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Old 02-09-2010, 04:13 PM   #1
Rich66
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Join Date: Feb 2008
Location: South East Wisconsin
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Radiation

(enhances CSC, needs Akt inhibition,w/endocrine,w/honokiol,w/curcumin,w/Zol,w/loratadine,w/glycolysis inhib,w/various chemo, w/cox2 inhib)



Breast Cancer Res. 2010 Feb 16;12(1):R13. [Epub ahead of print]
Survival, self-renewing capacity and multi-lineage potency of breast cancer initiating cells during fractionated radiation treatment.

FREE TEXT


Lagadec C, Vlashi E, Della Donna L, Meng Y, Dekmezian C, Kim K, Pajonk F.
ABSTRACT: INTRODUCTION: Recent data indicate a hierarchical organization of many solid cancers, including breast cancer with a small number of cancer initiating cells (CICs) that have the ability to self-renew and exhibit multi-lineage potency. We, and others, have demonstrated that CICs in breast cancer and glioma were relatively resistant to ionizing radiation if compared to their non-tumorigenic counterparts. However, the extent of the remaining self-renewing capacity of CICs after fractions of radiation is currently unknown. We hypothesized that CICs, in contrast with their non-tumorigenic counterparts, not only survive fractions of ionizing radiation but also retain the CIC phenotype as defined by operational means. METHODS: We used two marker systems to identify breast CICs (CD24-/low/CD44high, or lack of proteasome activity) and performed sphere-forming assays after multiple clinical fractions of radiation. Lineage tracking was performed by membrane staining. Cell cycle distribution and RNA content were assessed by flow cytometry and senescence was assessed by SZ-gal staining. RESULTS: We demonstrated that irradiated CICs survived and retained their self-renewal capacity for at least 4 generations. We show that fractionated radiation not only spared CICs but also mobilized CICs from a quiescent/G0 phase of the cell cycle into actively cycling cells while the surviving non-tumorigenic cells were driven into senescence. CONCLUSIONS: We conclude that increases in the number of cancer initiating cells after sublethal doses of radiation are potentially of clinically importance because the CIC population retains increased self-renewal capacity over several generations. Prevention of this process may therefore lead to improved clinical outcome.

PMID: 20158881 [PubMed - as supplied by publisher]



Stem Cells. 2010 Feb 4. [Epub ahead of print]
Radiation Resistance of Cancer Stem Cells - The 4R's of Radiobiology Revisited.

Pajonk F, Vlashi E, McBride WH.
Division of Molecular and Cellular Oncology, Department of Radiation Oncology, David Geffen School of Medicine at UCLA.
There is compelling evidence that many solid cancers are organized hierarchically and contain a small population of cancer stem cells (CSCs). It seems reasonable to suggest that cancer cure can only be achieved if this population is eliminated. Unfortunately, there is growing evidence that CSCs are inherently resistant to radiation, and perhaps other cancer therapies. In general, success or failure of standard clinical radiation treatment is determined by the 4 Rs of radiobiology: repair of DNA damage, redistribution of cells in the cell cycle, repopulation, and reoxygenation of hypoxic tumor areas. We relate recent findings on CSCs to these 4 phenomena and discuss possible consequences.

PMID: 20135685 [PubMed - as supplied by publisher]




J Cell Biochem. 2009 Oct 1;108(2):339-42.
Radiation responses of cancer stem cells.

Vlashi E, McBride WH, Pajonk F.
Division of Molecular and Cellular Oncology, Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1714, USA.
Recent experimental evidence indicates that many solid cancers have a hierarchical organization structure with a subpopulation of cancer stem cells (CSCs). The ability to identify CSCs prospectively now allows for testing the responses of CSCs to treatment modalities like radiation therapy. Initial studies have found CSCs in glioma and breast cancer relatively resistant to ionizing radiation and possible mechanisms behind this resistance have been explored. This review summarizes the landmark publications in this young field with an emphasis on the radiation responses of CSCs. The existence of CSCs in solid cancers place restrictions on the interpretation of many radiobiological observations, while explaining others. The fact that these cells may be a relatively quiescent subpopulation that are metabolically distinct from the other cells in the tumor has implications for both imaging and therapy of cancer. This is particularly true for biological targeting of cancer for enhanced radiotherapeutic benefit, which must consider whether the unique properties of this subpopulation allow it to avoid such therapies. (c) 2009 Wiley-Liss, Inc.

PMID: 19623582 [PubMed - indexed for MEDLINE]





Proc Natl Acad Sci U S A. 2010 Feb 3. [Epub ahead of print]
Selective targeting of radiation-resistant tumor-initiating cells.

Zhang M, Atkinson RL, Rosen JM.
Department of Molecular and Cellular Biology and Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030-3498.
Tumor-initiating cells (TICs) have been shown both experimentally and clinically to be resistant to radiation and chemotherapy, potentially resulting in residual disease that can lead to recurrence. In this study, we demonstrate that TICs isolated from p53 null mouse mammary tumors repair DNA damage following in vivo ionizing radiation more efficiently than the bulk of the tumor cells. Down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed both in fluorescence activated cell sorting (FACS)-isolated TICs as compared to non-TICs and in TIC-enriched mammospheres as compared to primary tumor cells depleted of TICs. This effect was accompanied by increased Akt signaling, as well as by the direct activation of the canonical Wnt/beta-catenin signaling pathway specifically within the TIC subpopulation by phosphorylation of beta-catenin on serine 552. Using limiting dilution transplantation performed on p53 null tumor cells transduced with Wnt reporter lentivirus, we demonstrated that FACS sorting of cells expressing TOP-eGFP resulted in a marked enrichment for TICs. Furthermore, FACS analysis demonstrated that cells with active Wnt signaling overlapped with the TIC subpopulation characterized previously using cell surface markers. Finally, pharmacological inhibition of the Akt pathway in both mammospheres and syngeneic mice bearing tumors was shown to inhibit canonical Wnt signaling as well as the repair of DNA damage selectively in TICs, sensitizing them to ionizing radiation treatment. Thus, these results suggest that pretreatment with Akt inhibitors before ionizing radiation treatment may be of potential therapeutic benefit to patients.

PMID: 20133717 [PubMed - as supplied by publisher]



Public release date: 22-Jul-2010
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http://www.eurekalert.org/pub_releas...-isc072210.php

Contact: Kim Irwin
kirwin@mednet.ucla.edu
310-206-2805
University of California - Los Angeles
Irradiating stem cell niche doubles survival in brain cancer patients

Patients with deadly glioblastomas who received high doses of radiation that hit a portion of the brain that harbors neural stem cells had double the progression-free survival time as patients who had lower doses or no radiation targeting the area, a study from the Radiation Oncology Department at UCLA's Jonsson Comprehensive Cancer Center has found.
Patients who underwent high doses of radiation that hit the specific neural stem cell site, known as the stem cell niche, experienced 15 months of progression-free survival, while patients receiving lower or no doses to this region experienced 7.2 months of progression-free survival, said Dr. Frank Pajonk, an associate professor of radiation oncology, a cancer center researcher and senior author of the study.
Pajonk said the study, published today in the early online edition of the journal BMC Cancer, could result in changes in the way radiation therapy is given to patients with these deadly brain cancers.
"Our study found that if you irradiated a part of the brain that was not necessarily part of the tumor the patients did better," Pajonk said. "We have been struggling for years to come up with new combinations of drugs and targeted therapies that would improve survival for patients with glioblastoma. It may be that by re-shaping our radiation techniques we can extend survival for these patients."
The retrospective study focused on the cases of 55 adult patients with grade 3 or grade 4 glioblastomas who received radiation at UCLA between February 2003 and May 2009. Pajonk said a prospective study is needed to confirm the results.
There is some evidence that many if not all cancers may spring from stem cells or progenitor cells that normally repair damage to the body, but that somehow become mutated and transform into cancer. In this case, Pajonk said the neural stem cell niche, called the periventricular region of the brain, may also be harboring stem cells that have transformed into brain cancer stem cells. However, the niche serves as a sort of safe harbor for the cancer stem cells, keeping them away from the site of the tumor but able to re-grow it once it's removed and the malignant areas of the brain have been treated.
Pajonk theorizes that the brain cancer stem cells in the patients whose niches were irradiated with higher doses may have been damaged or eliminated, giving these patients more time before their cancer recurred.

"This suggests that the neural stem cell niche in the brain may be harboring cancer stem cells, thus providing novel therapy targets," the study states. "We hypothesize that higher radiation doses to these niches improve patient survival by eradicating the cancer stem cells."
Glioblastomas are the deadliest form of brain cancer. Surgery, chemotherapy and radiation are not usually effective and life expectancy is about 12 to 18 months. New and more effective treatments are needed to help this patient population, Pajonk said.
The radiation therapy could damage neural stem cells as well as the cancer stem cells, Pajonk said, but those may be replaceable at some future date using induced pluripotent stem cells made from the patient's own cells. The induced pluripotent stem cells, which like embryonic stem cells can make every cell in the body, could be induced into becoming neural stem cells to replace those damaged or eradicated by the radiation to the niche.





http://www.thelancet.com/journals/la...013-9/abstract

The Lancet Oncology, Early Online Publication, 8 February 2010
doi:10.1016/S1470-2045(10)70013-9Cite or Link Using DOI

Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial

Original Text
Prof David Azria MD a , Prof Yazid Belkacemi MD b, Gilles Romieu MD a, Sophie Gourgou MSc a, Marian Gutowski MD a, Khalil Zaman MD c, Carmen Llacer Moscardo MD a, Claire Lemanski MD a, Michael Coelho MSc a, Prof Barry Rosenstein PhD d, Pascal Fenoglietto MSc a, Prof Nigel EA Crompton PhD e, Prof Mahmut Ozsahin MD c
Summary

Background

Letrozole radiosensitises breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting.

Methods

This phase 2 randomised trial was undertaken in two centres in France and one in Switzerland between Jan 12, 2005, and Feb 21, 2007. 150 postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n=75) or sequential radiotherapy and letrozole (n=75). Randomisation was open label with a minimisation technique, stratified by investigational centres, chemotherapy (yes vs no), radiation boost (yes vs no), and value of radiation-induced lymphocyte apoptosis (≤16% vs >16%). Whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44—50 Gy. Letrozole was administered orally once daily at a dose of 2·5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks post-radiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced grade 2 or worse toxic effects of the skin. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00208273.

Findings

All patients were analysed apart from one in the concurrent group who withdrew consent before any treatment. During radiotherapy and within the first 12 weeks after radiotherapy, 31 patients in the concurrent group and 31 in the sequential group had any grade 2 or worse skin-related toxicity. The most common skin-related adverse event was dermatitis: four patients in the concurrent group and six in the sequential group had grade 3 acute skin dermatitis during radiotherapy. At a median follow-up of 26 months (range 3—40), two patients in each group had grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis).

Interpretation

Letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy. Long-term follow-up is needed to investigate cardiac side-effects and cancer-specific outcomes.

Funding

Novartis Oncology France.




Orv Hetil. 2006 Jan 22;147(3):121-5.
[Interactions between radiation and hormonal therapy in breast cancer: simultaneous or sequential treatment]

[Article in Hungarian]
Fodor J.
Országos Onkológiai Intézet, Sugárterápiás Osztály, Budapest.
BACKGROUND: Combining radiation and hormone therapy (administration of selective estrogen receptor modulators) has become common clinical practice in recent years for receptor positive breast cancer. Little is known about a possible interaction of both treatment modalities if they are given simultaneously. Tamoxifen (antiestrogen molecule, triphenylethylene derivative) may theoretically render cancer cells less responsive to radiotherapy arresting hormone-receptor-positive cells in G0/G1 phase and increase the risk of breast and lung fibrosis stimulating the secretion of transforming growth factor beta in human fibroblasts. PURPOSE: This article reviews the published data to assess the impact of sequencing of hormonal and radiation therapy on outcomes in breast cancer. METHODS: Computerised searches for publications debating the sequencing of hormonal therapy relative to radiation therapy were done using MEDLINE data. RESULTS: Results of tamoxifen experiments with cell culture regarding radioprotection of tumour clonogens are conflicting. In contrast to in vitro results, in animal studies no protective effect of tamoxifen was observed. In one in vitro study, letrozole (non-steroid selective aromatase inhibitor) had a radiosensitizing effect on breast-cancer lines. No randomised clinical trials to date have studied sequencing of tamoxifen or other selective estrogen receptor modulators and radiotherapy. Results from retrospective clinical studies which included treatment arms with and without tamoxifen showed reduction in tumour recurrence with tamoxifen. Some of these studies have noted increased risk of lung and breast fibrosis with tamoxifen with radiotherapy. Results of three articles examined the effect of tamoxifen sequence showed no adverse effect on local control or survival in sequential versus concurrent tamoxifen and radiation patients. One of the three studies also assessed the risk of complications with respect to the timing of tamoxifen with radiotherapy. There was no difference in the rates of complications between the two groups. The association of radiation and selective aromatase inhibitors or aromatase inactivators has not been addressed in clinical studies. CONCLUSIONS: Combined application of tamoxifen and radiotherapy improves survival and local control in breast cancer. Available clinical studies do not indicate that the simultaneous application of tamoxifen and radiotherapy is disadvantageous, as was suggested by some of the in vitro studies. The risk of subcutaneous breast and lung fibrosis might be slightly increased if tamoxifen is given simultaneously with radiotherapy. Both treatment modalities should be started early after surgery. There is no sufficient evidence to withhold tamoxifen administration during irradiation of breast cancer. The issue of optimal sequencing of hormonal and radiotherapy should be addressed in randomised clinical trials.

PMID: 16515031 [PubMed - indexed for MEDLINE]




Radiat Oncol. 2009 Jul 11;4:24.
Concurrent chemo-radiotherapy following neoadjuvant chemotherapy in locally advanced breast cancer.

Alvarado-Miranda A, Arrieta O, Gamboa-Vignolle C, Saavedra-Perez D, Morales-Barrera R, Bargallo-Rocha E, Zinser-Sierra J, Perez-Sanchez V, Ramirez-Ugalde T, Lara-Medina F.
Department of Medical Oncology, Instituto Nacional de Cancerologia, Mexico City, Mexico. alberalvarmir@yahoo.com.mx


FREE TEXT

Abstract

BACKGROUND: Despite broad advances in multimodal treatment of locally advanced breast cancer (LABC), 30 to 40% of patients develop loco-regional relapse. The aim of this study was to analyze in a retrospective manner the effectiveness of concurrent chemo-radiotherapy (CCRTh) after neoadjuvant chemotherapy (NCT) in patients with LABC.
METHODS: One hundred twelve patients with LABC (stage IIB-IIIB) were treated with NCT (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (FAC), or doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (AC) IV in four 21-day courses) followed by CCRTh (60 Gy breast irradiation and weekly mitomycin 5 mg/m2, 5-fluorouracil 500 mg/m2, and dexamethasone 16 mg, or cisplatin 30 mg/m2, gemcitabine 100 mg/m2 and dexamethasone 16 mg), and 6-8 weeks later, surgery and two additional courses of FAC, AC, or paclitaxel 90 mg/m2 weekly for 12 weeks, and in case of estrogen-receptor positive patients, hormonal therapy.
RESULTS: Stages IIB, IIIA and -B were 21.4, 42.9, and 35.7%, respectively. Pathological complete response (pCR) in the breast was 42% (95% CI, 33.2-50.5%) and, 29.5% (95% CI, 21.4-37.5%) if including both the breast and the axillary nodes. Multivariate analysis showed that the main determinant of pCR was negative estrogen-receptor status (HR=3.8; 95% CI, 1.5-9; p=0.016). The 5-year disease-free survival (DFS) was 76.9% (95% CI, 68.2-84.7%). No relationship between pCR and DFS was found. Multivariate analysis demonstrated that the main DFS determinant was clinical stage (IIB and IIIA vs. IIIB, HR=3.1; 95% CI, 1.02-9.74; p=0.04). Only one patient had local recurrence. Five-year overall survival was 84.2% (95% CI, 75-93.2%). The toxicity profile was acceptable.
CONCLUSION: This non-conventional multimodal treatment has good loco-regional control for LABC. Randomized clinical trials of preoperative CCRTh following chemotherapy, in patients with LABC are warranted.

PMID: 19591689 [PubMed - indexed for MEDLINE]PMCID: PMC2716349Free PMC Article



J Cancer Res Clin Oncol. 2010 Sep 22. [Epub ahead of print]
Radioembolization and systemic chemotherapy improves response and survival for unresectable colorectal liver metastases.
Chua TC, Bester L, Saxena A, Morris DL.
Hepatobiliary and Surgical Oncology Unit, Department of Surgery, University of New South Wales, St. George Hospital, Sydney, NSW, Australia.



Abstract
PURPOSE: To evaluate the role of radioembolization and systemic chemotherapy as a combined modality therapy for unresectable colorectal liver metastases.
PATIENTS AND METHODS: Prospective database of a major yttrium-90 microsphere radioembolization treatment center in Sydney, Australia, that included 140 patients with unresectable colorectal liver metastases was analyzed. Tumor response, overall survival, treatment-related complications and an evaluation of its role as a combined modality therapy with systemic chemotherapy were performed.
RESULTS: One hundred and thirty-three patients (95%) had a single treatment, and seven patients (5%) had repeated treatments. Response following treatment was complete in two patients (1%), partial in 43 patients (31%), stable in 44 patients (31%), and 51 patients (37%) developed progressive disease. Combining chemotherapy with radioembolization was associated with a favorable treatment response (P = 0.007). The median overall survival was 9 (95% CI 6.4-11.3) months with a 1-, 2-, and 3-year survival rate of 42, 22, and 20%, respectively. Primary tumor site (P = 0.019), presence of extrahepatic disease (P = 0.033), and a favorable treatment response (P < 0.001) were identified as independent predictors for survival.
CONCLUSION: Combined modality therapy appears to improve tumor response rates. Survival is influenced by tumor site, presence of extrahepatic disease, and response to therapy. Yttrium-90 microsphere radioembolization is safe and may best be combined with systemic chemotherapy for patients with unresectable colorectal liver metastases.

PMID: 20859640 [PubMed - as supplied by publisher]










Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):534-42.
Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity.

Sandur SK, Deorukhkar A, Pandey MK, Pabón AM, Shentu S, Guha S, Aggarwal BB, Krishnan S.
Department of Experimental Therapeutics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
PURPOSE: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. METHODS AND MATERIALS: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-kappaB (NF-kappaB) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. RESULTS: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-kappaB activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-kappaB activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of kappaB alpha, inhibition of inhibitor of kappaB kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-kappaB-regulated gene products (Bcl-2, Bcl-x(L), inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). CONCLUSIONS: Our results suggest that transient inducible NF-kappaB activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy.

PMID: 19735878 [PubMed - indexed for MEDLINE]






Breast Cancer Res. 2006;8(4):R52.
In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells.

FULL TEXT


Ural AU, Avcu F, Candir M, Guden M, Ozcan MA.
Department of Hematology, Gulhane Military Medical Faculty, Ankara, Turkey. aural@gata.edu.tr
INTRODUCTION: Bisphosphonates are mostly used in the treatment of bone metastases. They have been shown to act synergistically with other chemotherapeutic agents. It is not known, however, whether similar synergistic effects exist with radiation on breast cancer cells. METHODS: Human MCF-7 breast cancer cells were treated with up to 100 microM zoledronic acid, were irradiated with up to 800 cGy or were exposed to combinations of both treatments to determine the antiproliferative effects of zoledronic acid and radiation. RESULTS: Zoledronic acid and radiation caused a dose-dependent and time-dependent decrease in cell viability (approximate 50% growth inhibition values were 48 microM and 20 microM for 24 hours and 72 hours, respectively, for zoledronic acid and 500 cGy for radiation). A synergistic cytotoxic effect of the combination of zoledronic acid and radiation was confirmed by isobologram analysis. CONCLUSION: These data constitute the first in vitro evidence for synergistic effects between zoledronic acid and radiation. This combination therapy might thus be expected to be more effective than either treatment alone in patients with metastatic breast carcinoma.

PMID: 16925824 [PubMed - indexed for MEDLINE]



Exp Mol Med. 2008 Dec 31;40(6):617-28.
Liposomal honokiol, a potent anti-angiogenesis agent, in combination with radiotherapy produces a synergistic antitumor efficacy without increasing toxicity.

FREE TEXT

Hu J, Chen LJ, Liu L, Chen X, Chen PL, Yang G, Hou WL, Tang MH, Zhang F, Wang XH, Zhao X, Wei YQ.
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. lijuan17@hotmail.com
Honokiol is an active compound purified from magnolia that has been shown to induce cell differentiation, apoptosis, and anti-angiogenesis effects, as well as an enhancement in tumor growth delay in combination with chemotherapeutic agents in several mouse xenograft models. Our goal was to investigate the radiosensitization effect of honokiol on lung carcinoma. The radiosensitization effect of liposomal honokiol in Lewis lung carcinoma cells (LL/2) was analyzed using an in vitro clonogenic survival assay. For an in vivo study, Lewis lung carcinoma-bearing C57BL/6 mice were treated with either liposomal honokiol at 25 mg/kg or 5 Gy of single tumor radiation, or a combination of both over 12 days of treatment. The tumor growth delay and the survival time were evaluated. In addition, histological analysis of tumor sections was performed to examine changes by detecting the microvessel density and apoptosis in tumor tissues. In the clonogenic survival assay, LL/2 cells treated with IC(50) Lipo-HNK for 24 h showed a radiation enhancement ratio of 1.9. After 12 days of combination treatment, the tumor volume decreased 78% and produced an anti-tumor activity 1.3-fold greater than a predicted additive effect of honokiol and radiation alone. This combination treatment also caused an 8.7 day delay in tumor growth. The cell cycle distribution and histological analysis demonstrated that liposomal honokiol has an anti-tumor effect via inducing apoptosis and inhibiting angiogenesis. Liposomal honokiol can enhance tumor cell radiosensitivity in vitro and in vivo, indicating that radiotherapy combined with liposomal honokiol can lead to greater anti-tumor efficacy.

PMID: 19116447 [PubMed - indexed for MEDLINE]




Alternatives to radiation for breast treatment:

http://www.technologyreview.com/biomedicine/19815/

2007

Fifteen of 28 patients received two cycles of chemotherapy, followed a few hours later by thermotherapy, in which a 915-megahertz microwave was focused on the tumor, raising its temperature to 108 ºF. After the combined treatments, 14 of the patients' tumors decreased enough for lumpectomy: the volume of the tumor shrank by about 88 percent, compared with 59 percent in patients who received chemotherapy alone. The trials were conducted at UCLA Medical Center, in Torrance, CA; the University of Oklahoma Health Science Center, in Oklahoma City, OK; the Comprehensive Breast Center, in Coral Springs, FL; and St. Joseph's Hospital, in Orange County, CA.


http://www.newsok.com/breast-cancer-...adlines_widget

Breast cancer treatment shows promise in trials
‘This therapy is a major advancement,’ OU researcher says


BY SUSAN SIMPSON The Oklahoman Comments 3 Published: January 16, 2010




Heating up breast tissue with microwave technology boosts the power of chemotherapy and shrinks cancerous tumors, University of Oklahoma Health Sciences Center researchers say.



The finding means that more women with late-stage breast cancer may avoid losing breasts to mastectomy, said Dr. William Dooley, a researcher at the OU Cancer Institute and director of surgical oncology at OU Medicine.
He said patient trials at OU and across the country are showing promising results from the technique, which was tried on tumors larger than an inch and reduced the need for mastectomies by almost 90 percent. Called focused microwave technology, it uses a modified version of Star Wars defense system technology. More patient trials are planned later this year.
"This therapy is a major advancement for women with later-stage breast cancer,” Dooley said.
"Right now most patients with large tumors lose their breast. With this treatment, along with chemotherapy, we were able to kill the cancer and save the breast tissue.”
Dooley said microwave heat of up to 110 degrees Fahrenheit is targeted at breast tissue.
"For some reason, we are uncertain still, cancer cells are very sensitive to microwave-generated heat,” he said. "We are ramping up the kill within the microwave field.”
Still, some women and some tumors see better results than others. Finding out why will be part of additional patient trials involving thousands of women. The technique also will be tried on larger breast tumors and by using nanotechnology to precisely target cancer cells.
Dooley said that the technology is likely to work with other types of cancer, as well.
Ellen Hopper, a cancer patient from Tuttle, was part of earlier trials testing the technology. She’s now cancer-free.
Hopper, a registered nurse who works at OU Medical Center, said treatments that spare patients’ breasts are welcomed.
"I think it’s very important for your image, for how you feel about your body,” she said.

Read more: http://www.newsok.com/breast-cancer-...#ixzz0cvpRfcKs





Mol Cancer Ther. 2009 Mar;8(3):533-42. Epub 2009 Mar 3.
Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression.

Konduri S, Colon J, Baker CH, Safe S, Abbruzzese JL, Abudayyeh A, Basha MR, Abdelrahim M.
Cancer Research Institute, M. D. Anderson Cancer Center Orlando, 110 Bonnie Loch Court, Mail Point 47, Orlando, FL 32806, USA.
Survivin is overexpressed in most human cancers, including pancreatic adenocarcinoma. Expression of survivin is regulated by specificity protein (Sp) proteins and related to resistance to radiation therapy. Tolfenamic acid induces Sp protein degradation in several cancer cell lines. The purpose of this study is to investigate whether tolfenamic acid inhibits survivin expression and sensitizes pancreatic cancer cells/tumor to radiotherapy. Panc1 and L3.6pl cells have been used to study the effect of radiation on survivin expression and to investigate the efficacy of tolfenamic acid in enhancing the response to radiation therapy. In addition, an orthotopic model for human pancreatic cancer has been used to confirm the efficacy of tolfenamic acid to enhance tumor response to radiation in vivo. Pancreatic cancer cell lines express variable levels of survivin mRNA/protein, which correlate with their radiosensitivity. Radiation increased survivin promoter activity and protein expression in Panc1 and L3.6pl cells and tolfenamic acid inhibited both constitutive and radiation-induced survivin protein expression and enhanced the response of pancreatic cancer cells to radiation therapy. In vivo studies show that tolfenamic acid enhanced the radiation-induced apoptosis associated with decreased survivin expression in tumors and this correlates with the enhanced response of these tumors to the radiation. Thus, tolfenamic acid significantly enhances pancreatic cancer cells/tumor response to radiation therapy. The underlying mechanism includes tolfenamic acid-induced degradation of Sp proteins, which in tumor decreases expression of the Sp-dependent antiapoptotic protein survivin. These preclinical data suggest that tolfenamic acid has the potential to increase the response of pancreatic adenocarcinoma to radiation therapy.

PMID: 19258429 [PubMed - indexed for MEDLINE]


Radiat Oncol. 2010 Feb 3;5:8.
Loratadine dysregulates cell cycle progression and enhances the effect of radiation in human tumor cell lines.

Soule BP, Simone NL, DeGraff WG, Choudhuri R, Cook JA, Mitchell JB.
Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. souleb@mail.nih.gov
BACKGROUND: The histamine receptor-1 (H1)-antagonist, loratadine has been shown to inhibit growth of human colon cancer xenografts in part due to cell cycle arrest in G2/M. Since this is a radiation sensitive phase of the cell cycle, we sought to determine if loratadine modifies radiosensitivity in several human tumor cell lines with emphasis on human colon carcinoma (HT29). METHODS: Cells were treated with several doses of loratadine at several time points before and after exposure to radiation. Radiation dose modifying factors (DMF) were determined using full radiation dose response survival curves. Cell cycle phase was determined by flow cytometry and the expression of the cell cycle-associated proteins Chk1, pChk1(ser345), and Cyclin B was analyzed by western blot. RESULTS: Loratadine pre-treatment of exponentially growing cells (75 microM, 24 hours) increased radiation-induced cytotoxicity yielding a radiation DMF of 1.95. However, treatment of plateau phase cells also yielded a DMF of 1.3 suggesting that mechanisms other than cell cycle arrest also contribute to loratadine-mediated radiation modification. Like irradiation, loratadine initially induced G2/M arrest and activation of the cell-cycle associated protein Chk1 to pChk1(ser345), however a subsequent decrease in expression of total Chk1 and Cyclin B correlated with abrogation of the G2/M checkpoint. Analysis of DNA repair enzyme expression and DNA fragmentation revealed a distinct pattern of DNA damage in loratadine-treated cells in addition to enhanced radiation-induced damage. Taken together, these data suggest that the observed effects of loratadine are multifactorial in that loratadine 1) directly damages DNA, 2) activates Chk1 thereby promoting G2/M arrest making cells more susceptible to radiation-induced DNA damage and, 3) downregulates total Chk1 and Cyclin B abrogating the radiation-induced G2/M checkpoint and allowing cells to re-enter the cell cycle despite the persistence of damaged DNA. CONCLUSIONS: Given this unique possible mechanism of action, loratadine has potential as a chemotherapeutic agent and as a modifier of radiation responsiveness in the treatment of cancer and, as such, may warrant further clinical evaluation.

PMID: 20128919 [PubMed - in process]





J Cancer Res Ther. 2009 Sep;5 Suppl 1:S57-60.
Modulation of cellular radiation responses by 2-deoxy-D-glucose and other glycolytic inhibitors: implications for cancer therapy.

Kalia VK, Prabhakara S, Narayanan V.
Department of Biophysics, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
BACKGROUND: 2-Deoxy-D-glucose (2-DG), a glycolytic inhibitor, was observed earlier to increase DNA, chromosomal, and cellular damage in tumor cells, by inhibiting energy-dependent repair processes. Lonidamine (LND) selectively inhibits glycolysis in cancer cells. It damages the condensed mitochondria in these cells, impairing thereby the activity of hexokinase (predominantly attached to the outer mitochondrial membranes). It inhibits repair of radiation-induced potentially lethal cellular damage in HeLa and Chinese hamster (HA-1) cells. However, other than a preliminary study on human glioma (BMG-1) cells in this laboratory, the effects of LND on radiation-induced cytogenetic damage have not been reported earlier. AIMS: These studies were carried out to investigate the effects of LND and 2-DG on cell proliferation, viability, and radiation response in the same human glioma cell line, under identical conditions. The respective drug concentrations were selected on the basis of earlier studies. MATERIALS AND METHODS: Human glioma (U373MG) cells were grown in the presence of LND or 2-DG for 2 days. Proliferation response and viability of U373MG human glioma cells were studied by cell counts and uptake of trypan blue dye. Radiosensitization (increase in micronuclei formation) was studied after short-term (4 h postirradiation) drug treatments. OBSERVATIONS: Both the drugs (1) inhibited proliferation response in a concentration-dependent manner; (2) did not induce micronuclei formation in the unirradiated cells; and (3) significantly increased radiation-induced micronuclei formation at nontoxic concentrations. CONCLUSIONS: These data suggest that the short-term presence of either lonidamine or 2-DG-at clinically relevant and nontoxic concentrations-could increase the treatment response of malignant gliomas at optimum radiation doses, reducing thereby the side effects of radiotherapy.

PMID: 20009297 [PubMed - in process]



Br J Cancer. 2011 Jul 26. doi: 10.1038/bjc.2011.260. [Epub ahead of print]
Radiation-enhancement of MDA-MB-231 breast cancer cell invasion prevented by a cyclooxygenase-2 inhibitor.

Paquette B, Therriault H, Desmarais G, Wagner R, Royer R, Bujold R.

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1] Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke [2] Center for Research in Radiotherapy, 3001, 12e Avenue Nord, Sherbrooke, Quebec, Canada J1H 5N4.

Abstract

Background:Recent evidences support that radiation can promote the invasion of cancer cells. As interactions between cancer cells and surrounding stromal cells can have an important role in tumour progression, we determined whether an irradiation to fibroblasts can enhance the invasiveness of breast cancer cells. The role of cyclooxygenase-2 (COX-2), an inflammatory enzyme frequently induced by radiotherapy, was investigated.Methods:Irradiated 3T3 fibroblasts were plated in the lower compartment of invasion chambers and used as chemoattractant for non-irradiated human breast cancer cell MDA-MB-231, which are oestrogen receptor negative (ER(-)) and the oestrogen receptor positive (ER(+)) MCF-7 cells. Stimulation of COX-2 expression in irradiated 3T3 cells was measured by a semi-quantitative qPCR and western blot. Capacity of the major product of COX-2, the prostaglandin E2 (PGE(2)), to stimulate the production of the matrix metalloproteinase-2 (MMP-2) and cancer cell invasion were assessed with a zymography gel and invasion chambers.Results:Irradiation (5 Gy) of 3T3 fibroblasts increased COX-2 expression and enhanced by 5.8-fold the invasiveness of non-irradiated MDA-MB-231 cells, while their migration was not modified. Addition of the COX-2 inhibitor NS-398 completely prevented radiation-enhancement of cancer cell invasion. Further supporting the potential role of COX-2, addition of PGE(2) has increased cancer cell invasion and release of MMP-2 from the MDA-MB-231 cells. This effect of radiation was dependant on the expression of membrane type 1 (MT1)-MMP, which is required to activate the MMP-2, but was not associated with the ER status. Although irradiated fibroblasts stimulated the invasiveness of MDA-MB-231 ER(-) cells, no enhancement was measured with the ER(+) cell line MCF-7.Conclusions:Radiation-enhancement of breast cancer cell invasion induced by irradiated 3T3 fibroblasts is not dependant on the ER status, but rather the expression of MT1-MMP. This adverse effect of radiation can be prevented by a specific COX-2 inhibitor.British Journal of Cancer advance online publication, 26 July 2011; doi:10.1038/bjc.2011.260 www.bjcancer.com.

PMID:
21792195
[PubMed - as supplied by publisher]
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Old 07-23-2010, 10:12 PM   #2
Rich66
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Re: Radiation

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Old 07-24-2010, 08:25 AM   #3
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Re: Radiation

Thannk you, Rich, for bumping this up. These studies are of interest to me not only because of the BC that I am fighting, but my first husband of 35 years died from a glioblastoma. Maybe one day there will be a cure for both........
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Diagnosed: 7/25/08 ~ age 63, no family history
Surgery: 8/14/08 Bilateral mastectomy; tumor left breast, node dissection; right prophylactic with expanders: 1/12/10 latisimuss dorsi flap on left side: 9/22/10 implants in
Pathology Report: ER/PR-; HER2+ (3+); Grade 3, StageIII; 3cm tumor plus 21/21 lymph nodes positive; 5cm DCIS
Chemo: A/C; Taxol/Herceptin/Tykerb; phase II study at Mayo adding Tykerb for early stage
Radiation: 25 rads
Vaccine: Walter Reed GP2/AE37 vaccine study ~ last booster 9/17/2012
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