Phase II study of the oxygen saturation curve left shifting agent BW12C incombination with the hypoxia activated drug mitomycin C in advanced colorectal cancer

BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglo bin, causing a reversible left-shift of the oxygen saturation curve (OSC) a nd tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia , In this phase II study, 17 patients with metastatic colorectal cancer res istant to 5-fluorouracil (5-FU) received BW12C and MMC. BW12C was given as a bolus loading dose of 45 mg kg(-1) over 1 h, followed by a maintenance in fusion of 4 mg kg(-1) h(-1) for 5 h. MMC 6 mg m(-2) was administered over 1 5 min immediately after the BW12C bolus. The 15 evaluable patients had prog ressive disease after a median of 2 (range 1-4) cycles of chemotherapy. Hae moglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting f or approximately 50% of total haemoglobin. The predominant toxicities - nau sea/vomiting and vein pain - were mild and did not exceed CIC grade 2. Live r P-31 magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combinin g a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour o xygen delivery by at least 50%. However, BW12C in combination with MMC for 5-FU-resistant colorectal cancer is not an effective regimen. This could be related to drug resistance rather than a failure to enhance cytotoxicity. (C) 2000 Cancer Research Campaign.