Enhanced Photothermal Treatment Efficacy and Normal Tissue Protection via Vascular Targeted Gold Nanocages.

A major challenge in photothermal treatment is generating sufficient heat to eradicate diseased tissue while sparing normal tissue. Au nanomaterials have shown promise as a means to achieve highly localized photothermal treatment. Toward that end, the synthetic peptide anginex was conjugated to Au nanocages. Anginex binds to galectin-1, which is highly expressed in dividing endothelial cells found primarily in the tumor vasculature. The skin surface temperature during a 10 min laser exposure of subcutaneous murine breast tumors did not exceed 43°C and no normal tissue damage was observed, yet a significant anti-tumor effect was observed when laser was applied 24 h post-injection of targeted nanocages. Untargeted particles showed little effect in immunocompetent, tumor-bearing mice under these conditions. Photoacoustic, photothermal, and ICP-MS mapping of harvested tissue showed distribution of particles near the vasculature throughout the tumor. This uptake pattern within the tumor combined with a minimal overall temperature rise were nonetheless sufficient to induce marked photothermal efficacy and evidence of tumor control. Importantly, this evidence suggests that bulk tumor temperature during treatment does not correlate with treatment outcome, which implies that targeted nanomedicine can be highly effective when closely bound/distributed in and around the tumor endothelium and extensive amounts of direct tumor cell binding may not be a prerequisite of effective photothermal approaches.

The traditional Chinese medicinal formula BDL301 suppresses tumor growth by inhibiting STAT3 pathway and inducing apoptosis in colorectal cancer cells.

The traditional Chinese medicinal formula BDL301 has been used to inhibit inflammation for hundreds of years. The development of colorectal cancer and chronic inflammation are closely related. In this study, we investigated whether BDL301 could inhibit tumor growth. We found that angiogenesis and tumor growth were both inhibited in vivo. In addition, apoptosis was induced and the signal transducer and activator of transcription-3 (STAT3) pathway were suppressed in the colorectal cancer cells in vitro and in vivo by BDL301. This study demonstrates that BDL301 exerted significant anticancer activity by inhibiting the STAT3 pathways and inducing apoptosis in colorectal cancer cells.

Immune consequences of decreasing tumor vasculature with antiangiogenic tyrosine kinase inhibitors in combination with therapeutic vaccines.

This study investigated the effects on the tumor microenvironment (TME) of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in two murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using three endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the TME, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can, thus, have a dramatic impact on the effectiveness of cancer immunotherapy.

Simultaneous delivery of doxorubicin and curcumin encapsulated in liposomes of pegylated RGDK-lipopeptide to tumor vasculature.

Curcumin, because of its distinguishing ability to inhibit activation of transcription factor linked to chemoresistance and drug transporters, is now being co-administered with various potent anti-cancer drugs. In the present study, we report on such potentiating capabilities of curcumin in anti-angiogenic cancer therapy. With a view to simultaneously deliver curcumin and doxorubicin to tumor vasculature in anti-angiogenic cancer therapy, herein we report on the design & synthesis of a tumor vasculature targeting pegylated RGDK-lipopeptide. We show that curcumin & doxorubicin co-encapsulated within the liposomes of the presently described pegylated RGDK-lipopeptide exhibit synergism in inhibiting proliferation, invasion and migration of both tumor and endothelial cells presumably by inhibiting proliferation and metastasis related genes both at mRNA & protein levels. Pronounced tumor growth inhibition was observed in mice treated with formulations containing both the drugs. Tumor growth inhibition was found to be 2-3 folds less in mice treated with formulations containing only curcumin or only doxorubicin. The presently described liposomal system is expected to find future use for simultaneously delivering potentially any combinations of hydrophilic and hydrophobic potent small molecule cancer therapeutics to tumor vasculature in anti-angiogenic cancer therapy.

Antitumor effects of dietary black and brown rice brans in tumor-bearing mice: relationship to composition.

SCOPE: Feeding a diet supplemented with 10% (w/w) black and brown rice brans inhibited growth of transplanted tumors in mice. METHODS AND RESULTS: Black and brown rice brans from Oryza sativa LK1-3-6-12-1 and Chuchung cultivars each contained 21 compounds characterized by GC/MS. Mice fed diets with added rice brans for 2 weeks were intracutaneously inoculated with CT-26 mouse cancer cells and fed the same diet for two additional weeks. Tumor mass was 35 and 19% lower in the black and brown bran-fed groups, respectively. Tumor inhibition was associated with increases in cytolytic activity of splenic natural killer (NK) cells; partial restoration of nitric oxide production and phagocytosis in peritoneal macrophages; increases in released tumor necrosis factor-α, IL-1ß, and IL-6 from macrophages; increases in infiltration of leukocyte into the tumor; and reduction in angiogenesis inside the tumor. Proangiogenic biomarkers vascular endothelial growth factor, cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX) were also reduced in mRNA and protein expression. ELISA of tumor cells confirmed reduced expression of COX-2 and 5-LOX. Reduced COX-2 and 5-LOX expression downregulated vascular endothelial growth factor and inhibited neoangiogenesis inside the tumors. CONCLUSION: Induction of NK activity and macrophages and inhibition of angiogenesis seem to contribute to tumor regression.

Valproic acid inhibits angiogenesis in vitro and glioma angiogenesis in vivo in the brain.

Antiangiogenic strategy is promising for malignant glioma. Histone deacetylase inhibitors (HDACIs) are unique anticancer agents that exhibit antiangiogenic effects. The in vitro and in vivo antiangiogenic effects of HDACIs, valproic acid (VPA), were investigated in malignant glioma in the brain. In vitro, VPA preferentially inhibited endothelial cell proliferation compared to glioma cell proliferation at the optimum concentration in a dose-dependent manner. VPA reduced vascular endothelial growth factor (VEGF) secretion of glioma cells in a dose-dependent manner under both normoxic and hypoxic conditions. VPA was also found to inhibit tube formation in the angiogenesis assay. In vivo, treatment with VPA combined with irinotecan reduced the number of vessels expressing factor VIII in the brain tumor model. VPA inhibits glioma angiogenesis by direct (inhibition of endothelial cell proliferation and tube formation) and indirect (decreased secretion of VEGF by glioma cells) mechanisms. These data suggest a potential role for VPA as an adjuvant therapy for patients with malignant glioma.

Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluation.

UNLABELLED: In research of the last decade, rhythmic (circadian) variations of vascular endothelial growth factor (VEGF) production by tumors were discovered. The present paper authors have earlier synthesized and characterized a new derivative photosensitizer - an immunoconjugate of hematoporphyrin with antiVEGF antibodies. AIM: To elaborate and to test a novel modification of the photodynamic therapy of tumors (PDT) method, founding upon a timed introduction of the immunoconjugated photosensitizer to tumor-bearing animals, so that this coincides with a maximum content of VEGF in tumor tissues. METHODS: Circadian variations of VEGF contents in murine transplanted tumors, Lewis lung carcinoma and sarcoma 180, were determined by ELISA method. Immunoconjugated photosensitizer concentrations in tumors were estimated by spectrofluorometry. Photoirradiation of the tumors was carried out with a red light (wavelength of 635 nm) from a semiconductor laser. Light doses were chosen, calculating on a partial inhibition of tumor growth, in order that a dependence of PDT efficiency on a daily time-moment (circadian rhythm phase) of the treatment could be observed distinctly. RESULTS: Circadian variations of the VEGF levels in Lewis lung carcinoma and sarcoma 180 were demonstrated with the maximum at 14:00 h and the minimum at 02:00 h. Intra-abdominal introduction into tumor-bearing mice of the immunoconjugated photosensitizer resulted in a greater accumulation of the immunoconjugate in tumors at 14:00 h than at 02:00 h. Laser irradiation of carcinomas and sarcomas at 14:00 h or 02:00 h after introduction of the immunoconjugated photosensitizer to mice the day before at the same time points, induced a significantly enhanced inhibition of tumor growth in animals treated at day-time versus those treated at night-time. CONCLUSION: The obtained results justify further attempts to transfer principles of tumor chronochemotherapy onto photodynamic therapy.

Cucurbitacin E, a tetracyclic triterpenes compound from Chinese medicine, inhibits tumor angiogenesis through VEGFR2-mediated Jak2-STAT3 signaling pathway.

Cucurbitacin E (CuE, α-elaterin), a tetracyclic triterpenes compound from folk traditional Chinese medicine plants, has been shown to inhibit cancer cell growth, inflammatory response and bilirubin-albumin binding. However, the effects of CuE on tumor angiogenesis and its potential molecular mechanism are still unknown. Here, we demonstrated that CuE significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration and tubulogenesis in vitro and blocked angiogenesis in chick embryo chorioallantoic membrane assay and mouse corneal angiogenesis model in vivo. Furthermore, we found that CuE remarkably induced HUVEC apoptosis, inhibited tumor angiogenesis and suppressed human prostate tumor growth in xenograft tumor model. Finally, we showed that CuE blocked vascular endothelial growth factor receptor (VEGFR) 2-mediated Janus kinase (Jak) 2-signal transducer and activator of transcription (STAT) 3 signaling pathway in endothelial cells and suppressed the downstream protein kinases, such as extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Therefore, our studies provided the first evidence that CuE inhibited tumor angiogenesis by inhibiting VEGFR2-mediated Jak-STAT3 and mitogen-activated protein kinases signaling pathways and CuE is a potential candidate in angiogenesis-related disease therapy.

Exploring vascular dysfunction caused by tirapazamine.

We have previously reported that the hypoxic cytotoxin tirapazamine causes central vascular dysfunction in HCT-116 xenografts. Here we further extend this finding to SiHa xenografts and SCCVII murine tumors. Within 1 day after treatment with tirapazamine both tumor types develop areas of non-perfused tissue in central regions of tumors. To explore the mechanism by which the hypoxic cytotoxin tirapazamine causes vascular dysfunction we altered the blood oxygen content with carbogen (95% O(2) and 5% CO(2)) breathing in tumor bearing mice. Carbogen treatment was able to decrease the number of tumors responding to tirapazamine but was not able to eradicate the vascular dysfunction completely. In complementary in vitro studies, immunohistochemical staining of tirapazamine-treated endothelial cells indicated that, unlike the vascular targeting agent (VTA) combretastatin-A-4-phosphate, the vascular effects caused by tirapazamine are not due to microtubule disruption. Another possible mechanism of action for tirapazamine could involve its ability to inhibit nitric oxide synthase (NOS). Studies combining other vascular targeting agents (VTAs) such as the combretastatins have shown a potentiation of vascular disruption in tumors when combined with NOS inhibitors, possibly due to vessel constriction from decreased nitric oxide (NO) levels. We propose the theory that vascular dysfunction caused by tirapazamine may be via NOS inhibition. In support of this hypothesis preliminary experiments showed NOS inhibition with L-NNA (N-omega-nitro-L-arginine) increases tumor necrosis, 1 day after administration, in our HCT-116 tumor model.

The effect of electromagnetic field and local inductive hyperthermia on nonlinear dynamics of the growth of transplanted animal tumors.

AIM: To examine the effects of electromagnetic field with amplified magnetic component and local inductive hyperthermia (IH) on nonlinear dynamics of the growth of animal tumors. MATERIALS AND METHODS: Guerin carcinoma, Lewis lung carcinoma, sarcoma 45, Walker 256 carcinosarcoma and Pliss lymphosarcoma were studied. The animal tumors were exposed inside of loop aerial, 3 cm in diameter locally for 30 min. Parameters of electromagnetic irradiation (EI): frequency 40 MHz, magnetic intensity 72 A/m, electric intensity 200 V/m and the output power 50 W. The temperature measured by immersion of thermocouple inside the center of the tumor didn't exceed 38.5-39.5 degrees C. Nonlinear dynamics of the growth of animal tumors was analyzed by autocatalytic equation. The heterogeneity of ultrasonic image of the tumor was analyzed by Moran spatial autocorrelation. RESULTS: The strongest inhibition effect under the influence of EI was in Pliss lymphosarcoma and sarcoma 45. The growth stimulation of animal tumors after EI was recorded in Walker 256 carcinosarcoma. The use of mild IH increased the blood flow in the tumor of Guerin carcinoma. CONCLUSION: These results are important for clinical application because they testify the necessity of optimization of schemes for local EI during anticancer neoadjuvant therapy with the use of drugs or magnetic nanoparticles. The use of mild IH as a basis for the monotherapy of malignant tumors is not expedient.

Plasma protein beta-2-glycoprotein 1 mediates interaction between the anti-tumor monoclonal antibody 3G4 and anionic phospholipids on endothelial cells.

A promising target on tumor vasculature is phosphatidylserine (PS), an anionic phospholipid that resides exclusively on the inner leaflet of the plasma membrane of resting mammalian cells. We have shown previously that PS becomes exposed on the surface of endothelial cells (EC) in solid tumors. To target PS on tumor vasculature, the murine monoclonal antibody 3G4 was developed. 3G4 localizes to tumor vasculature, inhibits tumor growth, and enhances anti-tumor chemotherapies without toxicity in mice. A chimeric version of 3G4 is in clinical trials. In this study, we investigated the basis for the interaction between 3G4 and EC with surface-exposed PS. We demonstrate that antibody binding to PS is dependent on plasma protein beta-2-glycoprotein 1 (beta2GP1). beta2GP1 is a 50-kDa glycoprotein that binds weakly to anionic phospholipids under physiological conditions. We show that 3G4 enhances binding of beta2GP1 to EC induced to expose PS. We also show that divalent 3G4-beta2GP1 complexes are required for enhanced binding, since 3G4 Fab' fragments do not bind EC with exposed PS. Finally, we demonstrate that an artificial dimeric beta2GP1 construct binds to EC with exposed PS in the absence of 3G4, confirming that antibody binding is mediated by dimerization of beta2GP1. Together, these data indicate that 3G4 targets tumor EC by increasing the avidity of beta2GP1 for anionic phospholipids through formation of multivalent 3G4-beta2GP1 complexes.

Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin.

In this study we investigated whether the flavonoid silybin and its bioavailable derivative IdB 1016 (silipide) could enhance the antitumour activity of cisplatin (CDDP), the most commonly used drug in the treatment of gynaecological malignancies. Silybin alone up to 10 (M was unable to produce a relevant in vitro growth inhibition of A2780 cells, whereas CDDP was effective, giving an IC50 value of 0.5+/-0.14 microM. When silybin was combined with CDDP, a dose-dependent and statistically significant (p<0.05) increase of the CDDP activity was noticed, yielding IC50 values of 0.35+/-0.07 and 0.263+/-0.004 microM at silybin concentrations of 1 and 10 microM, respectively. The same trend was observed for in vivo experiments. IdB 1016 alone (1350 mg/kg) did not significantly affect tumour growth, whereas CDDP at the Maximum Tolerated Dose (12 mg/kg) produced a tumour weight inhibition (TWI%) of 80% and a log10 cell kill (LCK) of 0.7. Administration of both drugs resulted in a potentiation of the antitumour activity and TWI% and LCK increased to 90% and 1, respectively. Interestingly, mice receiving the combination recovered earlier in terms of body weight loss as compared to CDDP-treated mice. CDDP at 6 mg/kg yielded TWI of 44% and LCK of 0. The concomitant administration of IdB 1016 (1800 mg/kg) enhanced CDDP anti-tumour activity, with 68% TWI and 0.6 LCK. Finally, an antiangiogenic effect of IdB 1016 in an in vivo experimental model was demonstrated. Median haemoglobin value for the Matrigel from the vehicle-treated controls was 2.43 versus a value of 0.321 for the IdB 1016-treated animals.

The susceptibility of tumors to the antivascular drug combretastatin A4 phosphate correlates with vascular permeability.

The acute effects of the antivascular drug, combretastatin A4 phosphate, on tumor energy status and perfusion were assessed using magnetic resonance imaging (MRI) and spectroscopy. Localized (31)P magnetic resonance spectroscopy showed that LoVo and RIF-1 tumors responded well to drug treatment, with significant increases in the P(i)/nucleoside triphosphate ratio within 3 h, whereas SaS, SaF, and HT29 tumors did not respond to the same extent. This variable response was also seen in MRI experiments in which tumor perfusion was assessed by monitoring the kinetics of inflow of the contrast agent, gadolinium diethylenetriaminepentaacetate. These data were analyzed to give the initial rate and time constant for inflow of contrast agent and the integral under the inflow curve. The differential susceptibility of the tumors to combretastatin A4 phosphate showed a positive correlation with prior MRI measurements of tumor vascular permeability, which was determined by measuring the inflow of a macromolecular contrast agent, BSA-gadolinium diethylenetriaminepentaacetate.

Induction of vascular endothelial growth factor (VEGF) by hyperthermia and/or an angiogenesis inhibitor.

Intratumoral localization of vascular endothelial growth factor (VEGF) following administration of hyperthermia (HT) and/or anti-angiogenic drugs (TNP-470) was evaluated using SCC VII tumours in C3H/He mice. Hyperthermia at 44.0 degrees C for 30 min was given with a water bath on day 0. TNP-470 (100 mg/kg) was administered alone or after HT on day 0 and day 3. Histological changes on day 4 were evaluated by haematoxylin-eosin (HE) staining and immunohistochemical staining for VEGF. The percentage of the necrotic area relative to the entire tumour area (the % necrotic area) was measured on HE stains. The average % necrotic area of the untreated SCC VII tumours was 7%, while those of tumours treated with TNP-470 alone and HT alone were 27 or 65%, respectively. When HT and TNP-470 were combined, the % necrotic area was 82%, which was significantly higher than that caused by HT alone (p < 0.05). Immunohistochemical staining for VEGF in untreated SCC VII tumours was weak, although strong staining for VEGF was noted in untreated EMT-6 tumours of BALB/c mice, which have spontaneous central necrosis. After administration of HT and/or TNP-470, layer-shaped staining by VEGF was observed in the residual SCC VII tumour cells adjacent to the necrotic area. In conclusion, the expression of VEGF increased in response to administration of HT and/or TNP-470. Hypoxia caused by heat-induced vascular damage may be attributable to increased expression of VEGF in SCC VII tumours.

Stereologic evaluation of the vasculature in a MX1 xenotransplanted tumour model after combinations of treatment with ifosfamide, hyperthermia and irradiation.

The vascularization of tumours is a critical parameter of their growing and metastatic behaviour. However, little is known about the morphologic reactions of the microvasculature, especially the capillary bed of tumours and the adjacent tissue. In this study, the vessels in MX1 xenotransplants in athymic nu/nu nude mice were quantified and the angioarchitecture was visualized with the aim of presenting stereologic parameters of vessels based on a morphometric analysis of post mortem tissue blocks which were processed by standard histological procedures. In order to study changes of the microvasculature of MX1 tumours, the xenotransplanted nude mice were treated by different therapeutic regimens. Standardized hyperthermia, ifosfamide and irradiation therapies were applied. Special interest was focused on early changes of capillaries and of the pre- as well as post-terminal vascular bed. The stereologic evaluation of capillaries and larger vessels immediately after the therapy with ifosfamide and hyperthermia shows an increase of the mean capillary sizes. Furthermore, tumour samples after the 5th day of irradiation (5 x 2 Gy) and combinations of irradiation and chemotherapy treatment have been investigated. After 5 days of irradiation, a significant decrease of the vascular density was found. The results presented here clearly show that the timing and the mode of therapy influence the capillary morphology and periterminal vasculature of xenotransplanted MX1 tumours.

Reduction of tumour blood flow with KB-R8498 potentiates the response of tumours to hyperthermia.

The anti-tumour activity and the effect on tumour and normal tissue perfusion of a newly discovered anticancer agent, KB-R8498 (Kanebo Ltd., Osaka, Japan), were investigated in FSa II tumours of C3H mice. The tumour perfusion, as measured by the 86Rb-uptake method, markedly decreased with relatively little change in the normal tissue perfusion after an i.v. injection of KB-R8498. Furthermore, the drug potentiated the effect of hyperthermia at 42.5 degrees C for 60 min to suppress the tumour growth. The results suggest that the preferential reduction in tumour blood flow relative to normal tissue blood flow by KB-R8498 may be exploited to enhance the anti-tumour effect of hyperthermia.

The optimal combination of hyperthermia and carbogen breathing to increase tumor oxygenation and radiation response.

PURPOSE: To determine the most effective combination of carbogen breathing with mild temperature hyperthermia (MTH) to increase the oxygenation and radiation response in murine tumors. METHODS AND MATERIALS: MTH at 41.5 degrees C for 60 min was applied by immersion of the tumor in a precisely controlled water bath. The tumor pO2 was measured with a polarographic microelectrode. The radiation response of the tumor was determined using the in vivo/in vitro assay for surviving tumor cells. RESULTS: In the FSaII fibrosarcoma the median pO2 increased from a control value of 6.5 +/- 0.5 mm Hg to 16.6 +/- 1.1 mm Hg immediately after MTH and was 10.9 +/- 1.3 mm Hg 24 h later. Carbogen breathing for 5 min increased the FSaII pO2 to 19.9 +/- 2.1 mm Hg. Carbogen breathing for 5 min beginning immediately after MTH increased the median pO2 more than 5 times to 35.4 +/- 3.8 mm Hg. This combined treatment also substantially increased the response of the tumors to a radiation exposure of 20 Gy. In another tumor model, the SCK mammary carcinoma, MTH treatment increased the median pO2 from the control level of 4.4 +/- 0.2 mm Hg to 12.6 +/- 1.2 mm Hg, and it returned to 4.3 +/- 0.3 mm Hg 24 h later. Carbogen breathing for 5 min increased the SCK tumor pO2 to 17.1 +/- 1.4 mm Hg. The median SCK pO2 was increased about 7 times to 31.2 +/- 4.2 mm Hg when MTH was followed immediately with carbogen breathing for 5 min. The radiation response was also markedly increased by this combination. When the animals breathed carbogen for 15 or 30 min, the pO2 and radiosensitivity in both tumor types either remained the same or was lower than that after 5 min of breathing. In addition, both FSaII and SCK tumors were radiosensitized 24 h after MTH treatment alone or with 5 min of carbogen breathing. CONCLUSIONS: A shorter carbogen breathing time immediately after MTH causes the most tumor radiosensitization. The results of this study also demonstrate that MTH increases radiosensitivity with and without carbogen breathing up to 24 h after the mild hyperthermia treatment.

Studies on hyperthermia combined with arterial blockade for treatment of tumors: (Part I) effectiveness of hyperthermia combined with arterial ligation.

Arterial ligation was combined with hyperthermia in rabbits with VX2 tumors implanted in the leg. For seven days after arterial ligation, blood flow was decreased and the pH was low in both normal muscle and tumor tissue. The temperature of normal muscle and tumor tissue increased faster and reached a higher level on heating immediately after ligation than without ligation. The antitumor effect of hyperthermia was stronger immediately after ligation than two or seven days afterwards. However, damage to normal muscle was severe with this combination therapy, so a better method of therapeutic arterial blockade is needed.

Studies on hyperthermia combined with arterial blockade for treatment of tumors: (Part II) effectiveness of hyperthermia combined with arterial embolization using degradable starch microspheres.

The efficacy of temporary arterial embolization using degradable starch microspheres combined with hyperthermia was investigated in rabbits bearing VX2 tumors. Microsphere injection caused a marked decrease of tumor blood flow and pH. During heating, there was a marked increase of the maximum temperature in tumor tissue compared with normal muscle. Tumor growth was suppressed 330% times at 3 weeks after hyperthermia alone and 270% times following combined treatment with microspheres and hyperthermia. Damage to normal muscle tissue was mild. In conclusion, this combination therapy may be useful for causing selective tumor damage and reducing the effect on normal tissues.

Tumor oxygenation after mild-temperature hyperthermia in combination with carbogen breathing: dependence on heat dose and tumor type.

We investigated the effect of hyperthermia at 40.5-42.5 degrees C as well as the combination of hyperthermia and carbogen breathing on oxygenation in the SCK murine mammary carcinoma. In addition, the important question of how long the effect of heating on tumor oxygenation lasts was addressed in both SCK and FSaII (murine fibrosarcoma) tumors. The median pO2 in control SCK tumors was 4.4 +/- 0.2 mm Hg, and it increased to a maximum of 12.6 +/- 1.2 mm Hg when the tumors were heated at 41.5 degrees C for 1 h. Carbogen breathing increased the median pO2 of SCK tumors to 17.1 +/- 1.4 mm Hg, but after heating at 41.5 degrees C, it elevated the pO2 in SCK tumors markedly to 31.3 +/- 4.2 mm Hg. The kinetics of the return to baseline oxygenation after hyperthermia was found to vary with the type of tumor and the heat dose. The pO2 of FSaII tumors remained significantly higher than that of control tumors 24 h after heating at 41.5 degrees C for 60 min. The pO2 of SCK tumors remained elevated for up to 3 h after heating at 41.5 degrees C for 30 min, but if the tumors were heated for 60 min at this temperature, the median oxygen tension declined to the control level within 1 h after heating. It was concluded that mild-temperature hyperthermia, i.e. 41.5 degrees C, alone and in combination with carbogen breathing dramatically improves the oxygenation of these murine tumors and that the tumor type influences the duration of changes in oxygenation induced by mild-temperature hyperthermia.