Dk. Kelleher et Pw. Vaupel, TUMOR MICROENVIRONMENT - CHARACTERIZATION AND SIGNIFICANCE FOR HYPERTHERMIA TREATMENT, Eksperimental'naa onkologia, 17(4), 1995, pp. 256-268
The complex (patho-)physiological events accompanying heating of tumor
tissues have been reviewed, with particular emphasis on the changes i
n blood flow, oxygenation, metabolic and bioenenergetic status. In hum
an tumors, pronounced heterogeneity is seen in rates of blood flow, an
d flow changes upon heating are unpredictable and spatially and tempor
ally variable. Flow increases in some cases may result in improved hea
t dissipation such that therapeutically relevant temperatures may not
be achieved. Tumor oxygenation changes tend to reflect alterations in
blood flow during hyperthermia with increases in oxygenation followed
by a return to baseline levels being reported for some human and exper
imental tumors, at least upon moderate hyperthermia. Also, a large amo
unt of variation is seen in changes in tumor glucose levels upon hyper
thermia, although these appear to be related to changes in blood flow
and the development of interstitial edema. Lactate levels increase upo
n hyperthermia as a result of intensified glycolysis. Tumor pH (both i
ntra- and extracellular) decrease upon high-dose hyperthermia, with su
bsequent recovery depending on the dose of hyperthermia delivered. Tum
or bioenergetic status worsens during hyperthermia, as evidenced by de
creases in ATP and phosphocreatine and increases in inorganic phosphat
e. ATP hydrolysis results in an accumulation of the purine catabolites
hypoxanthine, xanthine and uric acid and proton formation, which may
in turn contribute to a heat-induced acidosis. Additionally, the forma
tion of highly reactive oxygen species may contribute to heat induced
cytotoxicity.