Enhanced expression of poly(ADP‐ribose) synthetase gene in malignant lymphoma

Abstract

Over-expression of cellular protooncogenes has been proposed to function in the initiation and maintenance of malignancies. In order to distinguish malignant lymphoma from reactive proliferative diseases, we surveyed the expression levels of three protooncogenes(c-myc, c-fos and c-myb) in malignant lymphoma and reactive proliferative diseases. An increased level of c-myc or c-fos mRNA was observed in one case, respectively, out of three malignant lymphomata. The other cases exhibited no enhancement in protooncogenes. These oncogenes are critically regulated during differentiation, but the half-life of c-myc mRNA was very short, and the level of the mRNA decreased to the initial level very quickly. Thus, the high level of the expression of these oncogenes may not always be maintained in all malignant cells. We then examined the level of mRNA for poly(ADP-ribose) synthetase in those cases. An enhanced expression for the synthetase gene was observed in all five malignant lymphomata tested, but no increase in the level of the mRNA was observed in any reactive proliferative cases or normal lymph nodes. These results suggest that enhanced expression of poly(ADP-ribose) synthetase gene seems to be a common characteristic of protopathic malignant lymphoma. By using the characteristics of malignant lymphoma, the level of mRNA for the synthetase may be applicable for differential diagnosis of malignant lymphoma from several pathologically indistinguishable diseases.

Targeted cancer therapies based on the inhibition of DNA strand break repair

“…Consistent with these findings are the data from a number of PARP inhibitors based on nicotinamide analogues, ranging from those with low micromolar activity, such as 3-aminobenzamide (Durkacz et al, 1980) to the more potent and specific PARP inhibitors that have been generated more recently (Southan and Szabo, 2003;Curtin, 2005;Farmer et al, 2005;Ratnam and Low, 2007). Enhanced PARP-1 expression or activity has been observed in a number of different tumour cell lines (Tomoda et al, 1991;Shiobara et al, 2001) and could provide a greater level of resistance to both endogenous genotoxic stress, as well as to DNA damage-inducing therapeutic agents. Evidence that PARP inhibitors can sensitize tumour cells to cytotoxic therapies such as temozolomide, topoisomerase I inhibitors, platinums and radiation (for example Calabrese et al, 2004;Miknyoczki et al, 2003;Chalmers et al, 2004) has consequently provided sufficient interest for a number of these compounds to be developed as clinical candidates (see Table 2 and Plummer, 2005;Fong et al, 2006).…”

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

“…A higher level of PARP-1 mRNA was observed in malignant lymphoma cells compared with normal lymph nodes (Tomoda et al, 1991) and in colorectal adenocarcinoma biopsies compared with adjacent non-tumour tissues and hyperplastic polyps (Nosho et al, 2006). Evaluation of PARP-1 protein expression in hepatocellular carcinoma (HCC) by western blotting revealed that it was significantly increased in HCC, especially moderately differentiated, compared with the non-tumour samples (Shimizu et al, 2004).…”

Potentiation of Temozolomide Cytotoxicity by Poly(ADP)Ribose Polymerase Inhibitor ABT-888 Requires a Conversion of Single-Stranded DNA Damages to Double-Stranded DNA Breaks

“…For example, PARP mRNA levels were found to be enhanced in malignant lymphomas but not in normal lymph nodes or reactive proliferative lymph nodes (17). Elevated PARP activity was identified in peripheral lymphocytes from patients with low-grade malignant non -Hodgkin's lymphoma (18), hepatocellular carcinomas (19,20), small-cell lung cancer lines (21), cervical cancer cells from patients (22), and the prostate cancer cell line LnCaP (23).…”