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The changes of microregional perfusion in a hamster cheek pouch membrane were investigated. The vessel network of the membrane was visualized by preparing a transparent chamber, which was heated with circulating water at 42 degree C. Blood perfusion was monitored by using a laser Doppler flowmeter (LDF), which was used either in a conventional way by positioning the probe stationary or in a novel way by constantly moving the probe over the surface of the chamber (scanning). When a segment of tissue was subjected to the LDF scanning, the profile of scanned LDF values was well correlated with the distribution of vessels. Therefore, this scanning technique was useful in localizing the probe in tissues with respect to vessels. Since the scanning can be repeated every other minute, this technique also offered continuous monitoring of tissue blood flow at multiple sites. Upon heating, different vessels individually responded to the first and second heatings followed by coolings, suggesting a heterogeneous heat response in the connective tissue of the hamster cheek pouch membrane. This scanning technique proved very useful in collecting information for the study of the heterogeneous nature of blood flow in normal and tumour tissues.

The occurrence of differential heating and differential thermal sensitivity between malignant tumors and normal tissues is thought to be due to limited heat dissipation and energy depletion in many solid tumors which in turn results from an inadequately functioning tumor microcirculation (Jain and Ward-Hartley 1984; Song 1984, 1991; Vaupel and Kallinowski 1987; Reinhold 1988; Vaupel et al. 1988a; Vaupel 1990). As a consequence of the latter pathophysiological condition, supply and drainage function are restricted in many solid tumors or, at least, in some tumor areas, thus creating a hostile metabolic microenvironment characterized by tissue hypoxia, acidosis, and energy depletion. Thermal sensitivity has been shown to depend greatly on tumor pH, and on energy and nutritional status of the tumors treated. Although no conclusive evidence is so far available concerning the ranking of these pivotal factors, there is no doubt that the rate and homogeneity of blood perfusion plays a paramount role in determining the metabolic and energy status.

Severe disturbances in microcirculation during advanced phases of tumor growth lead to restrictions of convective and diffusive transport. In addition, an inhomogeneous distribution of transport conditions develops, resulting in insufficient and heterogeneous substrate supply and an inadequate drainage of wastes. Polarographic measurements of the local tissue oxygen tension (PO2) using gold microelectrodes reveal that very low PO2 values are prevalent in C3H mouse mammary carcinomas. The tissue PO2 frequency distributions are shifted to low PO2 values and limited in variability. The mean PO2 value is 7 mm Hg. The median is 4 mm Hg, the modal class being 0 to 5 mm Hg. Within different microareas of the same tumor, pronounced heterogeneities exist. Due to an elevated rate of lactic acid production and its subsequent inadequate removal, a severe tissue acidosis is evidenced in malignant tumors. For C3H mouse mammary carcinomas, most of the measured pH values are in the range of 6.4 to 7.1, the modal class being 6.7 to 6.8 (mean pH, 6.73; median pH, 6.75). Within different microareas of the same tumor, clear heterogeneities in the pH distribution do occur. Very low pH values (5.8 to 6.3) have been observed in large ulcerated tumors. In extensively necrotic areas, pH values even higher than the arterial pH could be detected.

Tumor acidosis and energy deprivation enhance thermal sensitivity. We have used in vivo 31P nuclear magnetic resonance spectroscopy to noninvasively monitor changes in pH and energy metabolism in FSaII mouse tumors after i.p. administration of glucose. A dose of 5 g/kg glucose induced a pH drop of 0.31 units without any statistically significant change in energy status. The pH changes resolved within 2 h. In contrast, administration of 10 g/kg glucose resulted in a severe acidosis (mean nadir pH of 6.19 corresponding to a mean pH drop of 0.96 units) and loss of energy, the latter most probably being due to an acidosis-induced inhibition of glycolysis during ischemic hypoxia. The resulting acidosis and energy loss were more persistent and resolved in 5.5-28 h. In contrast, after an identical dose of mannitol (10 g/kg), a pH drop of approximately only 0.1 units over 72 min was noted. The data suggest that both cleavage of glucose to lactic acid and blood flow inhibition are involved in glucose induced tumor acidosis. In vivo 31P nuclear magnetic resonance spectroscopy may be useful clinically to monitor therapeutic attempts at enhancing thermal sensitivity.

Responses of tumor microcirculation (RBC flux) to i.p. glucose or mannitol injections were studied in early generation isotransplants of a spontaneous C3Hf/Sed mouse fibrosarcoma (FSaII). RBC flux in superficial tumor microregions was assessed using laser Doppler flowmetry. After administration of glucose or mannitol (a nonmetabolized sugar alcohol), a dose-dependent reduction in laser Doppler flow, and a dose-dependent increase in systemic hematocrit occurred concurrently. Maximum flow reductions induced by i.p. glucose or mannitol were statistically indistinguishable for equal osmotic load. Maximum decreases in RBC flux for glucose or mannitol were 20 and 25% (1.25 mg/g i.p.), 42 and 48% (2.5 mg/g i.p.), 72 and 60% (5 mg/g i.p.), and 80 and 75% (10 mg/g i.p.), respectively. Maximum increases in systemic hematocrit ranged from 18% (1.25 mg/g glucose i.p.) to 33% (10 mg/g glucose i.p.). Examination of RBC count, blood hemoglobin concentration, and fluid accumulation in the abdominal cavity after glucose or mannitol administration were all compatible with a significant shift of intravascular/extracellular water into the abdominal cavity with resultant systemic hypovolemic hemoconcentration. RBC volume and mean hemoglobin content of RBC remained unchanged with glucose loading. The data suggest that reductions in laser Doppler flow are predominantly caused by hypovolemic hemoconcentration following i.p. administration of hyperosmolar sugar solutions. Changes in laser Doppler flow due to specific glucose-mediated or glucose-related phenomena are probably of minor importance in the murine tumor system investigated. Future studies on murine tumors, examining for specific effects of glucose on metabolism and/or therapy, should not use i.p. administration of hyperosmolar solutions.