title: A phase I study of the left-shifting agent BW12C79 plus mitomycin C and the effect on the skeletal muscle metabolism using 31P magnetic resonance spectroscopy.
abstract: BW12C79 stabilizes the oxyhemoglobin molecule resulting in a reversible left-shift of the oxygen saturation curve. The activity of a number of bioreductive anticancer drugs, such as mitomycin C, may be enhanced under hypoxic conditions. Twenty-four patients with various malignancies received BW12C79 and mitomycin C. BW12C79 was administered i.v. with a loading dose (20-50 mg/kg) over 1 h followed by a maintenance infusion of 4 mg/kg/h for 5 h. Percentage modification of the oxyhemoglobin (degree of left-shift) was dose related with maximum modification of 56% and was maintained for the duration of maintenance infusion of BW12C79. Hemoglobin electrophoresis showed a fast moving band consistent with the BW12C79-oxyhemoglobin complex. Side effects at the top dose level comprised headache, nausea/vomiting, vein irritation, and myocardial ischemia. One other patient suffered from an acute encephalopathy of unknown etiology a few days following BW12C79. 31P magnetic resonance spectroscopy of exercising calf muscles showed increased breakdown of high energy phosphate stores and a greater reduction in pH. Recovery of the high energy phosphate stores after exercise was slow. These results were consistent with reduced oxygen supply due to either a left shift of the oxygen saturation curve and/or reduced muscle blood flow. BW12C79 did not interfere with the pharmacokinetics of mitomycin C. In conclusion, this phase I study demonstrates the feasibility of achieving a significant left shift in the oxygen saturation curve in cancer patients which is maintained for at least 5 h with acceptable toxicity. The maximum tolerated dose of BW12C79 was 50 mg/kg loading infusion followed by a maintenance infusion of 4 mg/kg/h. Magnetic resonance spectroscopy results were consistent with reduced supply of oxygen to exercising skeletal muscle. BW12C79 may be of potential benefit as an adjunct to bioreductive drugs in the treatment of solid tumors.
authors.affiliation: Imperial Cancer Research Fund, Clinical Oncology Unit, Churchill Hospital, Headington, Oxford, United Kingdom.
authors.forename: P A
authors.initials: PA
authors.lastname: Philip
authors.forename: C H
authors.initials: CH
authors.lastname: Thompson
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
authors.forename: D
authors.initials: D
authors.lastname: Rea
authors.forename: K
authors.initials: K
authors.lastname: Mitchell
authors.forename: D J
authors.initials: DJ
authors.lastname: Taylor
authors.forename: N S
authors.initials: NS
authors.lastname: Stuart
authors.forename: I
authors.initials: I
authors.lastname: Dennis
authors.forename: B
authors.initials: B
authors.lastname: Rajagopalan
authors.forename: T
authors.initials: T
authors.lastname: Ganesan
mesh_terms: D000328:Adult; D000368:Aged; D001547:Benzaldehydes / Q000008:administration & dosage* / Q000009:adverse effects; D004359:Drug Therapy, Combination; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*
chemical_list: D001547:Benzaldehydes; D006454:Hemoglobins; D016685:Mitomycin; C039599:5-(2-formyl-3-hydroxyphenoxy)pentanoic acid; D010100:Oxygen