Reirradiation combined with hyperthermia in recurrent breast cancer results in a worthwhile local palliation.
Both experimental and clinical research have shown that hyperthermia (HT) gives valuable additional effects when applied in combination with radiotherapy (RT). The purpose of this study was evaluation of results in patients with recurrent breast cancer, treated at the Daniel den Hoed Cancer Center (DHCC) with reirradiation (re-RT; eight fractions of 4 Gy twice weekly) combined with HT. All 134 patients for whom such treatment was planned were included in the analysis. The complete response rate in 119 patients with macroscopic tumour was 71%. Including the 15 patients with microscopic disease, the local control rate was 73%. The median duration of local control was 32 months, and toxicity was acceptable. The complete response (CR) rate was higher, and the toxicity was less with the later developed 433-MHz HT technique compared with the 2450-MHz technique used initially. With this relatively well-tolerated treatment, palliation by local tumour control of a worthwhile duration is achieved in the majority of patients. The technique used for hyperthermia appeared to influence the achieved results. The value of HT in addition to this re-RT schedule has been confirmed by a prospective randomized trial in a similar patient group. In The Netherlands, this combined treatment is offered as standard to patients with breast cancer recurring in previously irradiated areas. (+info)
Effect of fever-like whole-body hyperthermia on lymphocyte spectrin distribution, protein kinase C activity, and uropod formation.
Regional inflammation and systemic fever are hallmarks of host immune responses to pathogenic stimuli. Although the thermal element of fever is thought to enhance the activity of immune effector cells, it is unclear what the precise role of increased body temperatures is on the activation state and effector functions of lymphocytes. We report here that mild, fever-like whole body hyperthermia (WBH) treatment of mice results in a distinct increase in the numbers of tissue lymphocytes with polarized spectrin cytoskeletons and uropods, as visualized in situ. WBH also induces a coincident reorganization of protein kinase C (PKC) isozymes and increased PKC activity within T cells. These hyperthermia-induced cellular alterations are nearly identical with the previously described effects of Ag- and mitogen-induced activation on lymphocyte spectrin and PKC. Immunoprecipitation studies combined with dual staining and protein overlay assays confirmed the association of PKC beta and PKC theta with spectrin following its reorganization. The receptor for activated C kinase-1 was also found to associate with the spectrin-based cytoskeleton. Furthermore, all these molecules (spectrin, PKC beta, PKC theta, and receptor for activated C kinase-1) cotranslocate to the uropod. Enhanced intracellular spectrin phosphorylation upon WBH treatment of lymphocytes was also found and could be blocked by the PKC inhibitor bisindolylmaleimide I (GF109203X). These data suggest that the thermal element of fever, as mimicked by these studies, can modulate critical steps in the signal transduction pathways necessary for effective lymphocyte activation and function. Further work is needed to determine the cellular target(s) that transduces the signaling pathway(s) induced by hyperthermia. (+info)
Dynamic association of L-selectin with the lymphocyte cytoskeletal matrix.
L-selectin mediates lymphocyte extravasation into lymphoid tissues through binding to sialomucin-like receptors on the surface of high endothelial venules (HEV). This study examines the biochemical basis and regulation of interactions between L-selectin, an integral transmembrane protein, and the lymphocyte cytoskeleton. Using a detergent-based extraction procedure, constitutive associations between L-selectin and the insoluble cytoskeletal matrix could not be detected. However, engagement of the L-selectin lectin domain by Abs or by glycosylation-dependent cell adhesion molecule-1, an HEV-derived ligand for L-selectin, rapidly triggered redistribution of L-selectin to the detergent-insoluble cytoskeleton. L-selectin attachment to the cytoskeleton was not prevented by inhibitors of actin/microtubule polymerization (cytochalasin B, colchicine, or nocodozole) or serine/threonine and tyrosine kinase activity (staurosporine, calphostin C, or genistein), although L-selectin-mediated adhesion of human PBL was markedly suppressed by these agents. Exposure of human PBL or murine pre-B transfectants expressing full-length human L-selectin to fever-range hyperthermia also markedly increased L-selectin association with the cytoskeleton, directly correlating with enhanced L-selectin-mediated adhesion. In contrast, a deletion mutant of L-selectin lacking the COOH-terminal 11 amino acids failed to associate with the cytoskeletal matrix in response to Ab cross-linking or hyperthermia stimulation and did not support adhesion to HEV. These studies, when taken together with the previously demonstrated interaction between the L-selectin cytoplasmic domain and the cytoskeletal linker protein alpha-actinin, strongly implicate the actin-based cytoskeleton in dynamically controlling L-selectin adhesion. (+info)
Antiviral effect of hyperthermic treatment in rhinovirus infection.
Human rhinoviruses (HRV) are recognized as the major etiologic agents for the common cold. Starting from the observation that local hyperthermic treatment is beneficial in patients with natural and experimental common colds, we have studied the effect of brief hyperthermic treatment (HT) on HRV replication in HeLa cells. We report that a 20-min HT at 45 degrees C is effective in suppressing HRV multiplication by more than 90% when applied at specific stages of the virus replication cycle. Synthesis of virus proteins is not affected by HT, indicating that the target for treatment is a posttranslational event. The antiviral effect is a transient cell-mediated event and is associated with the synthesis of the 70-kDa heat shock protein hsp70. Unlike poliovirus, rhinovirus infection does not inhibit the expression of hsp70 induced by heat. The possibility that hsp70 could play a role in the control of rhinovirus replication is suggested by the fact that a different class of HSP inducers, the cyclopentenone prostaglandins PGA1 and delta 12-PGJ2, were also effective in inhibiting HRV replication in HeLa cells. Inhibition of hsp70 expression by actinomycin D prevented the antiviral activity of prostaglandins in HRV-infected cells. These results indicate that the beneficial effect of respiratory hyperthermia may be mediated by the induction of a cytoprotective heat shock response in rhinovirus-infected cells. (+info)
Mild therapeutic hypothermia for postischemic vasoconstriction in the perfused rat liver.
BACKGROUND: Mild hypothermia, a promising therapy being evaluated for various clinical situations, may suppress the formation of reactive oxygen species during reperfusion and may ameliorate microcirculatory perfusion failure (the "no-reflow phenomenon"). METHODS: Isolated rat livers underwent 30 min of perfusion, 2.5 h of ischemia, and 3 h of reperfusion. The temperature was maintained at 34 degrees C (mild hypothermia, n = 5) or 38 degrees C (normothermia, n = 6) for all three periods by perfusion of a modified Krebs Henseleit solution, air surface cooling, or both. A third group of livers was normothermic before and during ischemia and mildly hypothermic during reperfusion (reperfusion hypothermia, n = 6). Control livers had 3 h of perfusion at normothermia. Chemiluminescence (a measure of the generation of reactive oxygen species) and hepatic vascular resistance were monitored simultaneously to evaluate the effect of temperature on the formation of reactive oxygen species and the development of no reflow. Also measured were thiobarbituric acid reactive species and lactate dehydrogenase, as indicators of oxidative stress and cell injury. RESULTS: Mild hypothermia decreased formation of reactive oxygen species and postischemic increases in vascular resistance. Reperfusion hypothermia also decreased postischemic increases in vascular resistance, but not as effectively as did mild hypothermia. Levels of thiobarbituric acid reactive species were lower for reperfusion hypothermia than for mild hypothermia at only 0 and 30 min of reperfusion. Lactate dehydrogenase was significant only at 0 min of reperfusion for the normothermic group. Oxygen consumption did not change. CONCLUSION: The prevention of hepatic vascular injury by suppression of oxidative stress may be an important protective mechanism of mild hypothermia. (+info)
The effects of extracorporeal whole body hyperthermia on the functional and phenotypic features of canine peripheral blood mononuclear cells (PBMC).
In this study the effect of transient 42.3 degrees C whole body hyperthermia (WBH) on the distribution of PBMC phenotypes and in vitro blastogenic responsiveness was determined in dogs. Hyperthermia (n = 6) was induced by heating venous blood during extracorporeal circulation (venous perfusion WBH); perfused non-heated dogs (n = 4) were used as controls. Both euthermic and hyperthermic perfusion produced transient lymphopenia which normalized in controls after perfusion but persisted in hyperthermic animals throughout the 8-day post-perfusion observation interval. The transient lymphopenia in control dogs was non-selective. In contrast, WBH-associated lymphopenia was selective, in that CD5+ T lymphocytes were more sensitive to hyperthermia than sIg+ B cells and, within the T cell compartment, suppressor (CD8+) cells were more sensitive to hyperthermic stress than helper (CD4+) lymphocytes. Functional analyses showed that WBH caused persistent suppression of PBMC blastogenesis in response to T cell phytomitogens. Increased plasma cortisol levels were correlated to peak lymphopenia and hyporesponsiveness to phytomitogens. Despite these alterations, high grade WBH was well tolerated and there was no evidence of opportunistic infection. (+info)
Characterization of mild whole-body hyperthermia protocols using human breast, ovarian, and colon tumors grown in severe combined immunodeficient mice.
OBJECTIVE: We have shown that one treatment of fever-like whole body hyperthermia (WBH) on mice bearing human breast tumors results in a tumor growth delay. Our goal was to repeat this study in mice bearing human ovarian or colon tumors. We further evaluated this WBH protocol by performing multiple and interrupted WBH treatments. METHODS: Human tumors were grown in severe combined immunodeficient (SCID) mice. For WBH, core body temperatures were maintained at 39.8+/-0.2 degrees C for 6-8 hours. Multiple treatments were given 6-7 days apart. Interrupted WBH consisted of three 2-hour heatings, 15 minutes apart. Tumor growth time (TGT) was the number of days to grow 1.5 or 2 times in volume. RESULTS: For WBH-treated ovarian tumors, TGT was 12+/-1.2d, compared with 5.0+/-0.1d for untreated mice (P < 0.05). For colon tumors with one WBH treatment TGT was 4.4+/-1.1d. Two and three treatments had TGTs of 9+/-2.3d and 8+/-1.6d. For the untreated tumors, TGT was 2+/-0.7d (P < 0.01 for one, two, and three treatments). Histological examination indicated that one and two treatments were associated with cellular damage within the tumors. With a slower growing colon tumor, the TGT was 24+/-3.3d with three WBH treatments, compared with 14+/-1.8d for controls (P < 0.01). The TGT of breast tumors treated with interrupted WBH was not significantly different than the noninterrupted, with TGT of 7.3+/-0.8d and 6.2+/-1.0d, respectively. CONCLUSIONS: These data illustrate that WBH causes a tumor growth delay in mice bearing human ovarian and colon tumors. This response is enhanced with a second treatment of WBH. Interrupted and noninterrupted WBH give comparable anti-tumor results. We will continue to evaluate WBH in various animal models to optimize its potential for clinical administration and maximize the anti-tumor response. (+info)
Nitric oxide is an initiator of intercellular signal transduction for stress response after hyperthermia in mutant p53 cells of human glioblastoma.
Nitric oxide is known to be a multifunctional physiological substance. Recently, it was suggested that nitric oxide is involved in p53-dependent response to many kinds of stress, such as heat shock and changes in cellular metabolism. To verify this hypothesis, we examined the effect of nitric oxide produced endogenously by heat-shocked cells on nonstressed cells using a human glioblastoma cell line, A-172, and its mutant p53 (mp53) transfectant (A-172/mp53). The accumulation of inducible nitric oxide synthase was caused by heat treatment of the mtp53 cells but not of the wild-type p53 (wtp53) cells. The accumulation of heat shock protein 72 (hsp72) and p53 was observed in nontreated mtp53 cells cocultivated with heated mp53 cells, and the accumulation of these proteins was suppressed by the addition of a specific inducible nitric oxide synthase inhibitor, aminoguanidine, to the medium. Furthermore, the accumulation of these proteins was observed in the wtp53 cells after exposure to the conditioned medium by preculture of the heated mp53 cells, and the accumulation was completely blocked by the addition of a specific nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, to the medium. In addition, the accumulation of hsp72 and p53 in the wtp53 cells was induced by the administration of an nitric oxide-generating agent, S-nitroso-N-acetylpenicillamine, to the medium. Finally, the thermosensitivity of the wtp53 cells was reduced in the conditioned medium by preculture of the heated mp53 cells as compared with conventional fresh growth medium. Our finding of the accumulation of hsp72 and p53 in nitric oxide-recipient cells cocultivated with heated nitric oxide-donor cells provides the first evidence for an intercellular signal transduction pathway via nitric oxide as intermediate without cell-to-cell interactions such as gap junctions. (+info)