Microcirculatory and pH Alterations in Isotransplanted Rat and Xenotransplanted Human Tumors Associated with Hyperthermia

The rationale for considering the use of hyperthermia as an antitumor agent is based on three different mechanisms of action depending on the hyperthermia levels chosen: At moderate hyperthermia levels (40°–42.5° C) heat can increase the radiosensitivity and/or the chemosensitivity. At higher tissue temperatures ( > 42.5° C) hyperthermia acts as a cytotoxic agent since mammalian cells die after heating in a temperature-, time-, and cell cycle-dependent manner. Besides direct effects on the cell membranes, on the cytoskeleton, on metabolic processes, on DNA replication, and on RNA and protein synthesis, indirect effects distinctly modulating the anticancer action of heat have to be considere…

Wachstumsgeschwindigkeit, Angiogenese, Durchblutung und lokale Gewebsoxygenierung ras-Onkogen-induzierter Tumoren

Bosartiges Wachstum beruht auf der Aktivierung sog. Onkogene oder auf dem Verlust von Tumorsuppressor-Genen. Solche genetischen Veranderungen konnen direkt die Sensibilitat der Tumorzellen fur verschiedene Therapieformen modulieren. Weiterhin kann sich sekundar in Tumoren ein besonderes Mikromilieu auspragen, das das biologische Verhalten der Tumorzellen beeinflust. Da bislang nur sparliche Daten vorliegen, wurden mogliche Zusammenhange zwischen einer Onkogen-Aktivierung, dem Wachstumsverhalten, der Durchblutung und der Oxygenierung maligner Tumoren an Onkogen-transformierten Rattenfibroblasten untersucht.

Blood flow, oxygen consumption and substrate utilization of human tumors xenotransplanted into nude rats

Evaluation of Oxygen Diffusion Distances in Human Breast Cancer Using Cell Line Specific in Vivo Data: Role of Various Pathogenetic Mechanisms in the Development of Tumor Hypoxia

Radiobiological hypoxia in malignant tumors has been shown to originate (i) from spatial and temporal functional disturbances of tumor microcirculation resulting in a limited convective O2 flux in microregions even in tissue areas exhibiting high vascular densities, and (ii) from morphological abnormalities of the microcirculatory bed leading to a limitation of the diffusive O2 flux. In addition to these pathogenetic mechanisms, systemic factors (anemia, arterial hypoxia) can also play a role in the development of tumor hypoxia.

Concurrent Measurements of O2 Partial Pressures and pH Values in Human Mammary Carcinoma Xenotransplants

Due to severe restrictions of convective and diffusive transport, hypoxic or even anoxic areas exist in malignant tumors. In addition, a high glycolytic rate in tumors both in the presence and absence of oxygen and the insufficient removal of the hereby produced lactic acid lead to an acidification of the tumor tissue. Both hypoxia and acidosis can influence the efficacy of irradiation, chemotherapy and hyperthermia. However, no comprehensive data on the development of both hypoxia and acidosis within the same tumor are available to date. In particular, there is no information regarding human tumors. Therefore, a new model has been developed which allows the systematic evaluation of both pa…

Tumour Blood Flow Following Local Ultrasound Heating Computed from Thermal Clearance Curves

Thermal clearance curves following termination of ultrasound-induced hyperthermia in human mammary carcinomas implanted into the flanks of nude rats were studied. They were found to be monoexponential in form, both with and without blood flow. From the difference between the inverse time constants with and without flow, the tumour blood flow rate could be calculated. Blood flow was found to increase with very short exposure times at the therapeutic hyperthermia temperature and subsequently decrease as the exposure time increased. A higher therapeutic hyperthermia temperature augmented this effect.

l-glutamine: a major substrate for tumor cells in vivo?

From 65 human breast cancer xenografts investigated, a net glutamine uptake was found in 13 tumors (mean +/- SE: 15.7 +/- 4.5 nmol/g per min) whereas a net release (22.5 +/- 3.3 nmol/g per min) was observed in 40 tumors. In 12 tumors neither a significant net uptake nor a net release was obvious. There is experimental evidence that glutamine is taken up by cancer cells only at arterial concentrations greater than 0.5 mM. Another parameter determining glutamine utilization by tumor cells may be the tissue oxygenation. In hypoxic or anoxic tumor areas, glutamine oxidation is unlikely since oxygen is required for the reoxidation of coenzymes which are reduced in the course of this metabolic pa…

Effects of tumor necrosis factor-alpha on tumor blood flow and hyperthermic treatment.

The impact of recombinant human tumor necrosis factor-alpha (rhTNF-alpha), given alone or in combination with local hyperthermia, on perfusion and growth of a moderately rhTNF-alpha-sensitive rat tumor (DS-carcinosarcoma) was investigated. DS-carcinosarcomas were implanted into the hind foot dorsum of Sprague-Dawley rats. Tumor blood flow (TBF) was measured with the krypton-85 clearance technique. Treatment with either tumor necrosis factor-alpha (0.1-1.0 mg/kg) or hyperthermia (43.3 and 44.3 degrees C, 40 min) can decrease the perfusion of malignant tumors. The TBF reduction was fully established 2 h after rhTNF-alpha injection and lasted for at least 4 h. The application of local hyperthe…

Pathophysiology of Tumors in Hyperthermia

The response of tumor cells to hyperthermia is critically influenced by a number of pathophysiological factors both in vitro and in vivo. The most relevant factors in this context are tumor blood flow, tissue oxygenation, the energy status, and the pH distribution, which in turn define the cellular microenvironment.

Physiological Effects of Hyperthermia

Hyperthermia as a modality for the treatment of malignant tumors, either alone or in combination with radiation or anticancer drugs, is rapidly becoming a clinical reality. Three different mechanisms of action have provided the rationale for considering the use of hyperthermia as an antitumor agent. At moderate hyperthermia (T=40˚ -42.5˚ C), heat can increase cell killing in a synergistic way following exposure of a tumor to ionizing radiation. This radiosensitization is probably based on, among other things, the inhibited repair of radiation-induced DNA lesions. Elevated tissue temperatures at 40˚ -42.5˚ C also sensitize tumor cells to certain chemotherapeutic drugs, particularly to alkyla…

Human Mammary Carcinomas in Nude Rats — A New Approach for Investigating Oxygen Transport and Substrate Utilization in Tumor Tissues

An understanding of tumor pathophysiology with respect to blood flow, oxygenation status, pH distribution and utilization of the relevant substrates which, all together, critically influence growth kinetics and the efficiency of nonsurgical therapeutic modalities in vivo requires information derived directly from human malignant tissues. At present, only inadequate knowledge of the relevant physiological factors in tumor tissues of patients are accessible. The little data available to date were obtained from clinical observations rather than from systematic studies, i.e., data were collected from various tumor types with differing staging and grading. For this reason generally valid stateme…

Blood Flow and Oxygen Supply to Human Mammary Carcinomas Transplanted into Nude Rats

Tumor blood flow (TBF), by itself, greatly influences the efficiency of nonsurgical therapeutic modalities, especially chemotherapy and hyperthermia. Furthermore, TBF is one of the most important determinants of tumor tissue oxygenation in vivo, thus playing a relevant role in tumor growth kinetics and in the development of regressive changes. In addition, the oxygenation of tumor tissue strongly determines the efficiency of radiation therapy and to a certain extent, pharmacodynamics of some antiproliferative drugs. Despite the considerable information available for rodent tumor systems, there are only sporadic ireports on blood flow (Beaney et al., 1984, Johnson, 1976, Mantyla, 1979, Manty…

Vascularity, perfusion rate and local tissue oxygenation of tumors derived from ras-transformed fibroblasts.

Tumors derived from ras-transformed rat fibroblasts were investigated in order to gain insight into possible interrelationships between oncogenic transformations and therapeutically relevant parameters of the metabolic micromilieu of solid tumors in vivo. Tumors grew in nude mice after injection of in vitro-passaged cells. Growth rates, early stages of angiogenesis, perfusion and tissue oxygenation were assessed. Compared with the parental cell line, both ras transformants grew very rapidly and exhibited an early onset of angiogenesis. Perfusion rates of one ras-transformed tumor line were similar to those of the parental tumors whereas reduced flow values were detected in tumors of the oth…