A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

Schippinger, Walter; Jagoditsch, Michael; Sorré, C; Gnant, Michael; Steger, Guenther G.; Hausmaninger, H.; Mlineritsch, Brigitte; Schaberl-Moser, Renate; Hj, Mischinger; Hofbauer, F; Holzberger, Peter T.; Mittlböck, Martina; Jakesz, R.

doi:10.1038/sj.bjc.6602555

Cited by 27 publications

(14 citation statements)

References 22 publications

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“…Although the detailed mechanism for oxaliplatin-induced TS gene downregulation needs to be further elucidated, our result is concordant with two previous reports (Raymond et al, 2002;Yeh et al, 2004), which indicated that oxaliplatin could downregulate TS in cancer cells and thus potentiate the efficacy of 5-FU. As oxaliplatin and 5-FU have been shown to be highly synergistic not only in preclinical models (Raymond et al, 1997) but also in subsequent clinical trials (Rothenberg et al, 2003;Chao et al, 2004;Lordick et al, 2005;Schippinger et al, 2005;Cavanna et al, 2006), our data provide important information regarding why the combination of oxaliplatin and 5-FU results in better objective response than single use alone.…”

Section: Discussionmentioning

confidence: 74%

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

Chen

Tsou

et al. 2007

Br J Cancer

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To identify mechanisms underlying oxaliplatin resistance, a subline of the human gastric adenocarcinoma TSGH cell line, S3, was made resistant to oxaliplatin by continuous selection against increasing drug concentrations. Compared with the parental TSGH cells, the S3 subline showed 58-fold resistance to oxaliplatin; it also displayed 11-, 2-, and 4.7-fold resistance to cis-diammine-dichloroplatinum (II) (CDDP), copper sulphate, and arsenic trioxide, respectively. Interestingly, S3 cells were fourfold more susceptible to 5-fluorouracilinduced cytotoxicity due to downregulation of thymidylate synthase. Despite elevated glutathione levels in S3 cells, there was no alteration of resistant phenotype to oxaliplatin or CDDP when cells were co-treated with glutathione-depleting agent, l-buthionine-(S,R)-sulphoximine. Cellular CDDP and oxaliplatin accumulation was decreased in S3 cells. In addition, amounts of oxaliplatin-and CDDP -DNA adducts in S3 cells were about 15 and 40% of those seen with TSGH cells, respectively. Western blot analysis showed increased the expression level of copper transporter ATP7A in S3 cells compared with TSGH cells. Partial reversal of the resistance of S3 cells to oxaliplatin and CDDP was observed by treating cell with ATP7A-targeted siRNA oligonucleotides or P-type ATPaseinhibitor sodium orthovanadate. Besides, host reactivation assay revealed enhanced repair of oxaliplatin-or CDDP-damaged DNA in S3 cells compared with TSGH cells. Together, our results show that the mechanism responsible for oxaliplatin and CDDP resistance in S3 cells is the combination of increased DNA repair and overexpression of ATP7A. Downregulation of thymidylate synthase in S3 cells renders them more susceptible to 5-fluorouracil-induced cytotoxicity. These findings could pave ways for future efforts to overcome oxaliplatin resistance.

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Section: Discussionmentioning

confidence: 74%

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

Chen

Tsou

et al. 2007

Br J Cancer

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“…For this purpose, we performed a retrospective biomarker analysis in a prospective randomized cohort of stage III colon cancer patients treated with adjuvant 5FU. The prospective randomized trial (ABCSG-90) was initially reported by the Austrian Breast and Colorectal Cancer Study Group (ABCSG) in 2005 ( Schippinger et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients

Kandioler¹,

Mittlböck²,

Kappel³

et al. 2015

EBioMedicine

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We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status.ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol.Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344–3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic.The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.

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“…The utility of interferons has been also demonstrated for the treatment of colon carcinoma in a number of studies, as agents that can be administered alone or in combination with chemotherapeutics [9,28,29]. Dexamethasone was incorporated in our study protocol because steroids are commonly used in the post-operative management of patients undergoing bowel resection due to inflammatory bowel diseases [2,3].…”

Section: Discussionmentioning

confidence: 99%

The use of morphometric and fractal parameters to assess the effects of 5-fluorouracil, interferon and dexamethasone treatment on colonic anastomosis healing: an experimental study in rats

Łętowska-Andrzejewicz¹,

Torres²,

Torres³

et al. 2011

Folia Histochem Cytobiol.

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Adjuvant chemotherapy and steroid therapy have been demonstrated to interfere with the wound healing process. The aim of this study was to evaluate the effects of 5-fluorouracil, interferon, and dexamethasone, on the healing of colon anastomosis by assessing morphometric and fractal parameters of the colonic wall. An experimental anastomosis of the ascending colon was performed in 60 male Wistar rats, which were then randomly assigned to four groups. On the second to sixth post-operative days, the rats were administered 5-fluorouracil, interferon-a, dexamethasone, or 0.9% NaCl solution as a control. Macroscopic, histomorphometric and microbiological evaluation was performed in order to assess healing of the anastomosis. In three animals from the dexamethasone group, there was leakage of anastomosis; adhesion formation was highest in the interferon group, and significantly higher than in the control and 5-fluorouracil groups. Histomorphometric parameter alterations were most pronounced on the seventh and fourteenth post-operative days in all treatment groups, with submucosal thickness the most affected parameter. Connective tissue fractal dimension was significantly decreased in those animals treated with interferon and dexamethasone. All three pharmaceutical agents impaired healing of anastomosis, and promoted infection in the anastomosis and skin wound sites. As dexamethasone induced both morphometric and macroscopic alterations, it was considered the most detrimental in this study.

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A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

Cited by 27 publications

References 22 publications

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients

The use of morphometric and fractal parameters to assess the effects of 5-fluorouracil, interferon and dexamethasone treatment on colonic anastomosis healing: an experimental study in rats

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