1 (LMP1), but evade cytotoxic responses normally directed at this antigen. We tested whether local production of the immunoregulatory interleukins (IL)-4 and -10 may have a role in this process. IL-4 RNA was not detectable in any of the HD cases. By contrast, isotopic in situ hybridization and correlation with the presence of EBV gene products showed significantly higher proportions of cases with IL-10 expressing tumor cells in LMP1-positive (17 of 26, 66%) as compared with LMP1-negative HD cases (six of 37, 16%). Absence of EBV BCRF1 RNA indicated that the transcripts originated from the cellular IL-10 gene. Similarly, an association between IL-10 expression and EBV-infection of tumor cells was found in AIDS-related malignant non-Hodgkin lymphomas (ARL). Very small proportions of EBV-infected cells, mainly blasts, expressed IL-10 in infectious mononucleosis tonsils. Thus, although not entirely exclusive to EBV-positive cases, IL-10 expression is frequently associated with EBV-infection in HD and ARL and appears to be upregulated by EBV, most likely through LMP1. In view of the established inhibitory effects of IL-10 on cell mediated immunity, it is suggested that IL-10 expression may contribute to evasion of LMP1- positive cells from cytotoxicity directed at viral antigens.

Tissue specimens from 26 cases of Hodgkin's disease (HD) and six HD-derived cell lines were analysed for tumour necrosis factor (TNF), lymphotoxin (LT), and interleukin (IL)-6 RNA transcripts by in situ hybridization, in some cases subsequent to immunohistology for CD30 antigen. LT and TNF transcripts were found in tumour cells of all cases; IL-6 gene transcripts were detectable in 19/23 cases. Presence of RNA specific for these cytokines was not correlated with any of the following parameters: sex, symptoms and histotype, as well as immunophenotype and association of the tumour cells with Epstein-Barr virus. Rather, the presence of LT, TNF and IL-6 transcripts appeared to characterize Hodgkin and Reed-Sternberg cells in general, supporting concepts which suggest that HD represents a malignancy of cytokine secreting activated cells, and that many of the features distinguishing HD from other malignant lymphomas may ultimately be due to expression of cytokines. LT and TNF RNA transcripts were also found in five HD-derived cell lines, whereas supernatants of these cell lines contained high levels of LT, but low or undetectable levels of TNF activity. This suggests that, although not detectable at the level of RNA transcripts, differences between HD cases may exist on the level of cytokine gene transcript processing, translation and polypeptide secretion.