REGIONAL PERFUSION AND OXYGENATION OF TUMORS UPON METHYLXANTHINE DERIVATIVE ADMINISTRATION

Purpose: The use of methylxanthine derivatives has been postulated as a means of increasing tumor perfusion and thus ameliorating tumor hypo xia. The aim of this study was to quantify and compare the effects of three methylxanthine derivatives: pentoxifylline (PX), torbafylline (T B), and HWA 138 (HW) on tumor perfusion and oxygenation. Methods and M aterials: Anesthetized Sprague Dawley rats with DS-sarcomas implanted subcutaneously onto the hind foot dorsum were used in this study. Mean arterial blood pressure (MABP) was measured throughout experiments. R egional red blood cell (RBC) flux was monitored using a multichannel l aser Doppler device and tumor oxygenation on a more global level was a ssessed polarographically using an O-2-sensitive catheter electrode. T he methylxanthine derivatives were administered as a single dose intra peritoneally (for PX 50 mg/kg; for TB and HW 75 mg/kg). Results: Follo wing drug administration, initial decreases in MABP down to 75% of bas eline values were observed for all-three substances. PX, HW, and TB ca used initial transient reductions in mean RBC flux followed by gradual increases to values of 137 +/- 27 %, 139 +/- 14 %, and 122 +/- 14 % r espectively at t = 60 min. Following a small initial decrease upon dru g administration, O-2 partial pressure (pO(2)) rose to 160 +/- 31 %, 1 53 +/- 34 %, and 121 +/- 11 % for PX, HW, and TB, respectively at t = 60 min. At the end of the observation period (t = 90 min), increases i n RBC flux and pO(2) were still evident. When individual tumors were c onsidered, a variety of patterns (including opposing effects) for chan ges in RBC flux were seen, not necessarily reflected in the mean value s. Thus, while the methylxanthine derivatives caused an increased aver age tumor perfusion, there is evidence suggesting that a redistributio n of tumor blood flow occurs which may amplify preexisting heterogenei ty. Conclusions: Substantial improvements in tumor oxygenation and per fusion were observed after administration of the methylxanthine deriva tives. These substances may therefore be of use during tumor therapies in which the outcome may be detrimentally affected by the presence of hypoxia. (C) 1998 Elsevier Science Inc.