Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: Data from a phase III trial

Sherar, Michael D.; Liu, Fei‐Fei; Pintilie, Melania; Levin, Wilfred; Hunt, J.W.; Hill, Richard P.; Hand, J.W.; Vernon, Clare C.; Rhoon, Gerard C. van; Zee, Jacoba van der; González, Dionisio González; Dijk, Jan van; Whaley, Jill B.; Machin, David

doi:10.1016/s0360-3016(97)00333-7

Cited by 164 publications

(137 citation statements)

References 25 publications

(5 reference statements)

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“…29 Hyperthermia has been demonstrated in Phase III randomized trials to benefit patients with both improved local control 1,4,5 and survival. 2 However, attainment of uniform temperature within the target tumor tissues is difficult to achieve, 30 hence any additional therapeutic manoeuvre that could enhance heat-induced cytotoxicity would be desirable. We have previously demonstrated that PKB can modulate heat sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Kinase-dead PKB gene therapy combined with hyperthermia for human breast cancer

Szmitko

Brade

et al. 2003

Cancer Gene Ther

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We have previously demonstrated that protein kinase B (PKB) is a mediator of heat-induced apoptosis for human breast cancer cells. To investigate the therapeutic potential of abrogating the function of this important survival protein, a novel replication-deficient adenovirus was constructed, wherein a mutant, kinase-inactive PKB gene (AAA) was inserted downstream of the CMV promoter. Two human breast cancer cell lines, MCF-7 and MDA-468, were treated, along with the MCF-10 serving as a ''normal'' mammary epithelial comparator. Apoptosis was increased with adv.AAA (25 PFU/cell) infection alone, but was significantly enhanced with the addition of heat exposure. Differential survival was observed with the MDA-468 cancer cells being more sensitive than the MCF-7 cells. The MCF-10 cells, in contrast, were most resistant to these treatments. Results from the clonogenic assay reflected the apoptosis data, with an apparent additive interaction between adv.AAA and hyperthermia treatments, again with greater differential sensitivity of the malignant, compared to the ''normal'' mammary epithelial cells. Heat or adv.b-gal treatments led to phosphorylation of PKB and Forkhead, but this phosphorylation was reduced with adv.AAA therapy. In parallel, the combination of adv.AAA and heat treatment reduced PKB kinase activity more so than with either heat or adv.b-gal alone. In conclusion, our results demonstrate that inhibition of the PKB-dependent survival pathway will promote apoptosis and thermosensitization in malignant breast cancer cells, with relative sparing of their normal counterpart, suggesting that a therapeutic gain could be achievable using this therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Kinase-dead PKB gene therapy combined with hyperthermia for human breast cancer

Szmitko

Brade

et al. 2003

Cancer Gene Ther

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“…(104) This parameter, cumulative equivalent minutes at 43°C achieved by 90% of the measured temperate points in the targeted area or CEM43T90, has been shown in multiple studies to correlate with clinical outcome. (83)(84)(105)(106)(107)(108)(109)(110)(111)(112) The field of thermal dosimetry continues to evolve given that most treatment thermal profiles are based on modest samples of temperature points in the heated region. Non-invasive approaches to temperature measurement capable of monitoring hundreds or thousands of points in real time is now possible albeit not widely available.…”

Section: Challenges To Clinical Implementationmentioning

confidence: 99%

Hyperthermia, Radiation and Chemotherapy: The Role of Heat in Multidisciplinary Cancer Care

Hurwitz

Stauffer

2014

Seminars in Oncology

118

104

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“…Temperature inhomogeneity has been shown to impact on outcome and this is due to technical challenges as well as the heat -sink effects caused by the tumor vasculature. 11,12 The temperatures reached in hyperthermia treatment activate the heat shock response in cells. Certain members of the heat shock gene family are quiescent in resting cells but strongly induced following heat damage.…”

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Heat-directed gene targeting of adenoviral vectors to tumor cells

et al. 2000

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Targeting therapeutic gene expression to tumor cells represents a major challenge for cancer gene therapy. The strong transcriptional response exhibited by heat shock genes, along with the beneficial therapeutic effects of hyperthermia have led us to develop a heatdirected gene -targeting strategy for cancer treatment. Heat shock gene expression is mediated in large part by the interaction of heat shock factor 1 with specific binding sites ( heat shock elements; HSE ) found in the promoters of heat -inducible genes. Here we present a quantitative analysis of heat -inducible gene expression mediated by the wild -type hsp70b gene promoter, as well as a modified hsp70b promoter containing additional HSE sequences. -Galactosidase ( -gal ) expression was induced between 50 -and 800 -fold in a panel of human breast cancer cell lines infected with an adenoviral vector containing the wild -type hsp70b promoter ( Ad.70b. g ) following treatment at 438C for 30 minutes. Infection with an adenoviral vector containing the modified hsp70b promoter ( Ad.HSE.70b. g ) resulted in a 200 -to 950 -fold increase in -gal expression under the same conditions, and also provided a 1 ± 28C decrease in the threshold of activation. Significant increases in the heat responsiveness of the Ad.HSE.70b. g construct were observed in five of six tumor cell lines tested, as well as under thermotolerant conditions. Finally, we demonstrate that localized heating of a HeLa cell xenograft can effectively target -gal gene expression following intratumoral injection of Ad.70b. g. Adenoviral vectors incorporating heat -inducible therapeutic genes may provide useful adjuncts for clinical hyperthermia. Cancer Gene Therapy ( 2000 ) 7, 1566 ± 1574

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Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: Data from a phase III trial

Cited by 164 publications

References 25 publications

Kinase-dead PKB gene therapy combined with hyperthermia for human breast cancer

Kinase-dead PKB gene therapy combined with hyperthermia for human breast cancer

Hyperthermia, Radiation and Chemotherapy: The Role of Heat in Multidisciplinary Cancer Care

Heat-directed gene targeting of adenoviral vectors to tumor cells

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