title: 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.
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.
authors.affiliation: ICRF Medical Oncology Unit, Churchill Hospital, Headington, Oxford, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Propper
authors.forename: N C
authors.initials: NC
authors.lastname: Levitt
authors.forename: K
authors.initials: K
authors.lastname: O'Byrne
authors.forename: J P
authors.initials: JP
authors.lastname: Braybrooke
authors.forename: D C
authors.initials: DC
authors.lastname: Talbot
authors.forename: T S
authors.initials: TS
authors.lastname: Ganesan
authors.forename: C H
authors.initials: CH
authors.lastname: Thompson
authors.forename: B
authors.initials: B
authors.lastname: Rajagopalan
authors.forename: T J
authors.initials: TJ
authors.lastname: Littlewood
authors.forename: R M
authors.initials: RM
authors.lastname: Dixon
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D001547:Benzaldehydes / Q000009:adverse effects / Q000627:therapeutic use*; D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000009:adverse effects / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism*
chemical_list: D001547:Benzaldehydes; D016685:Mitomycin; C039599:5-(2-formyl-3-hydroxyphenoxy)pentanoic acid; D010100:Oxygen