Acute effects of tumor necrosis factor alpha or lymphotoxin on global blood flow, laser Doppler flux, and bioenergetic status of subcutaneous rodent tumors.
Global blood flow (TBF), tumor vascular resistance, laser Doppler flow in superficial tumor areas, and mean arterial blood pressure were evaluated in rats bearing s.c. DS sarcomas. Measurements were performed before and after i.v. administration of rhTNF-alpha 2 or recombinant human lymphotoxin (rhLT) (1 mg/kg). Upon application of the cytokines a significant drop in TBF was found at t greater than or equal to 90 min with a stronger action following rhLT than rhTNF-alpha. At relatively constant mean arterial blood pressure values following the cytokine injection, the microcirculatory function in the tumor periphery was found to be impaired somewhat earlier than TBF, indicating that the cytokines do not preferentially act on the poorly perfused tumor center in the model chosen. This finding is inconsistent with previous histological studies on murine tumors. Acute flow changes encompassed only substantial reductions (i.e., hypoperfusion) rather than a complete ischemia. TBF was slightly increased during the first hour following rhLT whereas after rhTNF-alpha a continuous drop was observed. This differential response could not be observed during laser Doppler flowmetry. Tumor vascular resistance changes largely reflected alterations in TBF. 31P-Nuclear magnetic resonance spectroscopy on murine Meth-A fibrosarcomas revealed dose- and time-dependent decreases of ATP/Pi and phosphocreatine/Pi ratios following i.v. administration of rhTNF-alpha. From comparisons of dose-response curves rhLT appears to be more detrimental than rhTNF-alpha with respect to the bioenergetic status. The observed changes in tumor energy metabolism are similar to those described for TBF. It may therefore be concluded that most of the cytokine effects on the bioenergetic status are secondary to the inhibition of the microcirculatory function. As a major causative factor for the latter, an arterial hypotension can be excluded in the tumor model chosen.
Kluge
M
M
Department of Research and Development, Knoll AG, Ludwigshafen, Germany.
Elger
B
B
Engel
T
T
Schaefer
C
C
Seega
J
J
Vaupel
P
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D007834:Lasers; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008748:Methylcholanthrene; D051379:Mice; D008819:Mice, Nude; D010725:Phosphocreatine / Q000378:metabolism; D010758:Phosphorus; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D012513:Sarcoma, Experimental / Q000098:blood supply* / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D010725:Phosphocreatine; D010758:Phosphorus; D008748:Methylcholanthrene; D000255:Adenosine Triphosphate