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

D J Propper, N C Levitt, K O'Byrne, J P Braybrooke, D C Talbot, T S Ganesan, C H Thompson, B Rajagopalan, T J Littlewood, R M Dixon, A L Harris, D J Propper, N C Levitt, K O'Byrne, J P Braybrooke, D C Talbot, T S Ganesan, C H Thompson, B Rajagopalan, T J Littlewood, R M Dixon, A L Harris

Abstract

BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglobin, causing a reversible left-shift of the oxygen saturation curve (OSC) and tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia. In this phase II study, 17 patients with metastatic colorectal cancer resistant 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 infusion of 4 mg kg(-1) h(-1) for 5 h. MMC 6 mg m(-2) was administered over 15 min immediately after the BW12C bolus. The 15 evaluable patients had progressive disease after a median of 2 (range 1-4) cycles of chemotherapy. Haemoglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting for approximately 50% of total haemoglobin. The predominant toxicities--nausea/vomiting and vein pain--were mild and did not exceed CTC grade 2. Liver 31P magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combining a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour oxygen 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.

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