Induction or suppression of SV40 amplification by genotoxic carcinogens, non-genotoxic carcinogens or tumor promoters

Fahrig, Rudolf; Steinkamp-Zucht, Angela

doi:10.1016/0027-5107(96)00061-9

Cited by 11 publications

(3 citation statements)

References 33 publications

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“…(E)-5-(2-Bromovinyl)-2-deoxyuridine (BVDU, RP101) is well established as a highly potent and selective anti-viral agent, inhibiting both herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) [ 76 ]. BVDU has also been shown to suppress 2-amino-6-mercaptopurine-induced SV40 viral amplification in Chinese hamster cells and abolished triethylene melamine (TEM)-induced mitotic recombination in yeast [ 77 ]. Importantly, gene amplification and recombination may be regarded as contributors to acquired chemoresistance.…”

Section: Introductionmentioning

confidence: 99%

Novel strategies to prevent the development of multidrug resistance (MDR) in cancer

et al. 2017

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The development of multidrug resistance (MDR) is one of the major challenges to the success of traditional chemotherapy treatment in cancer patients. Most studies to date have focused on strategies to reverse MDR following its development. However, agents utilizing this approach have proven to be of limited clinical use, failing to demonstrate an improvement in therapeutic efficacy with almost no significant survival benefits observed in cancer clinical trials. An alternative approach that has been applied is to prevent or delay MDR prior or early in its development. Recent investigations have shown that preventing the emergence of MDR at the onset of chemotherapy treatment, rather than reversing MDR once it has developed, may assist in overcoming drug resistance. In this review, we focus on a number of novel strategies used by small-molecule inhibitors to prevent the development of MDR. These agents hold great promise for prolonging the efficacy of chemotherapy treatment and improving the clinical outcomes of patients with cancers that are susceptible to MDR development.

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Section: Introductionmentioning

confidence: 99%

Novel strategies to prevent the development of multidrug resistance (MDR) in cancer

et al. 2017

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“…Table 4 shows the main effects of RP101 in relation to each other to allow a better understanding of its mode of action [1,[35][36][37][38]. The numerous immunomodulatory and chemosensitizing properties of RP101 are probably working in concert to optimize chemotherapy and to inhibit chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

RP101 improves the efficacy of chemotherapy in pancreas carcinoma cell lines and pancreatic cancer patients

Fahrig¹,

Quietzsch²,

Heinrich³

et al. 2006

Anti-Cancer Drugs

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RP101 [(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU)], which supports apoptosis and prevents the acquisition of chemoresistance, was tested in cultured human pancreatic tumor cells. RP101 downregulated uridine phosphorylase, a marker of poor prognosis, and APEX1, which is involved in DNA repair, and repressed Stat3 and its target vascular endothelial growth factor. Furthermore, RP101 activated antitumor immunity as demonstrated by enhanced cytolytic activity of NK-92 natural killer cells. This was concomitant with an enhanced expression of lymphotoxins alpha and beta, natural killer cell transcript 4, tumor necrosis factor LIGHT/TNFSF-14, and intercellular adhesion molecule-1 in pancreas carcinoma cells. These results encouraged us to investigate the effect of RP101 in pancreas cancer patients. Here, we present data from two RP101 combination therapy schemes. In a first pilot study, 13 patients in stage III and VI of the disease were treated with gemcitabine +cisplatin+RP101. RP101 co-treatment enhanced remissions, survival and time to progression. Seventy-seven percent of the patients lived or have lived longer than 1 year, and 23% have lived more than 2 years. Median survival was 447 days, time to progression 280 days and the response rate 33%. A second study with 21 patients in similar stages of disease, treated with RP101+gemcitabine alone, confirmed the results of the pilot study. Eighty-three percent of the presently evaluable patients live or lived 0.5 years or longer and 33% 1 year or longer. Considering both studies, the tumor control was 94%. The data indicate that acquisition of chemoresistance was prevented and the antitumor efficacy of standard chemotherapy was improved. To our knowledge, RP101 co-treatment is more efficient than any other regimen published.

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“…However, several reports have described the genotoxicity of these compounds. Fahrig and Steinkamp-Zucht (1996) reported that TAA induced the amplification of SV40 virus DNA in transformed CO631-cells as well as genotoxic compounds. These results indicate that mutated cells with accumulated DNA damage due to increased proliferation respond to cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Detection of initiating potential of non-genotoxic carcinogens in a two-stage hepatocarcinogenesis study in rats

et al. 2014

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-We previously reported a toxicogenomics-based prediction model for hepatocarcinogens in which the expression patterns of signature genes following repeated doses of either genotoxic or nongenotoxic compounds were similar. Based on the results of our prediction model, we hypothesized that repeated doses of non-genotoxic carcinogens might have initiating potential. Here, we conducted a twostage hepatocarcinogenesis study in rats exposed to the initiating agent nitrosodiethylamine (DEN), and hepatotoxic compounds thioacetamide (TAA), methapyrilene (MP) and acetaminophen (APAP) for 1-2 weeks followed by the liver tumor promoter phenobarbital (PB). The duration of initial treatment was determined based on positive results from our prediction model. Combined treatment of 3 or 30 mg/kg of genotoxic DEN and PB induced marked increases in altered hepatocellular foci and a DEN dose-dependent increase in the number and area of glutathione S-transferase-placental form (GST-P)-positive foci. A low number of altered hepatocellular foci were also observed in rats treated with TAA at a dose of 45 mg/kg. MP at a dose of 100 mg/kg induced a very low number of foci, but APAP did not. Hierarchical clustering analysis using gene expression data revealed that 2-week treatment with TAA at a dose of 30 mg/kg and MP at 45 mg/kg induced specific expression of DNA damage-related genes, similar to 1-week treatment with DEN at a dose of 30 mg/kg. These results suggest that TAA and MP induce DNA damage, which partially supports our hypothesis. Although this study does not indicate whether tumor growth in response to these compounds can be assessed in this model, our results suggest that cumulative treatment with nongenotoxic TAA might have initiating potential in the liver.

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Induction or suppression of SV40 amplification by genotoxic carcinogens, non-genotoxic carcinogens or tumor promoters

Cited by 11 publications

References 33 publications

Novel strategies to prevent the development of multidrug resistance (MDR) in cancer

Novel strategies to prevent the development of multidrug resistance (MDR) in cancer

RP101 improves the efficacy of chemotherapy in pancreas carcinoma cell lines and pancreatic cancer patients

Detection of initiating potential of non-genotoxic carcinogens in a two-stage hepatocarcinogenesis study in rats

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