Changes in oxygenation status and blood flow in a rat tumor model by mild temperature hyperthermia

Shakil, Abdus; Osborn, John; Song, Chang W.

doi:10.1016/s0360-3016(98)00516-1

Cited by 72 publications

(55 citation statements)

References 21 publications

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“…Similar findings were reported by Iwata et al (32) and Shakil et al (33). In both studies an improvement in tumor oxygenation persisted for periods of up to 24 h after 1 h of 41.5°C hyperthermia treatment (32,33). Also, persistent improvement in oxygenation was observed in both human sarcoma and breast cancer patients 24 h after hyperthermia (20,34).…”

Section: Discussionmentioning

confidence: 92%

Thermochemoradiotherapy Improves Oxygenation in Locally Advanced Breast Cancer

Jones

Prosnitz

Dewhirst

et al. 2004

Clinical Cancer Research

130

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Purpose: The purpose of this research was to evaluate toxicity, response, and changes in oxygenation (pO 2 ) in patients with locally advanced breast cancer (LABC) treated with concurrent taxol, hyperthermia (HT), and radiation therapy (RT) followed by mastectomy.Experimental Design: Eighteen patients with LABC were enrolled from October 1995 through February 1999. Treatment consisted of taxol (175 mg/m 2 ) given every 3 weeks for three cycles. Radiation therapy included the breast and regional nodes with a dose of 50 Gy, followed by a boost to 60 -65 Gy for those not undergoing surgery. Mastectomy was performed for patients deemed resectable after this neoadjuvant program. HT was administered twice per week. Oxygenation was measured before the first HT treatment and 24 h after the first HT treatment.Results: Fifteen of 18 patients responded, 6 with a clinical complete response, 9 with a partial clinical response, and 3 nonresponders. Thirteen underwent mastectomy with 3 pathological complete responses. Tumor hypoxia was present in 8 of 13 patients (pO 2 ‫؍‬ 4.7 ؎ 1.2 mmHg). Five patients had well-oxygenated tumors (pO 2 ‫؍‬ 27.6 ؎ 7.8 mmHg). Patients with well-oxygenated tumors before treatment as well as those with significant reoxygenation had a favorable clinical response. Tumor reoxygenation appeared to be temperature dependent and associated with the lower thermal doses.Conclusions: This novel therapeutic program resulted in a high response rate in patients with LABC. Hyperthermia may offer a strategy for improving tumor reoxygenation with consequent treatment response. However, the effect of hyperthermia on tumor reoxygenation appears to depend on thermal dose and requires additional investigation.

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Section: Discussionmentioning

confidence: 92%

Thermochemoradiotherapy Improves Oxygenation in Locally Advanced Breast Cancer

Jones

Prosnitz

Dewhirst

et al. 2004

Clinical Cancer Research

130

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“…Many cancer patients are suffering from hypothermia and circulation failure (8,11,12,18) due to vessel constriction induced by sympathetic nerve activation (1, 19). As a result, immunosuppression is often accompanied with these patients, showing lymphocytopenia.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, hyperthermia could not be continued in Case 6 due to his worsened physical condition. The present data suggest that mild hyperthermia is a useful method to improve circulation failure, physical condition and clinical data.Many cancer patients are suffering from hypothermia and circulation failure (8,11,12,18) due to vessel constriction induced by sympathetic nerve activation (1, 19). As a result, immunosuppression is often accompanied with these patients, showing lymphocytopenia.…”

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confidence: 99%

Alkalization of blood pH is responsible for survival of cancer patients by mild hyperthermia

Ohishi

Nukuzuma

Seki³

et al. 2009

Biomed. Res.

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The effect of mild hyperthermia on venous blood pH was examined in 6 cancer patients. Mild hyperthermia was induced by continuation of a rectal temperature of 39.5°C for 30 min. All 6 patients were diagnosed as suffering from advanced cancer with or without surgery and chemotherapy pretreatments. In Cases 1 to 5, but not Case 6, venous blood pH was alkalized up to pH 7.7 by this mild hyperthermia and the effect was reproduced depending on the application of hyperthermia. At this time, alkalized pH was accompanied by increased PO 2 and decreased PCO 2 in the blood. These patients showed good physical conditions and improved clinical data. On the other hand, hyperthermia could not be continued in Case 6 due to his worsened physical condition. The present data suggest that mild hyperthermia is a useful method to improve circulation failure, physical condition and clinical data.Many cancer patients are suffering from hypothermia and circulation failure (8,11,12,18) due to vessel constriction induced by sympathetic nerve activation (1, 19). As a result, immunosuppression is often accompanied with these patients, showing lymphocytopenia. Restoration from this circulation failure seems to be important for the treatment of cancer. In this regard, there have been many trials of hyperthermia for the treatment of malignancy (6,9,17,20). Hyperthermia indeed ameliorates not only immune functions but also other physical conditions. In the course of these studies, we have noticed that hyperthermia (i.e., > 40°C) sometimes induced rather immunosuppression as a thermal stress (14). At this time, persons who experienced with hyperthermia showed granulocytosis and lymphocytopenia after the treatment. This might be due to the fact that overexposure of hyperthermia induced stressassociated sympathetic nerve activation and that granulocytes bear surface adrenergic receptors but lymphocytes bear surface cholinergic receptors (13,15). A similar response was also reported in animal studies (16). Dogs and cats which experienced with severe hyperthermia showed immunosuppression, showing granulocytosis and lymphocytopenia.In an earlier study, we showed that hyperthermia at the level up to 39.5°C (rectal temperature) for 30 min did not induce granulocytosis but rather induced immunopotentiation (14). In the present study, we applied this condition of hyperthermia for 6 cancer patients. As shown previously and in this study, an appropriate condition of hyperthermia is well correlated with the alkalization of blood pH with increased PO 2 and decreased PCO 2 after the application of hyperthermia. MATERIAL AND METHODS Subjects. Diagnosis of all cancer patients, including

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“…Mild HT-induced tumor reoxygenation is known to be caused by enhanced oxygen delivery (11) and decreased oxygen consumption (12)(13)(14)(15). However, the molecular mechanisms that control these physiological changes are unknown.…”

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confidence: 99%

NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment

Moon

Sonveaux²,

Porporato³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

139

126

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Hyperthermia (HT) is a strong adjuvant treatment with radiotherapy and chemotherapy because it causes tumor reoxygenation. However, the detailed molecular mechanisms of how HT enhances tumor oxygenation have not been elucidated. Here we report that 1 h of HT activates hypoxia-inducible factor-1 (HIF-1) in tumors and its downstream targets, vascular endothelial growth factor (VEGF) and pyruvate dehydrogenase kinase 1 (PDK1). Consistent with HIF-1 activation and up-regulation of its downstream genes, HT also enhances tumor perfusion/vascularization and decreases oxygen consumption. As a result, tumor hypoxia is reduced after HT, suggesting that these physiological changes contribute to HT-induced tumor reoxygenation. Because HIF-1 is a potent regulator of tumor vascularization and metabolism, our findings suggest that HIF-1 plays a role in HT-induced tumor reoxygenation by transactivating its downstream targets. We demonstrate that NADPH oxidasemediated reactive oxygen species production, as a mechanism, upregulates HIF-1 after HT. Furthermore, we determine that this pathway is initiated by increased transcription of NADPH oxidase-1 through the ERK pathway. In conclusion, this study determines that, although HIF-1 is a good therapeutic target, the timing of its inhibition needs to be optimized to achieve the most beneficial outcome when it is combined with other treatments of HT, radiation, and chemotherapy.

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Changes in oxygenation status and blood flow in a rat tumor model by mild temperature hyperthermia

Cited by 72 publications

References 21 publications

Thermochemoradiotherapy Improves Oxygenation in Locally Advanced Breast Cancer

Thermochemoradiotherapy Improves Oxygenation in Locally Advanced Breast Cancer

Alkalization of blood pH is responsible for survival of cancer patients by mild hyperthermia

NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment

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