Asco abstract. Just now getting around to them.
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Combretastatin A4 Phosphate (CA4P) Reduces Tumor Blood Flow in Animals and Man, Demonstrated by MRI.
Susan Mary Galbraith, Martin A Lodge, N. Jane Taylor, Ross Maxwell, Gill M Tozer, Vivien Prise, Ian Wilson, Luiza Sena, Adele Robbins, Anwar Padhani, Gordon Rustin, Mount Vernon Hospital, U.K., Middlesex, UK; Gray Laboratory Cancer Research Trust, Northwood, UK; Drug Development Office, The Cancer Research Campaign, London, UK; Mount Vernon Hospital, U.K. On behalf of the Phase I/II committee, The Cancer Resarch Campaign, Middlesex, UK.
CA4P dramatically reduces blood flow in animal tumors at non-toxic doses, causing haemorrhagic necrosis. Assessment of tumor microvascular kinetic changes in 17 of 32 patients in the CRC Phase I trial of CA4P were performed using dynamic contrast enhanced (DCE) MRI. Regions of interest (ROIs) were drawn around whole tumors and in skeletal muscle. The contrast concentration-time curve for each pixel was analyzed using a 4 compartment pharmacokinetic model and an assumed arterial input function. Median values of 2 parameters, Ktrans (transfer constant) and ve (leakage space) for each ROI were derived from this analysis. Verification that this technique reflects blood flow was performed by comparing DCE-MRI with measurement of absolute blood flow change using iodoantipyrine (IAP) in P22 carcinosarcomas in BD9 rats treated with 0, 10 and 100mg/kg of CA4P at 0, 1, 6 and 24hrs post treatment. Correlation between Ktrans and IAP measurements was good, R= 0.99*. Reproducibility of DCE-MRI kinetic estimates was assessed using 2 pretreatment scans performed within 1 week in 14 patients. From this data, group mean changes 15% (Ktrans), or 4% (ve) in tumor, and 15% or 18% in muscle might occur without treatment. In patients treated at 40mg/m2, there was no reduction in Ktrans. In 15 patients treated to date at 52mg/m2 there was a mean 41%* and 35%* reduction in Ktrans, and 15%* and 14%* reduction in ve, at 4 and 24 hrs after the first dose of CA4P. No significant changes were seen in muscle. DLT was reached at 114mg/m2. (*=p<0.05) These data show the potential of DCE-MRI as a response surrogate in novel antivascular treatment strategies. CA4P significantly reduces kinetic MR estimates that reflect tumor blood flow in man as well as animals at doses below the DLT. The trial was supported by OXiGENE Inc. |
