Regional perfusion and oxygenation of tumors upon methylxanthine derivative administration

The use of methylxanthine derivatives has been postulated as a means of increasing tumor perfusion and thus ameliorating tumor hypoxia. The aim of this study was to quantify and compare the effects of three methylxanthine derivatives: pentoxifylline (PX), torbafylline (TB), and HWA 138 (HW) on tumor perfusion and oxygenation.

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. Regional red blood cell (RBC) flux was monitored using a multichannel laser Doppler device and tumor oxygenation on a more global level was assessed polarographically using an O2-sensitive catheter electrode. The methylxanthine derivatives were administered as a single dose intraperitoneally (for PX 50 mg/kg; for TB and HW 75 mg/kg).

Following drug administration, initial decreases in MABP down to 75% of baseline values were observed for all three substances. PX, HW, and TB caused initial transient reductions in mean RBC flux followed by gradual increases to values of 137 +/- 27%, 139 +/- 14%, and 122 + 14% respectively at t = 60 min. Following a small initial decrease upon drug administration, O2 partial pressure (pO2) rose to 160 +/- 31%, 153 +/- 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 in RBC flux and pO2 were still evident. When individual tumors were considered, a variety of patterns (including opposing effects) for changes in RBC flux were seen, not necessarily reflected in the mean values. Thus, while the methylxanthine derivatives caused an increased average tumor perfusion, there is evidence suggesting that a redistribution of tumor blood flow occurs which may amplify preexisting heterogeneity.

Substantial improvements in tumor oxygenation and perfusion were observed after administration of the methylxanthine derivatives. These substances may therefore be of use during tumor therapies in which the outcome may be detrimentally affected by the presence of hypoxia.