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Here, we focused primarily on the acute mitochondrial impact of 5FU, and although we arrived at the combination of 5FU and mitochondrial inhibitors (more specifically, 5FU and metformin) somewhat serendipitously, we have now generated evidence to support the use of 5FU and metformin combinations not only in patients with resistant or relapsed disease as previously suggested by others, but also in treatment-naive, first-line chemotherapy settings