Do Changes in Tumor Blood Flow Necessarily Lead to Changes in Tissue Oxygenation and in Bioenergetic Status?

Abstract

An increasing number of investigations carried out in recent years provide evidence suggesting that “chronic” decreases in tumor blood flow and/or tissue oxygenation (e.g., during tumor growth) or acute declines in the tissue perfusion (e.g., following therapeutic measures) might be accompanied by significant reductions in the energy status. In several instances, positive correlations between energy status and tumor blood flow or oxygenation have been reported (Lilly et al., 1985; Evelhoch et al., 1986; Tozer et al., 1989; Vaupel et al., 1989a, 1989b; Steen and Graham, 1991), and these investigations have led to the conclusion that blood flow may be the limiting factor in determining the bioenergetic status of tumors during growth. Manipulations of tumor blood flow by vasodilators, hyperthermia, tumor necrosis factor-α (TNF-α), lymphotoxin, interleukin-1, x-irradiation or after i.p. mannitol administration were accompanied by parallel changes in tumor energy status. Only in studies where i.p. or i.v. glucose was administered was energy status found to be stable or even slightly improved despite significant reductions in tumor perfusion (Okunieff et al., 1989; Krüger et al., 1991; Mayer et al., 1992; Schaefer et al., 1993). Similar observations of a dissociation between changes in tumor blood flow, oxygenation and energetic status have been observed in normoglycemic mice during photodynamic therapy (Bremner et al., 1993) or following hydralazine administration in xenografted human and isotransplanted murine tumors (Bremner et al., 1991; Adams et al., 1992).