Data regarding oxidatively modified DNA bases suggest that cancer cells are more exposed to oxidative stress than adjacent non-tumorous tissue. This novel concept may contribute to the understanding of certain aspects of tumor biology such as activated transcription factors, genetic instability, chemotherapy-resistance and metastasis. We therefore tested this concept in human renal-cell carcinomas (RCCs) by evaluating the expression of hMTH1, an enzyme preventing the misincorporation into DNA of 8-0x0-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate), an oxidized form of dGTP in the nucleotide pool. The expression of hMTHl messenger RNA (mRNA) in RCC was significantly higher than that in adjacent nontumorous kidney. Moreover, advanced-stage tumors showed significantly higher hMTHl mRNA expression than early-stage tumors, and there was a modest linear correlation between hMTHl expression and c-myc expression. The results provide logical support for the concept of "persistent oxidative stress in cancer" and suggest a role of hMTHl mRNA level as a prognostic marker.o 1996 Wiley-Liss, Inc.It is generally accepted that reactive oxygen species (ROS) play a role in carcinogenesis by inducing mutagenic modifications in DNA (Halliwell and Gutteridge, 1989; Halliwell and Aruoma, 1993). However, ROS in tumor biology is a research area not intensively investigated so far. We recently measured in human renal-cell carcinoma (RCC) the amount of 8-0x0-2'-deoxyguanosine (8-0x0-dG, also called 8-hydroxy-2'-deoxyguanosine), a mutation-prone DNA base created by ROS (hydroxyl radical, singlet oxygen or direct photodynamic action) (Kasai and Nishimura, 1984; Kasai et al., 1992; Halliwell and Aruoma, 1993), and found significantly higher levels of 8-0x0-dG in RCC than in adjacent non-tumorous tissue at various stages of the disease (Okamoto et al., 1994). Based on our study and those of others, we hypothesized a concept of "persistent oxidative stress in cancer" that may contribute to aspects of tumor biology such as activated transcription factors and proto-oncogenes, genetic instability, chemotherapyresistance and metastasis (Toyokuni et al., 1995). A study was undertaken to test this hypothesis.At least 2 different metabolic pathways for the presence of 8-0x0-dG in DNA have been established (1) direct hydroxylation of C-8 of dG in DNA that causes a G:C to T A transversion upon replication (Kuchino et al
Summary Thymidine phosphorylase (TP) is associated with angiogenesis and the progression of solid tumours. High intracellular levels of this enzyme indicate increased chemosensitivity to pyrimidine antimetabolites. TP gene expression in 56 cases of epithelial ovarian cancer (27 of serous, 10 mucinous, 12 endometrioid, five clear cell and two undifferentiated) were analysed by polymerase chain reaction of RNA after reverse transcription. These included eight of low malignant potential. Twenty were stage I, four stage II, 27 stage III and five stage IV. The level of TP gene expression was presented by the relative yield of the TP gene to the β2-microglobulin gene. TP gene expression ranged from 0.19 to 5.38 (median 0.93). The value of TP gene expression in stage III-IV was significantly higher than that of TP gene expression in stage I-II (P = 0.0005). Histological grade significantly associated with TP gene expression (P = 0.008), but histological subtype did not (P = 0.166). A follow-up study of 34 cases after complete resection of the primary tumours by surgical operation was performed. TP gene expression of the cases with recurrence showed significantly higher levels compared to cases without recurrence (P = 0.049). Survival data were available for 47 of the 56 patients. The prognosis of the patients with high TP gene expression (equal to, or greater than, median) was to be significantly worse than patients with low TP gene expression (less than median) (P = 0.021). The TP gene expression level may play one of the key roles in the biology of ovarian epithelial cancer and define a more aggressive tumour phenotype. A new therapeutic intervention mediated by TP protein activity is anticipated.
We investigated immunohistochemical localization of P‐glycoprotein (F‐gp) on paraffin‐embedded sections from 103 cases of previously untreated pancreatic tumors and also analyzed multidrug resistance‐1 (MDR1) gene expression by polymerase chain reaction after reverse transcription in 35 cases. High positive staining for P‐gp was observed in 72.8% of pancreatic tumors and in 73.2% of ductal adenocarcinoma. In ductal adenocarcinoma, immunoreactivity of P‐gp was inversely correlated with biological aggressiveness of tumors determined by histologic grading (P<0.01), tumor size (P<0.01), retroperitoneal invasion (P<0.01) and portal invasion (P<0.05). Expression of the MDR1 gene was detected in all the pancreatic tumors examined and was significantly higher than that in normal pancreas (P<0.05). The levels of MDR1 mRNA showed a moderate correlation with those of P‐gp (r=0.62, P<0.0001). Higher expression levels of MDR1/P‐gp significantly correlated with better prognosis of patients with ductal carcinoma (P<0.05). Among patients with ductal carcinoma, the high staining group for P‐gp revealed a 3.5‐fold better prognosis compared with the low staining group (HR=3.47, 95% CI=1.62, 7.45; P=0.0016). In conclusion, MDR1 gene/P‐gp expression in pancreatic cancer without chemotherapy inversely correlates with biological aggressiveness and is an independent indicator of favorable prognosis.
Differences in cytogenetic changes, origins and natural histories between papillary and nonpapillary carcinoma may be associated with these distinct expression patterns of the resistance-related genes. Further study is required to clarify whether the differences in the expression patterns between these 2 structural types of carcinoma affect their chemosensitivities and clinical outcomes.
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