title: BW12C: effects on tumour hypoxia, tumour thermosensitivity and relative tumour and normal tissue perfusion in C3H mice.
abstract: BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) is an agent which stabilises oxyhaemoglobin and thus reduces oxygen delivery to tissues. It is of interest as a possible potentiator of bioreductive agents and/or hyperthermia. The increases in radiobiological hypoxic fraction of RIF-1 and KHT tumours 30 min after 70 mg kg-1 BW12C i.v. were measured and shown to be similar; factors (+/- 2 s.e.) ranged from 3.87 (2.84-5.29) to 5.92 (1.92-18.2) despite the large variation in initial hypoxic fraction, from 0.30 (0.18-0.50) % for RIF-1 intramuscularly in the leg to 16.3 (14.7-18.1) % for subcutaneous KHT flank tumours. Thermosensitivity of intramuscular KHT leg tumours was not enhanced by 70 mg kg-1 BW12C 30 min before heating at 43 degrees C, 43.5 degrees C or 44 degrees C, assayed by regrowth delay. The effect of 70 mg kg-1 BW12C on relative tissue perfusion (RTP), assayed by 86Rb extraction, was measured from 0.5 h to 6 h after treatment. After 1 h RTP (+/- 2 s.e.) in RIF-1 tumours was reduced to 84 +/- 5.7% and 68 +/- 9.6% of control in leg and flank tumours respectively, and to 86 +/- 6.4% in leg muscle while flank skin RTP was unaltered at 109 +/- 8.6%. There were substantial increases in kidney (149 +/- 10.7%) spleen (173 +/- 22.1%) and lung (128 +/- 10.4%) at 1 h but in liver there was a decrease at 2 h to 85 +/- 8.4%. Dose response studies showed that the threshold dose for reduction of tumour RTP is between 55 and 70 mg kg-1, but perturbations in normal tissue RTP occur at lower doses, e.g. 40 mg kg-1 for spleen. BW12C had minimal effects on renal function measured by 51CrEDTA clearance. The data as a whole indicate that reduction in tumour perfusion is likely to be an important determinant in the increase in tumour hypoxia induced by BW12C.
authors.affiliation: Medical Research Council Unit, Cambridge, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Honess
authors.forename: D E
authors.initials: DE
authors.lastname: Hu
authors.forename: N M
authors.initials: NM
authors.lastname: Bleehen
mesh_terms: D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006979:Hyperthermia, Induced; D007668:Kidney / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D012878:Skin Neoplasms / Q000098:blood supply / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D001547:Benzaldehydes; D011837:Radiation-Protective Agents; C039599:5-(2-formyl-3-hydroxyphenoxy)pentanoic acid