0000000000281017
AUTHOR
Paul Okunieff
Response of tumour red blood cell flux to hyperthermia and/or hyperglycaemia.
Laser Doppler flowmetry has been applied to subepidermal rat tumours during localized ultrasound hyperthermia and/or moderate, short-term hyperglycaemia. Blood glucose levels were elevated 4-fold by continuous i.v. infusion of D-glucose (4.8 g/kg/60 min). To determine whether the effects of hyperglycaemia on tumour blood flow involved increased rates of glycolysis and lactic acid production, galactose, a sugar not metabolized by the tumour, was administered using the same dose schedule. Hyperglycaemia was accompanied by a 3-fold increase in blood lactate levels and a slight hypervolaemic haemodilution without any significant systematic changes of the arterial blood pressure or respiratory b…
Measurements of Tumor Blood Flow Using Intraperitoneal Deuterium and 2H-NMR Spectroscopy
Tumors usually have a sparse, disorganized, and inefficient vascular network that leaves a large fraction of the tumor cells in an oxygen deprived and hostile metabolic microenvironment. Hence tumor blood flow, or more correctly nutritive perfusion, has important interactions with treatment efficacy. For example, hypoxic tumor cells, which occur in tumors with low blood flow, are less susceptible to radiation and are probably responsible for most radiation treatment failures (Adams, 1981). Similarly, cytotoxic drug delivery could be predicted by blood flow measurements, with clear implications regarding the expected success of chemotherapy. Thus, the ability to conveniently measure tumor bl…
The Role of Oxygen Tension Distribution on the Radiation Response of Human Breast Carcinoma
The response of tumors to radiation is heterogeneous even in animal tumor systems where tumors all originate from the same cell culture, are implanted in genetically similar age-matched animals in a constant anatomic locationl. Hence great heterogeneity of response exists even in situations where intrinsic genetic or epigenetic factors are minimally variable. Several metabolic factors are known to influence the probability of tumor control after radiation. These metabolic factors are also known to vary widely between tumors in humans2,3 and even in animal tumor models. Heterogeneous variables include tumor oxygen tension distribution, glutathione content, glucose delivery and utilization ra…
Interaction of Oxygen Partial Pressure and Energy Metabolism with the Relaxation Rate of Inorganic Phosphate: A 31P NMR Study
It is well known that oxygen molecules present in liquid or solid samples can shorten NMR spin-lattice relaxation times (T1) of the nucleus under investigation. Several studies have shown large decrements of 1H, 13C, and 19F relaxation times mediated by the O2 molecule (Lees and Muller, 1961; Ohuchi et al., 1979; Fishman et al., 1989). The positions of the 3lp atoms in phosphate compounds are stereometrically similar to some 13C atoms in organic compounds, and thus an effect of oxygen on the 31P T1 is expected. Recently, we have shown (Okunieff et al., 1988) that oxygen breathing can significantly reduce the T1 of 31p in the inorganic phosphate molecule (Pi). The degree to which this change…
Oxygenation of Mammary Tumors: From Isotransplanted Rodent Tumors to Primary Malignancies in Patients*
The role of oxygen in tumor cell proliferation, radiosensitivity, cytotoxicity of anticancer drugs and hyperthermia treatment has been the subject of a series of investigations (for reviews see Hall, 1988; Teicher et al., 1990, Vaupel et al., 1989a; Vaupel, 1990a,b). Despite the apparent importance of tumor oxygenation, data on pO2 values in solid tumors are mostly derived from experiments on rodents which might not necessarily reflect the variability of the clinical situation. Due to feasible techniques available now, considerable advances have been made in the past few years in the assessment of tumor hypoxia in patients (for reviews see Vaupel et al., 1989a; Vaupel, 1990a). The latter in…
Intracellular acidosis in murine fibrosarcomas coincides with ATP depletion, hypoxia, and high levels of lactate and total Pi
Bioenergetic and metabolic status of murine FSaII tumours were evaluated using 31P MRS, acid extracts ('global' techniques) and quantitative bioluminescence ('microregional' assay). Data obtained from s.c. tumours of varying sizes (44-600 mm3) have been correlated with the oxygenation status evaluated using O2-sensitive needle electrodes. beta-NTP/Pi and phosphocreatine (PCr)/Pi ratios derived from 31P MRS were positively correlated to the median tissue pO2 values. pH declined during growth with intracellular acidosis being evident in tumours > 350 mm3. Whereas lactic acid formation greatly contributed to this decline in small- and medium-sized tumours, ATP hydrolysis and slowing down of th…
Oxygenation and Bioenergetic Status of Murine Fibrosarcomas
The heterogeneity of cellular response to therapy is a major problem in non-surgical cancer therapy. This heterogeneity is influenced by both the genetic variability between different tumor cells and by epigenetic, physiological factors, such as the local metabolic milieu. A restriction of tumor microcirculation concomitant with regional hypoxia, nutrient depletion, accumulation of lactate, and an intensified tumor acidosis becomes evident during growth of many solid tumors1. These critical factors can greatly influence the efficiency of various non-surgical tumor therapies.
Evidence for and Against Hypoxia as the Primary Cause of Tumor Aggressiveness
In clinical trials, tumor hypoxia has consistently been associated with tumor aggressiveness. The evidence for an association between hypoxia and metastasis and more rapid tumor progression and death is seen in uterine cervical cancer, and sarcoma of soft tissue. Evidence is building in prostate, vulva, head and neck, and breast cancers. A major question is whether hypoxia precedes tumor aggressiveness or whether aggressive tumors incidentally are also hypoxic.
Measurement of Human Tumor Blood Flow: A Positron Technique Using an Artifact of High Energy Radiation Therapy
For at least three decades (1–6) there has been an interest in measuring tumor blood flow (TBF) and in the determination of its relation to the response of human tumors to radiation, drug therapies, and to the probability of development of distant metastases. The proton activation method which will be described below allows daily measurements of blood flow, in only 7 minutes, in patients being irradiated by photons of ≥20 MV, or by protons and other heavy particles.