Biochemical modulation of 5-fluorouracil by leucovorin with or without interferon-α-2c in patients with advanced colorectal cancer: final results of a randomised phase III study

Hausmaninger, H.; Moser, Renate; Samonigg, Hellmut; Mlineritsch, Brigitte; Schmidt, Herbert J.; Pecherstorfer, Martin; Fridrik, Michael A.; Kopf, Ch.; Nitsche, D.; Kaider, Alexandra; Ludwig, Heinz

doi:10.1016/s0959-8049(98)00397-9

Cited by 13 publications

(3 citation statements)

References 24 publications

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“…More than two decades ago, multiple studies have demonstrated that ectopic treatment with recombinant type I IFN or type II IFN can enhance 5‐FU‐mediated cytotoxicity in cell lines in vitro (e.g., Morikawa et al, 1989b; Houghton et al, 1993) and in xenograft models in immunodeficient mice (e.g., Morikawa et al, 1989a). However, in a clinical trial, systemic administration of IFN together with 5‐FU‐based chemotherapy showed more toxicity without clinical benefit over chemotherapy alone (Hausmaninger et al, 1999). In our data, the presence of STING does not substantially affect the in vitro sensitivity of colon cancer cells toward 5‐FU, suggesting that the levels of IFNs produced endogenous by cancer cells are insufficient to achieve enhanced cytotoxic effects in vitro .…”

Section: Discussionmentioning

confidence: 99%

5‐Fluorouracil efficacy requires anti‐tumor immunity triggered by cancer‐cell‐intrinsic STING

et al. 2021

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5‐Fluorouracil (5‐FU) is a widely used chemotherapeutic drug, but the mechanisms underlying 5‐FU efficacy in immunocompetent hosts in vivo remain largely elusive. Through modeling 5‐FU response of murine colon and melanoma tumors, we report that effective reduction of tumor burden by 5‐FU is dependent on anti‐tumor immunity triggered by the activation of cancer‐cell‐intrinsic STING. While the loss of STING does not induce 5‐FU resistance in vitro, effective 5‐FU responsiveness in vivo requires cancer‐cell‐intrinsic cGAS, STING, and subsequent type I interferon (IFN) production, as well as IFN‐sensing by bone‐marrow‐derived cells. In the absence of cancer‐cell‐intrinsic STING, a much higher dose of 5‐FU is needed to reduce tumor burden. 5‐FU treatment leads to increased intratumoral T cells, and T‐cell depletion significantly reduces the efficacy of 5‐FU in vivo. In human colorectal specimens, higher STING expression is associated with better survival and responsiveness to chemotherapy. Our results support a model in which 5‐FU triggers cancer‐cell‐initiated anti‐tumor immunity to reduce tumor burden, and our findings could be harnessed to improve therapeutic effectiveness and toxicity for colon and other cancers.

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Section: Discussionmentioning

confidence: 99%

5‐Fluorouracil efficacy requires anti‐tumor immunity triggered by cancer‐cell‐intrinsic STING

et al. 2021

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“…Palmeri et al (35) noted significantly longer survival in patients who achieved a complete response after IFN-• therapy; however, overall survival was not affected. Hausminger et al (36) reported that the addition of IFN to 5-FU/Leucovorin (LV), in schedules and doses used in the present study, did not provide any clinical benefit over 5-FU/LV. Colucci et al (37) reported that no differences in the objective response rate, median duration of response, time to progression, and median survival [comparison between combination of levofolinic acid (l-FA)/5-FU and combination of l-FA/5-FU/IFN].…”

Section: -----------------------------------------------------------------------------------------------------mentioning

confidence: 51%

Expression of type I interferon receptor as a predictor of clinical response to interferon-α therapy of gastrointestinal cancers

Ôta

Nagano²,

Doki³

et al. 2006

Oncol Rep

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Interferon (IFN) is used in the treatment of many malignancies and viral disorders. We recently reported a significant correlation between the efficacy of IFN-• combined with chemotherapy in the treatment of advanced hepatocellular carcinoma (HCC) and IFN-•/type I IFN receptor (IFNAR2) expression. It is possible that the expression of IFNAR2 in gastrointestinal cancerous tissue, apart from HCC, may predict the efficacy of IFN-• combination therapy. We investigated the expression of IFNAR2 in 100 gastrointestinal cancerous tissues. IFNAR2 expression was examined using immunohistochemistry, in surgically resected tissue samples (20 esophageal, 20 gastric, 20 colorectal, 20 cholangiocarcinoma, and 20 pancreatic samples). The expression rate of IFNAR2 was 35.0% (7/20), 25.0% (5/20), 20.0% (4/20), 45.0% (9/20), and 25.0% (5/20) in esophageal, gastric cancer, colorectal, cholangiocarcinoma and pancreatic cancer samples, respectively. In our previous report, the expression rate of IFNAR2 in HCC samples was 64.8% (59/91). Thus, the expression rates of IFNAR2 in the five types of gastrointestinal cancers tested here were low, compared with HCC. The clinical efficacy of IFN-• monoor combination therapies in patients with gastrointestinal neoplasms is expected to be lower than in patients with HCC based on the expression level of IFNAR2.

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“…Nevertheless, systemic administration of IFN-α [ 92 ] or IFN-β [ 93 ] should be considered as a supportive treatment after hepatectomy or tumor ablation, which may prevent or delay tumor relapses in patients with HCC [ 94 ]. A combination of IFN-α and chemotherapy was applied to patients for treatment of advanced HCC [ 95 , 96 ] and metastatic CRC to the liver [ 97 ]; however, randomized controlled studies failed to demonstrate that combination protocol results in improved outcome when compared to chemotherapy treatment alone [ 98 , 99 ].…”

Section: Systemic Use Of Immunostimulatory Cytokinesmentioning

confidence: 99%

Immunotherapy for liver tumors: present status and future prospects

et al. 2009

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Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field.

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Biochemical modulation of 5-fluorouracil by leucovorin with or without interferon-α-2c in patients with advanced colorectal cancer: final results of a randomised phase III study

Cited by 13 publications

References 24 publications

5‐Fluorouracil efficacy requires anti‐tumor immunity triggered by cancer‐cell‐intrinsic STING

5‐Fluorouracil efficacy requires anti‐tumor immunity triggered by cancer‐cell‐intrinsic STING

Expression of type I interferon receptor as a predictor of clinical response to interferon-α therapy of gastrointestinal cancers

Immunotherapy for liver tumors: present status and future prospects

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